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1
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Lu KC, Tsai KW, Wang YK, Hu WC. Types of cell death and their relations to host immunological pathways. Aging (Albany NY) 2024; 16:11755-11768. [PMID: 39120579 PMCID: PMC11346778 DOI: 10.18632/aging.206035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 07/17/2024] [Indexed: 08/10/2024]
Abstract
Various immune pathways have been identified in the host, including TH1, TH2, TH3, TH9, TH17, TH22, TH1-like, and THαβ immune reactions. While TH2 and TH9 responses primarily target multicellular parasites, host immune pathways directed against viruses, intracellular microorganisms (such as bacteria, protozoa, and fungi), and extracellular microorganisms can employ programmed cell death mechanisms to initiate immune responses or execute effective strategies for pathogen elimination. The types of programmed cell death involved include apoptosis, autophagy, pyroptosis, ferroptosis, necroptosis, and NETosis. Specifically, apoptosis is associated with host anti-virus eradicable THαβ immunity, autophagy with host anti-virus tolerable TH3 immunity, pyroptosis with host anti-intracellular microorganism eradicable TH1 immunity, ferroptosis with host anti-intracellular microorganism tolerable TH1-like immunity, necroptosis with host anti-extracellular microorganism eradicable TH22 immunity, and NETosis with host anti-extracellular microorganism tolerable TH17 immunity.
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Affiliation(s)
- Kuo-Cheng Lu
- Department of Medicine, Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan, ROC
- Department of Medicine, Division of Nephrology, Fu Jen Catholic University Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, ROC
| | - Kuo-Wang Tsai
- Department of Medical Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan, ROC
| | - Yu-Kuen Wang
- Department of Obstetrics and Gynecology, Taoyuan Armed Forced General Hospital, Taiwan, ROC
- Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Wan-Chung Hu
- Department of Medical Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan, ROC
- Department of Clinical pathology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan, ROC
- Department of Biotechnology, Ming Chuan University, Taoyuan City 333, Taiwan, ROC
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2
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Sinha S, Hassan N, Schwartz RE. Organelle stress and alterations in interorganelle crosstalk during liver fibrosis. Hepatology 2024; 79:482-501. [PMID: 36626634 DOI: 10.1097/hep.0000000000000012] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 10/03/2022] [Indexed: 01/12/2023]
Abstract
The synchronous functioning and quality control of organelles ensure cell survival and function and are essential for maintaining homeostasis. Prolonged exposure to stressors (viruses, bacteria, parasitic infections, alcohol, drugs) or genetic mutations often disrupt the functional integrity of organelles which plays a critical role in the initiation and progression of several diseases including chronic liver diseases. One of the most important pathologic consequences of chronic liver diseases is liver fibrosis, characterized by tissue scarring due to the progressive accumulation of extracellular matrix components. Left untreated, fibrosis may advance to life-threatening complications such as cirrhosis, hepatic decompensation, and HCC, which collectively accounts for ∼1 million deaths per year worldwide. Owing to the lack of treatment options that can regress or reverse cirrhosis, liver transplantation is currently the only available treatment for end-stage liver disease. However, the limited supply of usable donor organs, adverse effects of lifelong immunosuppressive regimes, and financial considerations pose major challenges and limit its application. Hence, effective therapeutic strategies are urgently needed. An improved understanding of the organelle-level regulation of fibrosis can help devise effective antifibrotic therapies focused on reducing organelle stress, limiting organelle damage, improving interorganelle crosstalk, and restoring organelle homeostasis; and could be a potential clinical option to avoid transplantation. This review provides a timely update on the recent findings and mechanisms covering organelle-specific dysfunctions in liver fibrosis, highlights how correction of organelle functions opens new treatment avenues and discusses the potential challenges to clinical application.
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Affiliation(s)
- Saloni Sinha
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA
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3
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Robea MA, Balmus IM, Girleanu I, Huiban L, Muzica C, Ciobica A, Stanciu C, Cimpoesu CD, Trifan A. Coagulation Dysfunctions in Non-Alcoholic Fatty Liver Disease-Oxidative Stress and Inflammation Relevance. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1614. [PMID: 37763733 PMCID: PMC10535217 DOI: 10.3390/medicina59091614] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/29/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. Its incidence is progressively rising and it is possibly becoming a worldwide epidemic. NAFLD encompasses a spectrum of diseases accounting for the chronic accumulation of fat within the hepatocytes due to various causes, excluding excessive alcohol consumption. In this study, we aimed to focus on finding evidence regarding the implications of oxidative stress and inflammatory processes that form the multifaceted pathophysiological tableau in relation to thrombotic events that co-occur in NAFLD and associated chronic liver diseases. Recent evidence on the pathophysiology of NAFLD suggests that a complex pattern of multidirectional components, such as prooxidative, proinflammatory, and prothrombotic components, better explains the multiple factors that promote the mechanisms underlying the fatty acid excess and subsequent processes. As there is extensive evidence on the multi-component nature of NAFLD pathophysiology, further studies could address the complex interactions that underlie the development and progression of the disease. Therefore, this study aimed to describe possible pathophysiological mechanisms connecting the molecular impairments with the various clinical manifestations, focusing especially on the interactions among oxidative stress, inflammation, and coagulation dysfunctions. Thus, we described the possible bidirectional modulation among coagulation homeostasis, oxidative stress, and inflammation that occurs in the various stages of NAFLD.
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Affiliation(s)
- Madalina Andreea Robea
- CENEMED Platform for Interdisciplinary Research, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.A.R.); (I.-M.B.); (C.D.C.)
| | - Ioana-Miruna Balmus
- CENEMED Platform for Interdisciplinary Research, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.A.R.); (I.-M.B.); (C.D.C.)
- Department of Exact Sciences and Natural Sciences, Institute of Interdisciplinary Research, “Alexandru Ioan Cuza” University of Iasi, Alexandru Lapusneanu Street, No. 26, 700057 Iasi, Romania
| | - Irina Girleanu
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.G.); (L.H.); (C.M.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Laura Huiban
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.G.); (L.H.); (C.M.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Cristina Muzica
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.G.); (L.H.); (C.M.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Alin Ciobica
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue, No. 20A, 700505 Iasi, Romania
- Centre of Biomedical Research, Romanian Academy, Carol I Avenue, No. 8, 700506 Iasi, Romania;
- Academy of Romanian Scientists, Splaiul Independentei nr. 54, Sector 5, 050094 Bucuresti, Romania
| | - Carol Stanciu
- Centre of Biomedical Research, Romanian Academy, Carol I Avenue, No. 8, 700506 Iasi, Romania;
| | - Carmen Diana Cimpoesu
- CENEMED Platform for Interdisciplinary Research, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.A.R.); (I.-M.B.); (C.D.C.)
- Department of Emergency Medicine, Emergency County Hospital “Sf. Spiridon”, 700111 Iasi, Romania
- Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa” Iasi, Blvd. Independentei 1, 700111 Iasi, Romania
| | - Anca Trifan
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.G.); (L.H.); (C.M.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
- Centre of Biomedical Research, Romanian Academy, Carol I Avenue, No. 8, 700506 Iasi, Romania;
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Wu Y, Tan HWS, Lin JY, Shen HM, Wang H, Lu G. Molecular mechanisms of autophagy and implications in liver diseases. LIVER RESEARCH 2023; 7:56-70. [PMID: 39959698 PMCID: PMC11792062 DOI: 10.1016/j.livres.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/03/2022] [Accepted: 02/15/2023] [Indexed: 02/22/2023]
Abstract
Autophagy is a highly conserved process in which cytosolic contents are degraded by the lysosome, which plays an important role in energy and nutrient balance, and protein or organelle quality control. The liver is the most important organ for metabolism. Studies to date have revealed a significant role of autophagy in the maintenance of liver homeostasis under basal and stressed conditions, and the impairment of autophagy has been closely linked to various liver diseases. Therefore, a comprehensive understanding of the roles of autophagy in liver diseases may help in the development of therapeutic strategies via targeting autophagy. In this review, we will summarize the latest understanding of the molecular mechanisms of autophagy and systematically discuss its implications in various liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, viral hepatitis, hepatocellular carcinoma, and acetaminophen-induced liver injury.
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Affiliation(s)
- Yuankai Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hayden Weng Siong Tan
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jin-Yi Lin
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Han-Ming Shen
- Department of Biomedical Sciences, Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China
| | - Haihe Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Guang Lu
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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Gee YJ, Sea YL, Lal SK. Viral modulation of lipid rafts and their potential as putative antiviral targets. Rev Med Virol 2023; 33:e2413. [PMID: 36504273 DOI: 10.1002/rmv.2413] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 11/12/2022] [Accepted: 11/20/2022] [Indexed: 12/14/2022]
Abstract
Lipid rafts are ubiquitous in cells. They are identified as cholesterol and glycosphingolipid enriched microdomains on cellular membranes. They serve as platforms for cellular communications by functioning in signal transduction and membrane trafficking. Such structural organisation fulfils cellular needs for normal function, but at the same time increases vulnerability of cells to pathogen invasion. Viruses rely heavily on lipid rafts in basically every stage of the viral life cycle for successful infection. Various mechanisms of lipid rafts modification exploited by diverse viruses for attachment, internalisation, membrane fusion, genome replication, assembly and release have been brought to light. This review focuses on virus-raft interactions and how a wide range of viruses manipulate lipid rafts at distinct stages of infection. The importance of virus-raft interactions in viral infections has inspired researchers to discover and develop antivirals that target this interaction, such as statins, methyl-β-cyclodextrin, viperin, 25-hydroxycholesterol and even anti-malarial drugs. The therapeutic modulations of lipid rafts as potential antiviral intervention from in vitro and in vivo evidence are discussed herein.
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Affiliation(s)
- Yee Jing Gee
- School of Science, Monash University, Bandar Sunway, Selangor DE, Malaysia
| | - Yi Lin Sea
- School of Science, Monash University, Bandar Sunway, Selangor DE, Malaysia
| | - Sunil Kumar Lal
- School of Science, Monash University, Bandar Sunway, Selangor DE, Malaysia.,Tropical Medicine & Biology Platform, Monash University, Bandar Sunway, Selangor DE, Malaysia
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Khreefa Z, Barbier MT, Koksal AR, Love G, Del Valle L. Pathogenesis and Mechanisms of SARS-CoV-2 Infection in the Intestine, Liver, and Pancreas. Cells 2023; 12:cells12020262. [PMID: 36672197 PMCID: PMC9856332 DOI: 10.3390/cells12020262] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/30/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
The novel coronavirus, SARS-CoV-2, rapidly spread worldwide, causing an ongoing global pandemic. While the respiratory system is the most common site of infection, a significant number of reported cases indicate gastrointestinal (GI) involvement. GI symptoms include anorexia, abdominal pain, nausea, vomiting, and diarrhea. Although the mechanisms of GI pathogenesis are still being examined, viral components isolated from stool samples of infected patients suggest a potential fecal-oral transmission route. In addition, viral RNA has been detected in blood samples of infected patients, making hematologic dissemination of the virus a proposed route for GI involvement. Angiotensin-converting enzyme 2 (ACE2) receptors serve as the cellular entry mechanism for the virus, and these receptors are particularly abundant throughout the GI tract, making the intestine, liver, and pancreas potential extrapulmonary sites for infection and reservoirs sites for developing mutations and new variants that contribute to the uncontrolled spread of the disease and resistance to treatments. This transmission mechanism and the dysregulation of the immune system play a significant role in the profound inflammatory and coagulative cascades that contribute to the increased severity and risk of death in several COVID-19 patients. This article reviews various potential mechanisms of gastrointestinal, liver, and pancreatic injury.
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Affiliation(s)
- Zaid Khreefa
- Department of Pathology, School of Medicine, Louisiana State University Health School of Medicine, New Orleans, LA 70112, USA
| | - Mallory T. Barbier
- Louisiana Cancer Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Ali Riza Koksal
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Gordon Love
- Department of Pathology, School of Medicine, Louisiana State University Health School of Medicine, New Orleans, LA 70112, USA
| | - Luis Del Valle
- Department of Pathology, School of Medicine, Louisiana State University Health School of Medicine, New Orleans, LA 70112, USA
- Louisiana Cancer Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
- Correspondence:
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Gutiérrez-Cuevas J, Lucano-Landeros S, López-Cifuentes D, Santos A, Armendariz-Borunda J. Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies. Cancers (Basel) 2022; 15:23. [PMID: 36612019 PMCID: PMC9818030 DOI: 10.3390/cancers15010023] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed.
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Affiliation(s)
- Jorge Gutiérrez-Cuevas
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Silvia Lucano-Landeros
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Daniel López-Cifuentes
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Arturo Santos
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
| | - Juan Armendariz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
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Potential Therapeutic Implication of Herbal Medicine in Mitochondria-Mediated Oxidative Stress-Related Liver Diseases. Antioxidants (Basel) 2022; 11:antiox11102041. [PMID: 36290765 PMCID: PMC9598588 DOI: 10.3390/antiox11102041] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/10/2022] [Accepted: 10/10/2022] [Indexed: 11/22/2022] Open
Abstract
Mitochondria are double-membrane organelles that play a role in ATP synthesis, calcium homeostasis, oxidation-reduction status, apoptosis, and inflammation. Several human disorders have been linked to mitochondrial dysfunction. It has been found that traditional therapeutic herbs are effective on alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) which are leading causes of liver cirrhosis and hepatocellular carcinoma. The generation of reactive oxygen species (ROS) in response to oxidative stress is caused by mitochondrial dysfunction and is considered critical for treatment. The role of oxidative stress, lipid toxicity, and inflammation in NAFLD are well known. NAFLD is a chronic liver disease that commonly progresses to cirrhosis and chronic liver disease, and people with obesity, insulin resistance, diabetes, hyperlipidemia, and hypertension are at a higher risk of developing NAFLD. NAFLD is associated with a number of pathological factors, including insulin resistance, lipid metabolic dysfunction, oxidative stress, inflammation, apoptosis, and fibrosis. As a result, the improvement in steatosis and inflammation is enough to entice researchers to look into liver disease treatment. However, antioxidant treatment has not been very effective for liver disease. Additionally, it has been suggested that the beneficial effects of herbal medicines on immunity and inflammation are governed by various mechanisms for lipid metabolism and inflammation control. This review provided a summary of research on herbal medicines for the therapeutic implementation of mitochondria-mediated ROS production in liver disease as well as clinical applications through herbal medicine. In addition, the pathophysiology of common liver disorders such as ALD and NAFLD would be investigated in the role that mitochondria play in the process to open new therapeutic avenues in the management of patients with liver disease.
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Pant A, Yao X, Lavedrine A, Viret C, Dockterman J, Chauhan S, Chong-Shan Shi, Manjithaya R, Cadwell K, Kufer TA, Kehrl JH, Coers J, Sibley LD, Faure M, Taylor GA, Chauhan S. Interactions of Autophagy and the Immune System in Health and Diseases. AUTOPHAGY REPORTS 2022; 1:438-515. [PMID: 37425656 PMCID: PMC10327624 DOI: 10.1080/27694127.2022.2119743] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
Autophagy is a highly conserved process that utilizes lysosomes to selectively degrade a variety of intracellular cargo, thus providing quality control over cellular components and maintaining cellular regulatory functions. Autophagy is triggered by multiple stimuli ranging from nutrient starvation to microbial infection. Autophagy extensively shapes and modulates the inflammatory response, the concerted action of immune cells, and secreted mediators aimed to eradicate a microbial infection or to heal sterile tissue damage. Here, we first review how autophagy affects innate immune signaling, cell-autonomous immune defense, and adaptive immunity. Then, we discuss the role of non-canonical autophagy in microbial infections and inflammation. Finally, we review how crosstalk between autophagy and inflammation influences infectious, metabolic, and autoimmune disorders.
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Affiliation(s)
- Aarti Pant
- Autophagy Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
| | - Xiaomin Yao
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, New York, United States of America
- Department of Microbiology, New York University Grossman School of Medicine, New York, New York, United States of America
| | - Aude Lavedrine
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
- Equipe Labellisée par la Fondation pour la Recherche Médicale, FRM
| | - Christophe Viret
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
- Equipe Labellisée par la Fondation pour la Recherche Médicale, FRM
| | - Jake Dockterman
- Department of Immunology, Duke University, Medical Center, Durham, North Carolina, USA
| | - Swati Chauhan
- Cell biology and Infectious diseases, Institute of Life Sciences, Bhubaneswar, India
| | - Chong-Shan Shi
- Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Ravi Manjithaya
- Autophagy Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
| | - Ken Cadwell
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, New York, United States of America
- Department of Microbiology, New York University Grossman School of Medicine, New York, New York, United States of America
- Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States of America
| | - Thomas A. Kufer
- Department of Immunology, Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | - John H. Kehrl
- Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Jörn Coers
- Department of Immunology, Duke University, Medical Center, Durham, North Carolina, USA
- Department of Molecular Genetics and Microbiology, Duke University, Medical Center, Durham, North Carolina, USA
| | - L. David Sibley
- Department of Molecular Microbiology, Washington University Sch. Med., St Louis, MO, 63110, USA
| | - Mathias Faure
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
- Equipe Labellisée par la Fondation pour la Recherche Médicale, FRM
| | - Gregory A Taylor
- Department of Immunology, Duke University, Medical Center, Durham, North Carolina, USA
- Department of Molecular Genetics and Microbiology, Duke University, Medical Center, Durham, North Carolina, USA
- Department of Molecular Microbiology, Washington University Sch. Med., St Louis, MO, 63110, USA
- Geriatric Research, Education, and Clinical Center, VA Health Care Center, Durham, North Carolina, USA
- Departments of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development, Duke University, Medical Center, Durham, North Carolina, USA
| | - Santosh Chauhan
- Cell biology and Infectious diseases, Institute of Life Sciences, Bhubaneswar, India
- CSIR–Centre For Cellular And Molecular Biology (CCMB), Hyderabad, Telangana
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Longo M, Paolini E, Meroni M, Dongiovanni P. Remodeling of Mitochondrial Plasticity: The Key Switch from NAFLD/NASH to HCC. Int J Mol Sci 2021; 22:4173. [PMID: 33920670 PMCID: PMC8073183 DOI: 10.3390/ijms22084173] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third-leading cause of cancer-related mortality. Currently, the global burden of nonalcoholic fatty liver disease (NAFLD) has dramatically overcome both viral and alcohol hepatitis, thus becoming the main cause of HCC incidence. NAFLD pathogenesis is severely influenced by lifestyle and genetic predisposition. Mitochondria are highly dynamic organelles that may adapt in response to environment, genetics and epigenetics in the liver ("mitochondrial plasticity"). Mounting evidence highlights that mitochondrial dysfunction due to loss of mitochondrial flexibility may arise before overt NAFLD, and from the early stages of liver injury. Mitochondrial failure promotes not only hepatocellular damage, but also release signals (mito-DAMPs), which trigger inflammation and fibrosis, generating an adverse microenvironment in which several hepatocytes select anti-apoptotic programs and mutations that may allow survival and proliferation. Furthermore, one of the key events in malignant hepatocytes is represented by the remodeling of glucidic-lipidic metabolism combined with the reprogramming of mitochondrial functions, optimized to deal with energy demand. In sum, this review will discuss how mitochondrial defects may be translated into causative explanations of NAFLD-driven HCC, emphasizing future directions for research and for the development of potential preventive or curative strategies.
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Affiliation(s)
- Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via Francesco Sforza 35, 20122 Milano, Italy
| | - Erika Paolini
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.L.); (E.P.); (M.M.)
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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12
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Autophagy and Immune-Related Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020. [PMID: 32671762 DOI: 10.1007/978-981-15-4272-5_27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register]
Abstract
As a result of its multifunction both in innate and adaptive immune systems, autophagy has been demonstrated to take part in the pathogenesis of several immune-related diseases. The study on the pathological mechanism of autophagy in these diseases may provide an experimental and theoretical basis for targeted intervention of autophagy in the prevention and treatment of immune diseases. To date, it has been reported that autophagy can eliminate impaired mitochondrial to inhibit the activation of NLRP3 inflammasome which promotes the progression of atherosclerosis. Moreover, enhanced autophagy can effectively prevent the occurrence of GVHD. It also plays a key role in the development of viral hepatitis. Therefore, autophagy might be a promising regulatory target for the treatment of immune-related diseases.
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13
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Dash S, Aydin Y, Wu T. Integrated stress response in hepatitis C promotes Nrf2-related chaperone-mediated autophagy: A novel mechanism for host-microbe survival and HCC development in liver cirrhosis. Semin Cell Dev Biol 2020; 101:20-35. [PMID: 31386899 PMCID: PMC7007355 DOI: 10.1016/j.semcdb.2019.07.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/26/2019] [Accepted: 07/30/2019] [Indexed: 02/06/2023]
Abstract
The molecular mechanism(s) how liver damage during the chronic hepatitis C virus (HCV) infection evolve into cirrhosis and hepatocellular carcinoma (HCC) is unclear. HCV infects hepatocyte, the major cell types in the liver. During infection, large amounts of viral proteins and RNA replication intermediates accumulate in the endoplasmic reticulum (ER) of the infected hepatocyte, which creates a substantial amount of stress response. Infected hepatocyte activates a different type of stress adaptive mechanisms such as unfolded protein response (UPR), antioxidant response (AR), and the integrated stress response (ISR) to promote virus-host cell survival. The hepatic stress is also amplified by another layer of innate and inflammatory response associated with cellular sensing of virus infection through the production of interferon (IFN) and inflammatory cytokines. The interplay between various types of cellular stress signal leads to different forms of cell death such as apoptosis, necrosis, and autophagy depending on the intensity of the stress and nature of the adaptive cellular response. How do the adaptive cellular responses decode such death programs that promote host-microbe survival leading to the establishment of chronic liver disease? In this review, we discuss how the adaptive cellular response through the Nrf2 pathway that promotes virus and cell survival. Furthermore, we provide a glimpse of novel stress-induced Nrf2 mediated compensatory autophagy mechanisms in virus-cell survival that degrade tumor suppressor gene and activation of oncogenic signaling during HCV infection. Based on these facts, we hypothesize that the balance between hepatic stress, inflammation and different types of cell death determines liver disease progression outcomes. We propose that a more nuanced understanding of virus-host interactions under excessive cellular stress may provide an answer to the fundamental questions why some individuals with chronic HCV infection remain at risk of developing cirrhosis, cancer and some do not.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA.
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA
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14
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Ríos-Ocampo WA, Navas MC, Buist-Homan M, Faber KN, Daemen T, Moshage H. Hepatitis C Virus Proteins Core and NS5A Are Highly Sensitive to Oxidative Stress-Induced Degradation after eIF2α/ATF4 Pathway Activation. Viruses 2020; 12:v12040425. [PMID: 32283772 PMCID: PMC7232227 DOI: 10.3390/v12040425] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 04/07/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infection is accompanied by increased oxidative stress and endoplasmic reticulum stress as a consequence of viral replication, production of viral proteins, and pro-inflammatory signals. To overcome the cellular stress, hepatocytes have developed several adaptive mechanisms like anti-oxidant response, activation of Unfolded Protein Response and autophagy to achieve cell survival. These adaptive mechanisms could both improve or inhibit viral replication, however, little is known in this regard. In this study, we investigate the mechanisms by which hepatocyte-like (Huh7) cells adapt to cellular stress in the context of HCV protein overexpression and oxidative stress. Huh7 cells stably expressing individual HCV (Core, NS3/4A and NS5A) proteins were treated with the superoxide anion donor menadione to induce oxidative stress. Production of reactive oxygen species and activation of caspase 3 were quantified. The activation of the eIF2α/ATF4 pathway and changes in the steady state levels of the autophagy-related proteins LC3 and p62 were determined either by quantitative polymerase chain reaction (qPCR) or Western blotting. Huh7 cells expressing Core or NS5A demonstrated reduced oxidative stress and apoptosis. In addition, phosphorylation of eIF2α and increased ATF4 and CHOP expression was observed with subsequent HCV Core and NS5A protein degradation. In line with these results, in liver biopsies from patients with hepatitis C, the expression of ATF4 and CHOP was confirmed. HCV Core and NS5A protein degradation was reversed by antioxidant treatment or silencing of the autophagy adaptor protein p62. We demonstrated that hepatocyte-like cells expressing HCV proteins and additionally exposed to oxidative stress adapt to cellular stress through eIF2a/ATF4 activation and selective degradation of HCV pro-oxidant proteins Core and NS5A. This selective degradation is dependent on p62 and results in increased resistance to apoptotic cell death induced by oxidative stress. This mechanism may provide a new key for the study of HCV pathology and lead to novel clinically applicable therapeutic interventions.
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Affiliation(s)
- W. Alfredo Ríos-Ocampo
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (M.B.-H.); (K.N.F.); (H.M.)
- Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
- Gastrohepatology Group, Medicine School, University of Antioquia, Medellin 050010, Colombia;
- Correspondence: ; Tel.: +31-50-361-2364 or +31-638-955-716
| | - María-Cristina Navas
- Gastrohepatology Group, Medicine School, University of Antioquia, Medellin 050010, Colombia;
| | - Manon Buist-Homan
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (M.B.-H.); (K.N.F.); (H.M.)
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (M.B.-H.); (K.N.F.); (H.M.)
| | - Toos Daemen
- Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (M.B.-H.); (K.N.F.); (H.M.)
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15
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Complex Cell Type-Specific Roles of Autophagy in Liver Fibrosis and Cirrhosis. Pathogens 2020; 9:pathogens9030225. [PMID: 32197543 PMCID: PMC7157207 DOI: 10.3390/pathogens9030225] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/14/2020] [Accepted: 03/17/2020] [Indexed: 02/06/2023] Open
Abstract
The lysosomal degradation pathway, or autophagy, plays a fundamental role in cellular, tissue, and organismal homeostasis. A correlation between dysregulated autophagy and liver fibrosis (including end-stage disease, cirrhosis) is well-established. However, both the up and downregulation of autophagy have been implicated in fibrogenesis. For example, the inhibition of autophagy in hepatocytes and macrophages can enhance liver fibrosis, whereas autophagic activity in hepatic stellate cells and reactive ductular cells is permissive towards fibrogenesis. In this review, the contributions of specific cell types to liver fibrosis as well as the mechanisms underlying the effects of autophagy are summarized. In view of the functional effects of multiple cell types on the complex process of hepatic fibrogenesis, integrated approaches that consider the role of autophagy in each liver cell type should be a focus of future research.
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16
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Vescovo T, Pagni B, Piacentini M, Fimia GM, Antonioli M. Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development. Front Cell Dev Biol 2020; 8:47. [PMID: 32181249 PMCID: PMC7059124 DOI: 10.3389/fcell.2020.00047] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 01/20/2020] [Indexed: 12/14/2022] Open
Abstract
About 20% of total cancer cases are associated to infections. To date, seven human viruses have been directly linked to cancer development: high-risk human papillomaviruses (hrHPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and human T-lymphotropic virus 1 (HTLV-1). These viruses impact on several molecular mechanisms in the host cells, often resulting in chronic inflammation, uncontrolled proliferation, and cell death inhibition, and mechanisms, which favor viral life cycle but may indirectly promote tumorigenesis. Recently, the ability of oncogenic viruses to alter autophagy, a catabolic process activated during the innate immune response to infections, is emerging as a key event for the onset of human cancers. Here, we summarize the current understanding of the molecular mechanisms by which human oncogenic viruses regulate autophagy and how this negative regulation impacts on cancer development. Finally, we highlight novel autophagy-related candidates for the treatment of virus-related cancers.
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Affiliation(s)
- Tiziana Vescovo
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy
| | - Benedetta Pagni
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy.,Department of Biology, University of Rome "Tor Vergata," Rome, Italy
| | - Mauro Piacentini
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy.,Department of Biology, University of Rome "Tor Vergata," Rome, Italy
| | - Gian Maria Fimia
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy.,Department of Molecular Medicine, University of Rome "Sapienza," Rome, Italy
| | - Manuela Antonioli
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy
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17
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Hazari Y, Bravo-San Pedro JM, Hetz C, Galluzzi L, Kroemer G. Autophagy in hepatic adaptation to stress. J Hepatol 2020; 72:183-196. [PMID: 31849347 DOI: 10.1016/j.jhep.2019.08.026] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/13/2019] [Accepted: 08/28/2019] [Indexed: 02/06/2023]
Abstract
Autophagy is an evolutionarily ancient process whereby eukaryotic cells eliminate disposable or potentially dangerous cytoplasmic material, to support bioenergetic metabolism and adapt to stress. Accumulating evidence indicates that autophagy operates as a critical quality control mechanism for the maintenance of hepatic homeostasis in both parenchymal (hepatocytes) and non-parenchymal (stellate cells, sinusoidal endothelial cells, Kupffer cells) compartments. In line with this notion, insufficient autophagy has been aetiologically involved in the pathogenesis of multiple liver disorders, including alpha-1-antitrypsin deficiency, Wilson disease, non-alcoholic steatohepatitis, liver fibrosis and hepatocellular carcinoma. Here, we critically discuss the importance of functional autophagy for hepatic physiology, as well as the mechanisms whereby defects in autophagy cause liver disease.
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Affiliation(s)
- Younis Hazari
- Biomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile, Santiago, Chile; FONDAP Center for Geroscience (GERO), Brain Health and Metabolism, Santiago, Chile; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
| | - José Manuel Bravo-San Pedro
- Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France
| | - Claudio Hetz
- Biomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile, Santiago, Chile; FONDAP Center for Geroscience (GERO), Brain Health and Metabolism, Santiago, Chile; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile; Buck Institute for Research in Aging, Novato, CA, USA.
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA; Université Paris Descartes/Paris V, Paris, France
| | - Guido Kroemer
- Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes/Paris V, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Suzhou Institute for Systems Medicine, Chinese Academy of Sciences, Suzhou, China; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
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18
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Autophagy Promotes Porcine Parvovirus Replication and Induces Non-Apoptotic Cell Death in Porcine Placental Trophoblasts. Viruses 2019; 12:v12010015. [PMID: 31861933 PMCID: PMC7020067 DOI: 10.3390/v12010015] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 12/16/2019] [Accepted: 12/18/2019] [Indexed: 12/16/2022] Open
Abstract
Autophagy plays important roles in the infection and pathogenesis of many viruses, yet the regulatory roles of autophagy in the process of porcine parvovirus (PPV) infection remain unclear. Herein, we show that PPV infection induces autophagy in porcine placental trophoblasts (PTCs). Induction of autophagy by rapamycin (RAPA) inhibited the occurrence of apoptotic cell death, yet promoted viral replication in PPV-infected cells; inhibition of autophagy by 3-MA or ATG5 knockdown increased cellular apoptosis and reduced PPV replication. Interestingly, we found that in the presence of caspase-inhibitor zVAD-fmk, PPV induces non-apoptotic cell death that was characterized by lysosomal damage and associated with autophagy. Induction of complete autophagy flux by RAPA markedly promoted PPV replication compared with incomplete autophagy induced by RAPA plus bafilomycin (RAPA/BAF) in the early phase of PPV infection (24 h.p.i.). Meanwhile, induction of complete autophagy with RAPA increased lysosomal damage and non-apoptotic cell death in the later phase of PPV infection. Therefore, our data suggest that autophagy can enhance PPV replication and promote the occurrence of lysosomal-damage-associated non-apoptotic cell death in PPV-infected porcine placental trophoblasts.
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19
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Dash S, Aydin Y, Moroz K. Chaperone-Mediated Autophagy in the Liver: Good or Bad? Cells 2019; 8:E1308. [PMID: 31652893 PMCID: PMC6912708 DOI: 10.3390/cells8111308] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 10/17/2019] [Accepted: 10/22/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection triggers autophagy processes, which help clear out the dysfunctional viral and cellular components that would otherwise inhibit the virus replication. Increased cellular autophagy may kill the infected cell and terminate the infection without proper regulation. The mechanism of autophagy regulation during liver disease progression in HCV infection is unclear. The autophagy research has gained a lot of attention recently since autophagy impairment is associated with the development of hepatocellular carcinoma (HCC). Macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) are three autophagy processes involved in the lysosomal degradation and extracellular release of cytosolic cargoes under excessive stress. Autophagy processes compensate for each other during extreme endoplasmic reticulum (ER) stress to promote host and microbe survival as well as HCC development in the highly stressed microenvironment of the cirrhotic liver. This review describes the molecular details of how excessive cellular stress generated during HCV infection activates CMA to improve cell survival. The pathological implications of stress-related CMA activation resulting in the loss of hepatic innate immunity and tumor suppressors, which are most often observed among cirrhotic patients with HCC, are discussed. The oncogenic cell programming through autophagy regulation initiated by a cytoplasmic virus may facilitate our understanding of HCC mechanisms related to non-viral etiologies and metabolic conditions such as uncontrolled type II diabetes. We propose that a better understanding of how excessive cellular stress leads to cancer through autophagy modulation may allow therapeutic development and early detection of HCC.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
- Southeast Louisiana Veterans Health Care System, 2400 Canal Street, New Orleans, LA 70119, USA.
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
| | - Krzysztof Moroz
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
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20
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Fan X, Men R, Wang H, Shen M, Wang T, Ye T, Luo X, Yang L. Methylprednisolone Decreases Mitochondria-Mediated Apoptosis and Autophagy Dysfunction in Hepatocytes of Experimental Autoimmune Hepatitis Model via the Akt/mTOR Signaling. Front Pharmacol 2019; 10:1189. [PMID: 31680966 PMCID: PMC6813226 DOI: 10.3389/fphar.2019.01189] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 09/17/2019] [Indexed: 02/05/2023] Open
Abstract
Autoimmune hepatitis (AIH) is characterized by massive immune cell-mediated hepatocyte destruction. Glucocorticoids, particularly methylprednisolone (MP), are the most effective treatment for AIH; however, the mechanism underlying the effects of glucocorticoid treatment has not been fully elucidated. The present study explored the effects of MP on damaged hepatocytes in mice with concanavalin A (ConA)-induced experimental autoimmune hepatitis (EAH). C57BL/6 mice were divided into three groups: a normal control group (injected with normal saline), a ConA (20 mg/kg) group, and a ConA + MP (3.12 mg/kg) group. The serum levels of liver enzymes, cytokines, activated T cells, and apoptosis- and autophagy-associated marker proteins were determined 12 h after ConA injection. Human hepatocyte cell line LO2 was used to verify the effects of ConA and MP in vitro. MP treatment significantly decreased inflammatory reactions in the serum and liver tissues and activated the Akt/mTOR signaling pathway to inhibit apoptosis and autophagy in hepatocytes in vivo. Transmission electron microscopy (TEM) revealed fewer autophagosomes in the MP-treated group than in the ConA-treated group. MP treatment obviously suppressed apoptosis and mitochondrial membrane potential (ΔΨm) loss in hepatocytes in vitro. Furthermore, ConA treatment increased the levels of LC3-II, p62/SQSTM1, and Beclin-1, while bafilomycin A1 did not augment the levels of LC3-II. MP treatment decreased the levels of LC3-II, p62/SQSTM1, and Beclin-1 and upregulated the levels of phosphorylated (p)-Akt and p-mTOR. In conclusion, MP ameliorated mitochondria-mediated apoptosis and autophagy dysfunction in ConA-induced hepatocyte injury in vivo and in vitro via the Akt/mTOR signaling pathway.
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Affiliation(s)
- Xiaoli Fan
- Department of Gastroenterology and Hepatology, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre,West China Hospital, Sichuan University, Chengdu, China
| | - Ruoting Men
- Department of Gastroenterology and Hepatology, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre,West China Hospital, Sichuan University, Chengdu, China
| | - Haoran Wang
- Department of Gastroenterology and Hepatology, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre,West China Hospital, Sichuan University, Chengdu, China
| | - Mengyi Shen
- Department of Gastroenterology and Hepatology, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre,West China Hospital, Sichuan University, Chengdu, China
| | - Tingting Wang
- Department of Gastroenterology and Hepatology, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre,West China Hospital, Sichuan University, Chengdu, China
| | - Tinghong Ye
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xuefeng Luo
- Department of Gastroenterology and Hepatology, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre,West China Hospital, Sichuan University, Chengdu, China
| | - Li Yang
- Department of Gastroenterology and Hepatology, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre,West China Hospital, Sichuan University, Chengdu, China
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21
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Ríos-Ocampo WA, Navas MC, Faber KN, Daemen T, Moshage H. The cellular stress response in hepatitis C virus infection: A balancing act to promote viral persistence and host cell survival. Virus Res 2018; 263:1-8. [PMID: 30599163 DOI: 10.1016/j.virusres.2018.12.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 12/03/2018] [Accepted: 12/28/2018] [Indexed: 01/14/2023]
Abstract
Oxidative- and endoplasmic reticulum (ER)-stress are common events during hepatitis C virus (HCV) infection and both regulate cell survival and determine clinical outcome. In response to intrinsic and extrinsic cellular stress, different adaptive mechanisms have evolved in hepatocytes to restore cellular homeostasis like the anti-oxidant response, the unfolded protein response (UPR) and the integrated stress response (ISR). In this review, we focus on the cellular stress response in the context of acute and chronic HCV infection. The mechanisms of induction and modulation of oxidative- and ER-stress are reviewed and analyzed from both perspectives: viral persistence and cell survival. Besides, we delve into the activation of the eIF2α/ATF4 pathway and selective autophagy induction; pathways involved in the elimination of harmful viral proteins after oxidative stress induction. For this, the negative role of autophagy upon HCV infection or negative regulation of viral replication is analyzed. Finally, we hypothesize that the cellular stress response in hepatocytes plays a major role for HCV control thus acting as an important host-factor for virus clearance during the early stages of HCV infection.
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Affiliation(s)
- W Alfredo Ríos-Ocampo
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Grupo Gastrohepatología, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia.
| | - María-Cristina Navas
- Grupo Gastrohepatología, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Toos Daemen
- Department Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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22
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Alcohol-induced autophagy via upregulation of PIASy promotes HCV replication in human hepatoma cells. Cell Death Dis 2018; 9:898. [PMID: 30185779 PMCID: PMC6123814 DOI: 10.1038/s41419-018-0845-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 06/28/2018] [Accepted: 07/02/2018] [Indexed: 02/07/2023]
Abstract
Both alcohol and hepatitis C virus (HCV) infection could induce cellular autophagy in liver cells, which is considered to be essential for productive HCV replication. However, whether alcohol-induced autophagy is involved in the pathogenesis of HCV infection is still poorly understood. Alcohol treatment could induce autophagy in Huh7 cells (a hepatoma cell line that supports HCV JFH-1 replication), evidenced by the increase of LC3B-II levels, the conversion of LC3B-I to LC3B-II, and the formation of GFP-LC3 puncta as well as the decrease of p62 level in alcohol-treated cells compared with control cells. Alcohol treatment also significantly increased PIASy (a member of the PIAS family) expression, which can act as a SUMO (small ubiquitin-like modifier protein) E3 ligase to regulate a broader range of cellular processes including autophagy. Overexpression or the silencing expression of PIASy in alcohol-treated Huh7 cells could increase or decrease autophagic activation caused by alcohol treatment, respectively, and thus affect HCV replication correspondingly. In the absence of alcohol, overexpression or silencing expression of PIASy increase or decrease the level of cellular autophagy, judged by the changes of LC3B-II and p62 levels in the presence or absence of chloroquine (CQ), a lysosome inhibitor. More importantly, in the presence of 3-methyladenine (3-MA), an inhibitor in the early stage of autophagy, the effects of overexpression or silencing expression of PIASy on HCV replication were largely blocked. Furthermore, PIASy could selectively drive the accumulation of SUMO1-conjugated proteins, along with upregulation of the expression of several important autophagy factors, including ATG7 and ATG5–ATG12. In conclusion, alcohol promotes HCV replication through activation of autophagy in Huh7 cells, which partly attributes to its induction of PIASy expression. PIASy-enhanced accumulation of SUMO1-conjugated proteins may contribute to its inducing effect of autophagy. Our findings provide a novel mechanism for the action of alcohol-promoting HCV replication in the context of cellular autophagy.
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Mansouri A, Gattolliat CH, Asselah T. Mitochondrial Dysfunction and Signaling in Chronic Liver Diseases. Gastroenterology 2018; 155:629-647. [PMID: 30012333 DOI: 10.1053/j.gastro.2018.06.083] [Citation(s) in RCA: 525] [Impact Index Per Article: 75.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 05/23/2018] [Accepted: 06/10/2018] [Indexed: 12/12/2022]
Abstract
Mitochondria regulate hepatic lipid metabolism and oxidative stress. Ultrastructural mitochondrial lesions, altered mitochondrial dynamics, decreased activity of respiratory chain complexes, and impaired ability to synthesize adenosine triphosphate are observed in liver tissues from patients with alcohol-associated and non-associated liver diseases. Increased lipogenesis with decreased fatty acid β-oxidation leads to the accumulation of triglycerides in hepatocytes, which, combined with increased levels of reactive oxygen species, contributes to insulin resistance in patients with steatohepatitis. Moreover, mitochondrial reactive oxygen species mediate metabolic pathway signaling; alterations in these pathways affect development and progression of chronic liver diseases. Mitochondrial stress and lesions promote cell death, liver fibrogenesis, inflammation, and the innate immune responses to viral infections. We review the involvement of mitochondrial processes in development of chronic liver diseases, such as nonalcoholic fatty, alcohol-associated, and drug-associated liver diseases, as well as hepatitis B and C, and discuss how they might be targeted therapeutically.
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Affiliation(s)
- Abdellah Mansouri
- Centre de Recherche sur l'Inflammation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1149, Université Paris Diderot, PRES Paris Sorbonne Cité, Paris, France
| | - Charles-Henry Gattolliat
- Centre de Recherche sur l'Inflammation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1149, Université Paris Diderot, PRES Paris Sorbonne Cité, Paris, France
| | - Tarik Asselah
- Centre de Recherche sur l'Inflammation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1149, Université Paris Diderot, PRES Paris Sorbonne Cité, Paris, France; Department of Hepatology, Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Clichy, France.
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24
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Hepatitis C Virus NS5A Protein Promotes the Lysosomal Degradation of Hepatocyte Nuclear Factor 1α via Chaperone-Mediated Autophagy. J Virol 2018; 92:JVI.00639-18. [PMID: 29695419 DOI: 10.1128/jvi.00639-18] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Accepted: 04/17/2018] [Indexed: 12/31/2022] Open
Abstract
Hepatitis C virus (HCV) infection is closely associated with type 2 diabetes. We reported that HCV infection induces the lysosomal degradation of hepatocyte nuclear factor 1 alpha (HNF-1α) via interaction with HCV nonstructural protein 5A (NS5A) protein, thereby suppressing GLUT2 gene expression. The molecular mechanisms of selective degradation of HNF-1α caused by NS5A are largely unknown. Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway. Here, we investigated whether CMA is involved in the selective degradation of HNF-1α in HCV-infected cells and observed that the pentapeptide spanning from amino acid (aa) 130 to aa 134 of HNF-1α matches the rule for the CMA-targeting motif, also known as KFERQ motif. A cytosolic chaperone protein, heat shock cognate protein of 70 kDa (HSC70), and a lysosomal membrane protein, lysosome-associated membrane protein type 2A (LAMP-2A), are key components of CMA. Immunoprecipitation analysis revealed that HNF-1α was coimmunoprecipitated with HSC70, whereas the Q130A mutation (mutation of Q to A at position 130) of HNF-1α disrupted the interaction with HSC70, indicating that the CMA-targeting motif of HNF-1α is important for the association with HSC70. Immunoprecipitation analysis revealed that increasing amounts of NS5A enhanced the association of HNF-1α with HSC70. To determine whether LAMP-2A plays a role in the degradation of HNF-1α protein, we knocked down LAMP-2A mRNA by RNA interference; this knockdown by small interfering RNA (siRNA) recovered the level of HNF-1α protein in HCV J6/JFH1-infected cells. This result suggests that LAMP-2A is required for the degradation of HNF-1α. Immunofluorescence study revealed colocalization of NS5A and HNF-1α in the lysosome. Based on our findings, we propose that HCV NS5A interacts with HSC70 and recruits HSC70 to HNF-1α, thereby promoting the lysosomal degradation of HNF-1α via CMA.IMPORTANCE Many viruses use a protein degradation system, such as the ubiquitin-proteasome pathway or the autophagy pathway, for facilitating viral propagation and viral pathogenesis. We investigated the mechanistic details of the selective lysosomal degradation of hepatocyte nuclear factor 1 alpha (HNF-1α) induced by hepatitis C virus (HCV) NS5A protein. Using site-directed mutagenesis, we demonstrated that HNF-1α contains a pentapeptide chaperone-mediated autophagy (CMA)-targeting motif within the POU-specific domain of HNF-1α. The CMA-targeting motif is important for the association with HSC70. LAMP-2A is required for degradation of HNF-1α caused by NS5A. We propose that HCV NS5A interacts with HSC70, a key component of the CMA machinery, and recruits HSC70 to HNF-1α to target HNF-1α for CMA-mediated lysosomal degradation, thereby facilitating HCV pathogenesis. We discovered a role of HCV NS5A in CMA-dependent degradation of HNF-1α. Our results may lead to a better understanding of the role of CMA in the pathogenesis of HCV.
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25
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Drinane MC, Yaqoob U, Yu H, Luo F, Greuter T, Arab JP, Kostallari E, Verma VK, Maiers J, De Assuncao TM, Simons M, Mukhopadhyay D, Kisseleva T, Brenner DA, Urrutia R, Lomberk G, Gao Y, Ligresti G, Tschumperlin DJ, Revzin A, Cao S, Shah VH. Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms. JCI Insight 2017; 2:92821. [PMID: 29263300 DOI: 10.1172/jci.insight.92821] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 11/22/2017] [Indexed: 12/30/2022] Open
Abstract
The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor receptor (PDGFR) is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway and development of liver fibrosis. Mice with deletion of synectin from HSC were found to be protected from liver fibrosis. mRNA sequencing revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes, including PDGFR-β. Chromatin IP assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300 histone acetyltransferase. Synectin knockdown was found to downregulate PDGFR-α protein levels, as well, but through an alternative mechanism: protection from autophagic degradation. Site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues was responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF-dependent migration and proliferation of HSC after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin protein levels. This work provides insight into differential transcriptional and posttranslational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.
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Affiliation(s)
- Mary C Drinane
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Usman Yaqoob
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Haibin Yu
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.,Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Fanghong Luo
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.,Medical College, Xiamen University, Xiamen, Fujian, China
| | - Thomas Greuter
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Juan P Arab
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Enis Kostallari
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Vikas K Verma
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jessica Maiers
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Thiago Milech De Assuncao
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael Simons
- Section of Cardiovascular Medicine, Yale University, New Haven, Connecticut, USA
| | - Debabrata Mukhopadhyay
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida, USA
| | | | | | - Raul Urrutia
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gwen Lomberk
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Yandong Gao
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA
| | - Giovanni Ligresti
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA
| | - Daniel J Tschumperlin
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA
| | - Alexander Revzin
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA
| | - Sheng Cao
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Vijay H Shah
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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26
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Cevik O, Li D, Baljinnyam E, Manvar D, Pimenta EM, Waris G, Barnes BJ, Kaushik-Basu N. Interferon regulatory factor 5 (IRF5) suppresses hepatitis C virus (HCV) replication and HCV-associated hepatocellular carcinoma. J Biol Chem 2017; 292:21676-21689. [PMID: 29079574 DOI: 10.1074/jbc.m117.792721] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 10/23/2017] [Indexed: 01/08/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a major risk factor for the development of chronic liver disease. The disease typically progresses from chronic HCV to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and death. Chronic inflammation associated with HCV infection is implicated in cirrhosis and HCC, but the molecular players and signaling pathways contributing to these processes remain largely unknown. Interferon regulatory factor 5 (IRF5) is a molecule of interest in HCV-associated HCC because it has critical roles in virus-, Toll-like receptor (TLR)-, and IFN-induced signaling pathways. IRF5 is also a tumor suppressor, and its expression is dysregulated in several human cancers. Here, we present first evidence that IRF5 expression and signaling are modulated during HCV infection. Using HCV infection of human hepatocytes and cells with autonomously replicating HCV RNA, we found that levels of IRF5 mRNA and protein expression were down-regulated. Of note, reporter assays indicated that IRF5 re-expression inhibited HCV protein translation and RNA replication. Gene expression analysis revealed significant differences in the expression of cancer pathway mediators and autophagy proteins rather than in cytokines between IRF5- and empty vector-transfected HCV replicon cells. IRF5 re-expression induced apoptosis via loss in mitochondrial membrane potential, down-regulated autophagy, and inhibited hepatocyte cell migration/invasion. Analysis of clinical HCC specimens supports a pathologic role for IRF5 in HCV-induced HCC, as IRF5 expression was down-regulated in livers from HCV-positive versus HCV-negative HCC patients or healthy donor livers. These results identify IRF5 as an important suppressor of HCV replication and HCC pathogenesis.
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Affiliation(s)
- Ozge Cevik
- From the Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103.,the Department of Biochemistry, Faculty of Pharmacy, Cumhuriyet University, Sivas, Turkey 58140
| | - Dan Li
- From the Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103.,Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, New Jersey 07103.,the Center for Autoimmune and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York 11030
| | - Erdene Baljinnyam
- From the Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103
| | - Dinesh Manvar
- From the Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103
| | - Erica M Pimenta
- From the Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103.,Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, New Jersey 07103
| | - Gulam Waris
- the Rosalind Franklin University of Medicine and Science, Chicago, Illinois 60064, and
| | - Betsy J Barnes
- From the Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103, .,Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, New Jersey 07103.,the Center for Autoimmune and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York 11030
| | - Neerja Kaushik-Basu
- From the Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103, .,the Infectious Diseases and Microbiology Integrated Review Group, National Institutes of Health Center for Scientific Review, Bethesda, Maryland 20892
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27
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Hepatitis C Virus-Induced Autophagy and Host Innate Immune Response. Viruses 2017; 9:v9080224. [PMID: 28805674 PMCID: PMC5580481 DOI: 10.3390/v9080224] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 08/04/2017] [Accepted: 08/11/2017] [Indexed: 02/07/2023] Open
Abstract
Autophagy is a catabolic process that is important for maintaining cellular homeostasis. This pathway in hepatocytes is stimulated and controlled by the hepatitis C virus (HCV)—upon infection—to promote its own replication. HCV induces autophagy indirectly and directly through different mechanisms and temporally controls the autophagic flux. This enables the virus to maximize its replication and attenuate the innate immune responses that it activates. In this review, we discuss the relationship between HCV and autophagy, and the crosstalk between HCV-induced autophagy and host innate immune responses.
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28
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Onal G, Kutlu O, Gozuacik D, Dokmeci Emre S. Lipid Droplets in Health and Disease. Lipids Health Dis 2017; 16:128. [PMID: 28662670 PMCID: PMC5492776 DOI: 10.1186/s12944-017-0521-7] [Citation(s) in RCA: 187] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 06/16/2017] [Indexed: 12/16/2022] Open
Abstract
Lipids are essential building blocks synthesized by complex molecular pathways and deposited as lipid droplets (LDs) in cells. LDs are evolutionary conserved organelles found in almost all organisms, from bacteria to mammals. They are composed of a hydrophobic neutral lipid core surrounding by a phospholipid monolayer membrane with various decorating proteins. Degradation of LDs provide metabolic energy for divergent cellular processes such as membrane synthesis and molecular signaling. Lipolysis and autophagy are two main catabolic pathways of LDs, which regulate lipid metabolism and, thereby, closely engaged in many pathological conditons. In this review, we first provide an overview of the current knowledge on the structural properties and the biogenesis of LDs. We further focus on the recent findings of their catabolic mechanism by lipolysis and autophagy as well as their connection ragarding the regulation and function. Moreover, we discuss the relevance of LDs and their catabolism-dependent pathophysiological conditions.
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Affiliation(s)
- Gizem Onal
- Department of Medical Biology, Hacettepe University, 06100, Ankara, Turkey
| | - Ozlem Kutlu
- Nanotechnology Research and Application Center (SUNUM) & Center of Excellence for Functional Surfaces and Interfaces for Nano Diagnostics (EFSUN), Sabanci University, 34956, Istanbul, Turkey
| | - Devrim Gozuacik
- Molecular Biology, Genetics, and Bioengineering Program & Center of Excellence for Functional Surfaces and Interfaces for Nano Diagnostics (EFSUN), Sabanci University, 34956, Istanbul, Turkey
| | - Serap Dokmeci Emre
- Department of Medical Biology, Hacettepe University, 06100, Ankara, Turkey.
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29
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Abstract
The concept of macroautophagy was established in 1963, soon after the discovery of lysosomes in rat liver. Over the 50 years since, studies of liver autophagy have produced many important findings. The liver is rich in lysosomes and possesses high levels of metabolic-stress-induced autophagy, which is precisely regulated by concentrations of hormones and amino acids. Liver autophagy provides starved cells with amino acids, glucose and free fatty acids for use in energy production and synthesis of new macromolecules, and also controls the quality and quantity of organelles such as mitochondria. Although the efforts of early investigators contributed markedly to our current knowledge of autophagy, the identification of autophagy-related genes represented a revolutionary breakthrough in our understanding of the physiological roles of autophagy in the liver. A growing body of evidence has shown that liver autophagy contributes to basic hepatic functions, including glycogenolysis, gluconeogenesis and β-oxidation, through selective turnover of specific cargos controlled by a series of transcription factors. In this Review, we outline the history of liver autophagy study, and then describe the roles of autophagy in hepatic metabolism under healthy and disease conditions, including the involvement of autophagy in α1-antitrypsin deficiency, NAFLD, hepatocellular carcinoma and viral hepatitis.
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Affiliation(s)
- Takashi Ueno
- Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Masaaki Komatsu
- Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan
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30
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The autophagy elongation complex (ATG5-12/16L1) positively regulates HCV replication and is required for wild-type membranous web formation. Sci Rep 2017; 7:40351. [PMID: 28067309 PMCID: PMC5220323 DOI: 10.1038/srep40351] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 12/05/2016] [Indexed: 12/13/2022] Open
Abstract
Hepatitis C virus (HCV) infection induces intracellular membrane rearrangements, thus forming a membranous web (MW) in which HCV replication and assembly occur. The HCV-induced MW is primarily composed of double membrane vesicles (DMVs) transfused by multi-membrane vesicles. The autophagy machinery has been proposed to participate in the formation of such vesicles. However, no clear evidence has been found linking autophagy to the formation of these DMVs. In this study, we evaluated the role of the autophagy elongation complex (ATG5-12/16L1) in HCV replication and MW formation. Using a dominant negative form of ATG12 and an siRNA approach, we demonstrated that the ATG5-12 conjugate, but not LC3-II formation, is crucial for efficient viral replication. Furthermore, purification of HCV MW revealed the presence of ATG5-12 and ATG16L1 along with HCV nonstructural proteins. Interestingly, LC3 was not recruited along with the elongation complex to the site of viral replication. Finally, inhibition of the elongation complex, but not LC3, greatly impaired the formation of the wild-type MW phenotype. To our knowledge, this study provides the first evidence of the involvement of autophagy proteins in the formation of wild-type MWs.
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31
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Abstract
Autophagy is a catabolic process by which cells remove protein aggregates and damaged organelles for recycling. It can also be used by cells to remove intracellular microbial pathogens, including viruses, in a process known as xenophagy. However, many viruses have developed mechanisms to subvert this intracellular antiviral response and even use this pathway to support their own replications. Hepatitis C virus (HCV) is one such virus and is an important human pathogen that can cause severe liver diseases. Recent studies indicated that HCV could activate the autophagic pathway to support its replication. This review summarizes the current knowledge on the interplay between HCV and autophagy and how this interplay affects HCV replication and host innate immune responses.
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32
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Lagaye S, Brun S, Gaston J, Shen H, Stranska R, Camus C, Dubray C, Rousseau G, Massault PP, Courcambeck J, Bassisi F, Halfon P, Pol S. Anti-hepatitis C virus potency of a new autophagy inhibitor using human liver slices model. World J Hepatol 2016; 8:902-14. [PMID: 27478540 PMCID: PMC4958700 DOI: 10.4254/wjh.v8.i21.902] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 06/01/2016] [Accepted: 06/27/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the antiviral potency of a new anti-hepatitis C virus (HCV) antiviral agent targeting the cellular autophagy machinery. METHODS Non-infected liver slices, obtained from human liver resection and cut in 350 μm-thick slices (2.7 × 10(6) cells per slice) were infected with cell culture-grown HCV Con1b/C3 supernatant (multiplicity of infection = 0.1) cultivated for up to ten days. HCV infected slices were treated at day 4 post-infection with GNS-396 for 6 d at different concentrations. HCV replication was evaluated by strand-specific real-time quantitative reverse transcription - polymerase chain reaction. The infectivity titers of supernatants were evaluated by foci formation upon inoculation into naive Huh-7.5.1 cells. The cytotoxic effect of the drugs was evaluated by lactate dehydrogenase leakage assays. RESULTS The antiviral efficacy of a new antiviral drug, GNS-396, an autophagy inhibitor, on HCV infection of adult human liver slices was evidenced in a dose-dependent manner. At day 6 post-treatment, GNS-396 EC50 was 158 nmol/L without cytotoxic effect (compared to hydroxychloroquine EC50 = 1.17 μmol/L). CONCLUSION Our results demonstrated that our ex vivo model is efficient for evaluation the potency of autophagy inhibitors, in particular a new quinoline derivative GNS-396 as antiviral could inhibit HCV infection in a dose-dependent manner without cytotoxic effect.
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Affiliation(s)
- Sylvie Lagaye
- Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
| | - Sonia Brun
- Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
| | - Jesintha Gaston
- Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
| | - Hong Shen
- Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
| | - Ruzena Stranska
- Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
| | - Claire Camus
- Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
| | - Clarisse Dubray
- Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
| | - Géraldine Rousseau
- Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
| | - Pierre-Philippe Massault
- Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
| | - Jerôme Courcambeck
- Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
| | - Firas Bassisi
- Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
| | - Philippe Halfon
- Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
| | - Stanislas Pol
- Sylvie Lagaye, Jesintha Gaston, Stanislas Pol, Institut Pasteur, INSERM U1223, 75015 Paris, France
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Hepatitis C Virus Infection Induces Autophagy as a Prosurvival Mechanism to Alleviate Hepatic ER-Stress Response. Viruses 2016; 8:v8050150. [PMID: 27223299 PMCID: PMC4885105 DOI: 10.3390/v8050150] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 05/04/2016] [Accepted: 05/18/2016] [Indexed: 12/17/2022] Open
Abstract
Hepatitis C virus (HCV) infection frequently leads to chronic liver disease, liver cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms by which HCV infection leads to chronic liver disease and HCC are not well understood. The infection cycle of HCV is initiated by the attachment and entry of virus particles into a hepatocyte. Replication of the HCV genome inside hepatocytes leads to accumulation of large amounts of viral proteins and RNA replication intermediates in the endoplasmic reticulum (ER), resulting in production of thousands of new virus particles. HCV-infected hepatocytes mount a substantial stress response. How the infected hepatocyte integrates the viral-induced stress response with chronic infection is unknown. The unfolded protein response (UPR), an ER-associated cellular transcriptional response, is activated in HCV infected hepatocytes. Over the past several years, research performed by a number of laboratories, including ours, has shown that HCV induced UPR robustly activates autophagy to sustain viral replication in the infected hepatocyte. Induction of the cellular autophagy response is required to improve survival of infected cells by inhibition of cellular apoptosis. The autophagy response also inhibits the cellular innate antiviral program that usually inhibits HCV replication. In this review, we discuss the physiological implications of the HCV-induced chronic ER-stress response in the liver disease progression.
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Dash S, Chava S, Chandra PK, Aydin Y, Balart LA, Wu T. Autophagy in hepatocellular carcinomas: from pathophysiology to therapeutic response. Hepat Med 2016; 8:9-20. [PMID: 26955295 PMCID: PMC4772942 DOI: 10.2147/hmer.s63700] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Autophagy is an intracellular lysosomal degradation process performed by the cells to maintain energy balance. The autophagy response plays an important role in the progression of liver disease due to hepatitis virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, liver cirrhosis, and hepatocellular carcinoma (HCC). An increased autophagy response also contributes to the pathogenesis of liver disease through modulation of innate and adaptive immune responses; a defective cellular autophagy response leads to the development of HCC. Recent progress in the field indicates that autophagy modulation provides a novel targeted therapy for human liver cancer. The purpose of this review is to update our understanding of how the cellular autophagy response impacts the pathophysiology of liver disease and HCC treatment.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA; Department of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Srinivas Chava
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Partha K Chandra
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Yucel Aydin
- Department of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Luis A Balart
- Department of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
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35
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Hung TM, Yuan RH, Huang WP, Chen YH, Lin YC, Lin CW, Lai HS, Lee PH. Increased Autophagy Markers Are Associated with Ductular Reaction during the Development of Cirrhosis. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:2454-67. [PMID: 26158232 DOI: 10.1016/j.ajpath.2015.05.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 05/04/2015] [Accepted: 05/12/2015] [Indexed: 02/07/2023]
Abstract
Autophagy is a regulatory pathway in liver fibrosis. We investigated the roles of autophagy in human cirrhotic livers. Cirrhotic and noncirrhotic liver tissues were obtained from patients with hepatocellular carcinoma, and liver tissues from live donors served as control. Patients with cirrhotic livers had significantly increased levels of various essential autophagy-related genes compared with noncirrhotic livers. In addition, colocalization of autophagy marker microtubule-associated protein 1 light chain 3B (LC3B) with lysosome-associated membrane protein-1, increased levels of lysosome-associated membrane protein-2, and increased maturation of lysosomal cathepsin D were observed in cirrhotic livers. By using dual-immunofluorescence staining, we demonstrated that increased LC3B was located mainly in the cytokeratin 19-labeled ductular reaction (DR) in human cirrhotic livers and in an experimental cirrhosis induced by 2-acetylaminofluorene (AAF) with carbon tetrachloride (CCl4), indicating a conserved response to chronic liver damage. Furthermore, an AAF/CCl4-mediated increase in DR and fibrosis were attenuated after chloroquine treatment, suggesting that the autophagy-lysosome pathway was essential for AAF/CCl4-induced DR-fibrosis. In conclusion, we demonstrated that increased autophagy marker positively correlated with DR during the development of cirrhosis. Therefore, targeting autophagy may hold therapeutic value for liver cirrhosis.
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Affiliation(s)
- Tzu-Min Hung
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Research, E-DA Hospital, Kaohsiung, Taiwan
| | - Ray-Hwang Yuan
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan
| | - Wei-Pang Huang
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Yu-Hsuan Chen
- Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yu-Chun Lin
- Department of Medical Research, E-DA Hospital, Kaohsiung, Taiwan
| | - Chih-Wen Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, E-DA Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Hong-Shiee Lai
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Po-Huang Lee
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Surgery, E-DA Hospital, Kaohsiung, Taiwan.
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Cellular stress responses in hepatitis C virus infection: Mastering a two-edged sword. Virus Res 2015; 209:100-17. [PMID: 25836277 DOI: 10.1016/j.virusres.2015.03.013] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 03/21/2015] [Accepted: 03/23/2015] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus (HCV) infection affects chronically more than 150 million humans worldwide. Chronic HCV infection causes severe liver disease and hepatocellular carcinoma. While immune response-mediated events are major players in HCV pathogenesis, the impact that viral replication has on cellular homeostasis is increasingly recognized as a necessary contributor to pathological manifestations of HCV infection such as steatosis, insulin-resistance or liver cancer. In this review, we will briefly overview the different cellular stress pathways that are induced by hepatitis C virus infection, the response that the cell promotes to attempt regaining homeostasis or to induce dysfunctional cell death, and how the virus co-opts these response mechanisms to promote both viral replication and survival of the infected cell. We will review the role of unfolded protein and oxidative stress responses as well as the role of auto- and mitophagy in HCV infection. Finally, we will discuss the recent discovery of a cellular chaperone involved in stress responses, the sigma-1 receptor, as a cellular factor required at the onset of HCV infection and the potential molecular events underlying the proviral role of this cellular factor in HCV infection.
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Persistent hepatitis C virus infection impairs ribavirin antiviral activity through clathrin-mediated trafficking of equilibrative nucleoside transporter 1. J Virol 2014; 89:626-42. [PMID: 25339775 DOI: 10.1128/jvi.02492-14] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
UNLABELLED Ribavirin (RBV) continues to be an important component of interferon-free hepatitis C treatment regimens, as RBV alone does not inhibit hepatitis C virus (HCV) replication effectively; the reason for this ineffectiveness has not been established. In this study, we investigated the RBV resistance mechanism using a persistently HCV-infected cell culture system. The antiviral activity of RBV against HCV was progressively impaired in the persistently infected culture, whereas interferon lambda 1 (IFN-λ1), a type III IFN, showed a strong antiviral response and induced viral clearance. We found that HCV replication in persistently infected cultures induces an autophagy response that impairs RBV uptake by preventing the expression of equilibrative nucleoside transporter 1 (ENT1). The Huh-7.5 cell line treated with an autophagy inducer, Torin 1, downregulated membrane expression of ENT1 and terminated RBV uptake. In contrast, the autophagy inhibitors hydroxychloroquine (HCQ), 3-methyladenine (3-MA), and bafilomycin A1 (BafA1) prevented ENT1 degradation and enhanced RBV antiviral activity. The HCV-induced autophagy response, as well as treatment with Torin 1, degrades clathrin heavy chain expression in a hepatoma cell line. Reduced expression of the clathrin heavy chain by HCV prevents ENT1 recycling to the plasma membrane and forces ENT1 to the lysosome for degradation. This study provides a potential mechanism for the impairment of RBV antiviral activity in persistently HCV-infected cell cultures and suggests that inhibition of the HCV-induced autophagy response could be used as a strategy for improving RBV antiviral activity against HCV infection. IMPORTANCE The results from this work will allow a review of the competing theories of antiviral therapy development in the field of HCV virology. Ribavirin (RBV) remains an important component of interferon-free hepatitis C treatment regimens. The reason why RBV alone does not inhibit HCV replication effectively has not been established. This study provides a potential mechanism for why RBV antiviral activity is impaired in persistently HCV-infected cell cultures and suggests that inhibition of the HCV-induced autophagy response could be used as a strategy to increase RBV antiviral activity against HCV infection. Therefore, it is anticipated that this work would generate a great deal of interest, not only among virologists but also among the general public.
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Chandra PK, Gunduz F, Hazari S, Kurt R, Panigrahi R, Poat B, Bruce D, Cohen AJ, Behorquez HE, Carmody I, Loss G, Balart LA, Wu T, Dash S. Impaired expression of type I and type II interferon receptors in HCV-associated chronic liver disease and liver cirrhosis. PLoS One 2014; 9:e108616. [PMID: 25265476 PMCID: PMC4180933 DOI: 10.1371/journal.pone.0108616] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 08/22/2014] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Chronic Hepatitis C Virus (HCV)-infected patients with liver cirrhosis (LC) respond poorly to interferon-alpha (IFN-α) and ribavirin (RBV) combination therapy, but the reason for this is unclear. We previously reported that HCV-infection induces endoplasmic reticulum (ER) stress and autophagy response that selectively down regulates the type I IFN-α receptor-1 (IFNAR1) and RBV transporters (CNT1 and ENT1), leading to IFN-α/RBV resistance. The goal of this study is to verify whether an increase in ER stress and autophagy response is also associated with the reduced expression of IFNAR1 and RBV transporters in chronic HCV-infected patients. METHODS Primary human hepatocytes (PHH) were infected with cell culture grown HCV particles (JFH-ΔV3-Rluc). HCV replication was confirmed by the detection of viral RNA by RT-qPCR and HCV-core protein by Western blotting. The ER stress and autophagy response and expression of IFN receptors and RBV transporters in HCV infected PHH and liver tissues derived from patients were measured by Western blotting. RESULT HCV infection of PHH showed impaired expression of IFNAR1, IFNγR1 (Type II IFN receptor) and RBV transporters but not IL10Rβ (Type III IFN-λ receptor). ER stress markers (BiP, IRE1α and peIF2α) and autophagy response (LC3II, Beclin 1 and ATG5) were induced in HCV infected chronic liver disease (CLD) and LC patients. Liver biopsies (CLD) show a 50% reduced expression of IFNAR1 and RBV transporters. Furthermore, the expression of IFNAR1 and RBV transporters was impaired in almost all LC patients. CONCLUSION HCV infection induces ER stress and autophagy response in infected PHH and chronically infected liver tissues. The expression of IFNAR1, IFNγR1 and RBV transporters were significantly impaired in CLD and cirrhotic livers. Our study provides a potential explanation for the reduced response rate of IFN-α and RBV combination therapy in HCV infected patients with liver cirrhosis.
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Affiliation(s)
- Partha K. Chandra
- Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Feyza Gunduz
- Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Sidhartha Hazari
- Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Ramazan Kurt
- Department of Medicine, Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Rajesh Panigrahi
- Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Bret Poat
- Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - David Bruce
- Transplant Surgery Section, Ochsner Medical Center, New Orleans, Louisiana, United States of America
| | - Ari J. Cohen
- Transplant Surgery Section, Ochsner Medical Center, New Orleans, Louisiana, United States of America
| | - Humberto E. Behorquez
- Transplant Surgery Section, Ochsner Medical Center, New Orleans, Louisiana, United States of America
| | - Ian Carmody
- Transplant Surgery Section, Ochsner Medical Center, New Orleans, Louisiana, United States of America
| | - George Loss
- Transplant Surgery Section, Ochsner Medical Center, New Orleans, Louisiana, United States of America
| | - Luis A. Balart
- Department of Medicine, Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Tong Wu
- Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Srikanta Dash
- Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
- Department of Medicine, Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
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Fukuo Y, Yamashina S, Sonoue H, Arakawa A, Nakadera E, Aoyama T, Uchiyama A, Kon K, Ikejima K, Watanabe S. Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease. Hepatol Res 2014; 44:1026-36. [PMID: 24299564 DOI: 10.1111/hepr.12282] [Citation(s) in RCA: 139] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Revised: 11/25/2013] [Accepted: 11/26/2013] [Indexed: 02/08/2023]
Abstract
AIM Recent evidences indicate that hepatic steatosis suppresses autophagic proteolysis. The present study evaluated the correlation between autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease (NAFLD). METHODS Liver biopsy specimens were obtained from patients with chronic liver diseases (chronic hepatitis C [CHC; n = 20], chronic hepatitis B [CHB; n = 16], primary biliary cirrhosis [PBC; n = 23], NAFLD [n = 22] and control [n = 14]). The number of autophagic vesicles in hepatocytes was counted by using transmission electron microscopy. Expression of cathepsin B, D, L and p62 in the liver section was analyzed by immunohistochemical staining. The histological severity of NAFLD is assessed by NAFLD activity score (NAS). RESULTS The number of autophagic vesicles in hepatocytes was significantly increased in both CHC and NAFLD groups, but not CHB and PBC, more than control. Although hepatocytes with aggregation of p62 were observed in less than 15% of CHC, p62 aggregation was detected in approximately 65% of NAFLD. Cathepsin B, D and L expression was significantly suppressed in the liver from NAFLD patients. Suppression of cathepsin B, D and L expression was not observed in CHB, CHC and PBC. In NAFLD patients, p62 aggregation was correlated with serum alanine aminotransferase value and inflammatory activity by NAS. CONCLUSION These results indicate that a decrease in hepatic cathepsin expression in NAFLD is associated with autophagic dysfunction. Hepatic inflammation correlates with autophagic dysfunction in NAFLD. These findings indicate that the suppression of autophagic proteolysis by hepatic steatosis is involved in the pathogenesis of NAFLD.
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Affiliation(s)
- Yuka Fukuo
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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Autophagy in HCV infection: keeping fat and inflammation at bay. BIOMED RESEARCH INTERNATIONAL 2014; 2014:265353. [PMID: 25162004 PMCID: PMC4138948 DOI: 10.1155/2014/265353] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 07/11/2014] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease. Viral persistence and pathogenesis rely mainly on the ability of HCV to deregulate specific host processes, including lipid metabolism and innate immunity. Recently, autophagy has emerged as a cellular pathway, playing a role in several aspects of HCV infection. This review summarizes current knowledge on the molecular mechanisms that link the HCV life cycle with autophagy machinery. In particular, we discuss the role of HCV/autophagy interaction in dysregulating inflammation and lipid homeostasis and its potential for translational applications in the treatment of HCV-infected patients.
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41
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Bao L, Chandra PK, Moroz K, Zhang X, Thung SN, Wu T, Dash S. Impaired autophagy response in human hepatocellular carcinoma. Exp Mol Pathol 2014; 96:149-154. [PMID: 24369267 PMCID: PMC4364514 DOI: 10.1016/j.yexmp.2013.12.002] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 12/03/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND Autophagy is a cellular lysosomal degradation mechanism that has been implicated in chronic liver diseases and hepatocellular carcinoma (HCC). Association of autophagy defect with the development of human HCC has been shown in transgenic mouse model. AIM We performed this study to verify whether a defect in autophagy would play a role in human hepatocellular carcinoma (HCC). METHODS Archival tissue sections of 20 patients with HCC with or without hepatitis C virus (HCV) infection were studied. All slides were immunostained using monoclonal antibodies to p62 and glypican-3 with appropriate positive and negative controls. The expression of p62 and glycican-3 in the HCC and the surrounding non-tumor was semiquantitated. The cytoplasmic staining was graded as negative, weak or strong. RESULTS Positive p62 staining was found in 20 out of 20 (100%) HCCs and negative staining was observed in 20 out of 20 non-tumor areas and cirrhotic nodules. Positive glypican-3 staining was found in 70% of HCCs and negative staining was seen in all non-tumor areas. An autophagy defect leading to increased expression of p62 and glypican-3 was also seen in the HCC cell line (Huh-7.5), but not in the primary human hepatocytes. Activation of cellular autophagy in Huh-7.5 cells efficiently cleared p62 and glypican-3 expression and inhibition of autophagy induced the expression of p62 and glypican-3. CONCLUSIONS This study shows that p62 is increased in HCC compared to the surrounding non-tumorous liver tissue suggesting that human HCCs are autophagy defective. We provide further evidence that glypican-3 expression in HCC may also be related to defective autophagy. Our study indicates that p62 immunostain may represent a novel marker for HCC.
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Affiliation(s)
- Lili Bao
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
| | - Partha K Chandra
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
| | - Krzysztof Moroz
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
| | - Xuchen Zhang
- The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Swan N Thung
- The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA
| | - Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
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Chandra PK, Bao L, Song K, Aboulnasr FM, Baker DP, Shores N, Wimley WC, Liu S, Hagedorn CH, Fuchs SY, Wu T, Balart LA, Dash S. HCV infection selectively impairs type I but not type III IFN signaling. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 184:214-29. [PMID: 24215913 DOI: 10.1016/j.ajpath.2013.10.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 09/26/2013] [Accepted: 10/01/2013] [Indexed: 02/07/2023]
Abstract
A stable and persistent Hepatitis C virus (HCV) replication cell culture model was developed to examine clearance of viral replication during long-term treatment using interferon-α (IFN-α), IFN-λ, and ribavirin (RBV). Persistently HCV-infected cell culture exhibited an impaired antiviral response to IFN-α+RBV combination treatment, whereas IFN-λ treatment produced a strong and sustained antiviral response that cleared HCV replication. HCV replication in persistently infected cells induced chronic endoplasmic reticulum (ER) stress and an autophagy response that selectively down-regulated the functional IFN-α receptor-1 chain of type I, but not type II (IFN-γ) or type III (IFN-λ) IFN receptors. Down-regulation of IFN-α receptor-1 resulted in defective JAK-STAT signaling, impaired STAT phosphorylation, and impaired nuclear translocation of STAT. Furthermore, HCV replication impaired RBV uptake, because of reduced expression of the nucleoside transporters ENT1 and CNT1. Silencing ER stress and the autophagy response using chemical inhibitors or siRNA additively inhibited HCV replication and induced viral clearance by the IFN-α+RBV combination treatment. These results indicate that HCV induces ER stress and that the autophagy response selectively impairs type I (but not type III) IFN signaling, which explains why IFN-λ (but not IFN-α) produced a sustained antiviral response against HCV. The results also indicate that inhibition of ER stress and of the autophagy response overcomes IFN-α+RBV resistance mechanisms associated with HCV infection.
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Affiliation(s)
- Partha K Chandra
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Lili Bao
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Kyoungsub Song
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Fatma M Aboulnasr
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | | | - Nathan Shores
- Department of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, Louisiana
| | - William C Wimley
- Department of Biochemistry, Tulane University School of Medicine, New Orleans, Louisiana
| | - Shuanghu Liu
- Department of Medicine and Pathology, University of Utah School of Medicine, Salt Lake City, Utah
| | - Curt H Hagedorn
- Department of Medicine and Pathology, University of Utah School of Medicine, Salt Lake City, Utah
| | - Serge Y Fuchs
- Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Luis A Balart
- Department of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
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Tovilovic G, Ristic B, Milenkovic M, Stanojevic M, Trajkovic V. The Role and Therapeutic Potential of Autophagy Modulation in Controlling Virus-Induced Cell Death. Med Res Rev 2013; 34:744-67. [DOI: 10.1002/med.21303] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Gordana Tovilovic
- Institute for Biological Research; University of Belgrade; Despot Stefan Boulevard 142 11000 Belgrade Serbia
| | - Biljana Ristic
- Institute of Microbiology and Immunology; School of Medicine; University of Belgrade; Dr. Subotica 1 11000 Belgrade Serbia
| | - Marina Milenkovic
- Institute of Microbiology and Immunology; School of Medicine; University of Belgrade; Dr. Subotica 1 11000 Belgrade Serbia
| | - Maja Stanojevic
- Institute of Microbiology and Immunology; School of Medicine; University of Belgrade; Dr. Subotica 1 11000 Belgrade Serbia
| | - Vladimir Trajkovic
- Institute of Microbiology and Immunology; School of Medicine; University of Belgrade; Dr. Subotica 1 11000 Belgrade Serbia
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Czaja MJ, Ding WX, Donohue TM, Friedman SL, Kim JS, Komatsu M, Lemasters JJ, Lemoine A, Lin JD, Ou JHJ, Perlmutter DH, Randall G, Ray RB, Tsung A, Yin XM. Functions of autophagy in normal and diseased liver. Autophagy 2013; 9:1131-58. [PMID: 23774882 DOI: 10.4161/auto.25063] [Citation(s) in RCA: 366] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Autophagy has emerged as a critical lysosomal pathway that maintains cell function and survival through the degradation of cellular components such as organelles and proteins. Investigations specifically employing the liver or hepatocytes as experimental models have contributed significantly to our current knowledge of autophagic regulation and function. The diverse cellular functions of autophagy, along with unique features of the liver and its principal cell type the hepatocyte, suggest that the liver is highly dependent on autophagy for both normal function and to prevent the development of disease states. However, instances have also been identified in which autophagy promotes pathological changes such as the development of hepatic fibrosis. Considerable evidence has accumulated that alterations in autophagy are an underlying mechanism of a number of common hepatic diseases including toxin-, drug- and ischemia/reperfusion-induced liver injury, fatty liver, viral hepatitis and hepatocellular carcinoma. This review summarizes recent advances in understanding the roles that autophagy plays in normal hepatic physiology and pathophysiology with the intent of furthering the development of autophagy-based therapies for human liver diseases.
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Affiliation(s)
- Mark J Czaja
- Department of Medicine; Marion Bessin Liver Research Center; Albert Einstein College of Medicine; Bronx, NY USA
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Oczypok EA, Oury TD, Chu CT. It's a cell-eat-cell world: autophagy and phagocytosis. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 182:612-22. [PMID: 23369575 PMCID: PMC3589073 DOI: 10.1016/j.ajpath.2012.12.017] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Accepted: 12/06/2012] [Indexed: 11/26/2022]
Abstract
The process of cellular eating, or the phagocytic swallowing of one cell by another, is an ancient manifestation of the struggle for life itself. Following the endosymbiotic origin of eukaryotic cells, increased cellular and then multicellular complexity was accompanied by the emergence of autophagic mechanisms for self-digestion. Heterophagy and autophagy function not only to protect the nutritive status of cells, but also as defensive responses against microbial pathogens externally or the ill effects of damaged proteins and organelles within. Because of the key roles played by phagocytosis and autophagy in a wide range of acute and chronic human diseases, pathologists have played similarly key roles in elucidating basic regulatory phases for both processes. Studies in diverse organ systems (including the brain, liver, kidney, lung, and muscle) have defined key roles for these lysosomal pathways in infection control, cell death, inflammation, cancer, neurodegeneration, and mitochondrial homeostasis. The literature reviewed here exemplifies the role of pathology in defining leading-edge questions for continued molecular and pathophysiological investigations into all forms of cellular digestion.
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Affiliation(s)
- Elizabeth A. Oczypok
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Tim D. Oury
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Charleen T. Chu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Ni HM, Williams JA, Yang H, Shi YH, Fan J, Ding WX. Targeting autophagy for the treatment of liver diseases. Pharmacol Res 2012; 66:463-74. [PMID: 22871337 DOI: 10.1016/j.phrs.2012.07.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Accepted: 07/18/2012] [Indexed: 12/19/2022]
Abstract
Autophagy is a lysosomal degradation pathway that can degrade bulk cytoplasm and superfluous or damaged organelles, such as mitochondria, to maintain cellular homeostasis. It is now known that dysregulation of autophagy can cause pathogenesis of numerous human diseases. Here, we discuss the critical roles that autophagy plays in the pathogenesis of liver diseases such as non-alcoholic and alcoholic fatty liver, drug-induced liver injury, protein aggregate-related liver diseases, viral hepatitis, fibrosis, aging and liver cancer. In particular, we discuss the emerging therapeutic potential by pharmacological modulation of autophagy for these liver diseases.
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Affiliation(s)
- Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, United States
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Abstract
Until recently, chronic hepatitis C caused by persistent infection with the hepatitis C virus (HCV) has been treated with a combination of pegylated interferon-alpha (PEG-IFNα) and ribavirin (RBV). This situation has changed with the development of two drugs targeting the NS3/4A protease, approved for combination therapy with PEG-IFNα/RBV for patients infected with genotype 1 viruses. Moreover, two additional viral proteins, the RNA-dependent RNA polymerase (residing in NS5B) and the NS5A protein have emerged as promising drug targets and a large number of antivirals targeting these proteins are at different stages of clinical development. Although this progress is very promising, it is not clear whether these new compounds will suffice to eradicate the virus in an infected individual, ideally by using a PEG-IFNα/RBV-free regimen, or whether additional compounds targeting other factors that promote HCV replication are required. In this respect, host cell factors have emerged as a promising alternative. They reduce the risk of development of antiviral resistance and they increase the chance for broad-spectrum activity, ideally covering all HCV genotypes. Work in the last few years has identified several host cell factors used by HCV for productive replication. These include, amongst others, cyclophilins, especially cyclophilinA (cypA), microRNA-122 (miR-122) or phosphatidylinositol-4-kinase III alpha. For instance, cypA inhibitors have shown to be effective in combination therapy with PEG-IFN/RBV in increasing the sustained viral response (SVR) rate significantly compared to PEG-IFN/RBV. This review briefly summarizes recent advances in the development of novel antivirals against HCV.
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Affiliation(s)
- Sandra Bühler
- Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
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48
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Estrabaud E, De Muynck S, Asselah T. Activation of unfolded protein response and autophagy during HCV infection modulates innate immune response. J Hepatol 2011; 55:1150-3. [PMID: 21723841 DOI: 10.1016/j.jhep.2011.04.025] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2011] [Revised: 04/20/2011] [Accepted: 04/21/2011] [Indexed: 01/07/2023]
Abstract
Autophagy, a process for catabolizing cytoplasmic components, has been implicated in the modulation of interactions between RNA viruses and their host. However, the mechanism underlying the functional role of autophagy in the viral life cycle still remains unclear. Hepatitis C virus (HCV) is a single-stranded, positive-sense, membrane-enveloped RNA virus that can cause chronic liver disease. Here we report that HCV induces the unfolded protein response (UPR), which in turn activates the autophagic pathway to promote HCV RNA replication in human hepatoma cells. Further analysis revealed that the entire autophagic process through to complete autolysosome maturation was required to promote HCV RNA replication and that it did so by suppressing innate antiviral immunity. Gene silencing or activation of the UPR-autophagy pathway activated or repressed, respectively, IFN-β activation mediated by an HCV-derived pathogen-associated molecular pattern (PAMP). Similar results were achieved with a PAMP derived from Dengue virus (DEV), indicating that HCV and DEV may both exploit the UPR-autophagy pathway to escape the innate immune response. Taken together, these results not only define the physiological significance of HCV-induced autophagy, but also shed light on the knowledge of host cellular responses upon HCV infection as well as on exploration of therapeutic targets for controlling HCV infection.
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Affiliation(s)
- Emilie Estrabaud
- Service d'Hépatologie and INSERM U773 CRB3, Beaujon Hospital, University Paris VII, France
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Dreux M, Chisari FV. Impact of the autophagy machinery on hepatitis C virus infection. Viruses 2011; 3:1342-57. [PMID: 21994783 PMCID: PMC3185811 DOI: 10.3390/v3081342] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2011] [Revised: 07/20/2011] [Accepted: 07/21/2011] [Indexed: 12/16/2022] Open
Abstract
Autophagy is a cellular process that catabolizes cytoplasmic components and maintains energy homeostasis. As a stress response, the autophagy machinery interconnects a wide range of cellular pathways, enhancing the spread of certain pathogens while limiting others, and has become a highly active research area over the past several years. Independent laboratories have recently reported that autophagy vesicles accumulate in hepatitis C virus (HCV) infected cells and that autophagy proteins can function as proviral factors required for HCV replication. In this review, we summarize what is currently known about the interplay between autophagy and HCV and the possible mechanisms whereby autophagy proteins might favor HCV propagation.
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Affiliation(s)
- Marlène Dreux
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
- Ecole Normale Supérieure de Lyon, Lyon, F-69007, France
- Université de Lyon, Lyon, F-69007, France
- INSERM, U758, Lyon, F-69007, France
- Authors to whom correspondence should be addressed; E-Mails: (M.D.), (F.V.C.); Tel.: +33-426-233834 (M.D.); +1-858-784-8228 (F.V.C.); Fax: +33-472-728137 (M.D.); +1-858-784-2160 (F.V.C.)
| | - Francis V. Chisari
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
- Authors to whom correspondence should be addressed; E-Mails: (M.D.), (F.V.C.); Tel.: +33-426-233834 (M.D.); +1-858-784-8228 (F.V.C.); Fax: +33-472-728137 (M.D.); +1-858-784-2160 (F.V.C.)
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