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Makhoba XH. Two sides of the same coin: heat shock proteins as biomarkers and therapeutic targets for some complex diseases. Front Mol Biosci 2025; 12:1491227. [PMID: 40051500 PMCID: PMC11882428 DOI: 10.3389/fmolb.2025.1491227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 01/31/2025] [Indexed: 03/09/2025] Open
Abstract
Heat shock proteins are molecular chaperones that play crucial roles in the folding and unfolding of complex polypeptides within the cellular system. These molecules are involved in various processes, including vesicular transport, prevention of protein aggregation in the cytosol, and cell signaling. They are also linked to autoimmunity, infection immunity, and tumor immunology. Stressors like heat shock, exposure to heavy metals, cytokines, reactive oxygen species, inflammation, and viruses can influence the production of these molecules. In complex diseases such as cancer, malaria, and COVID-19, heat shock proteins are considered both biomarkers and drug targets. The upregulation of small heat shock proteins like hsp27 and major heat shock proteins 70/90 has been recognized as crucial biomarkers and therapeutic targets for cancer. Additionally, it has been reported that the invasion of Plasmodium falciparum, the causative agent of malaria, leads to the upregulation of heat shock proteins such as hsp40, hsp70, and hsp90. This sudden increase is a protective mechanism from the human host and enhances the parasite's growth, making these proteins significant as biomarkers and malarial drug targets. The presence of the SARS-CoV-2 virus in the human cellular system correlates with a substantial increase in heat shock protein 70 production from host cells. Furthermore, our research group has demonstrated that SARS-CoV-2 hijacks the host's heat shock proteins, and we are currently developing tools to prevent the virus from utilizing the host's protein folding system. This review aims to highlight the role of heat shock proteins as biomarkers and therapeutic targets for selected refractory diseases, focusing on cancer, malaria, and COVID-19. A fundamental molecular docking study was performed to investigate the interaction between a non-structural complex from SARS-CoV-2 and chosen small molecules, which is emphasized in this review.
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Affiliation(s)
- Xolani Henry Makhoba
- Department of Life and Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa (UNISA), Florida Campus, Roodepoort, South Africa
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2
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Tukaj S. Dual role of autoantibodies to heat shock proteins in autoimmune diseases. Front Immunol 2024; 15:1421528. [PMID: 38903496 PMCID: PMC11187000 DOI: 10.3389/fimmu.2024.1421528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 05/27/2024] [Indexed: 06/22/2024] Open
Abstract
Autoimmune diseases are characterized by the recognition of self-antigens (autoantigens) by immune system cells. Loss of immunological tolerance may lead to the generation of autoantibodies and, consequently, tissue damage. It has already been proven that highly immunogenic bacterial and autologous extracellular heat shock proteins (eHsps) interact with immune cells of the innate and adaptive arms of the immune system. The latter interactions may stimulate a humoral (auto)immune response and lead to the generation of anti-Hsps (auto)antibodies. Although circulating levels of anti-Hsps autoantibodies are often elevated in patients suffering from multiple inflammatory and autoimmune diseases, their role in the development of pathological conditions is not fully established. This mini-review presents the dual role of anti-Hsps autoantibodies - protective or pathogenic - in the context of the development of selected autoimmune diseases.
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Affiliation(s)
- Stefan Tukaj
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Gdańsk, Poland
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Felipe Perez R, Mochi G, Khan A, Woodford M. Mitochondrial Chaperone Code: Just warming up. Cell Stress Chaperones 2024; 29:483-496. [PMID: 38763405 PMCID: PMC11153887 DOI: 10.1016/j.cstres.2024.05.002] [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: 04/17/2024] [Revised: 05/13/2024] [Accepted: 05/14/2024] [Indexed: 05/21/2024] Open
Abstract
More than 99% of the mitochondrial proteome is encoded by the nucleus and requires refolding following import. Therefore, mitochondrial proteins require the coordinated action of molecular chaperones for their folding and activation. Several heat shock protein (Hsp) molecular chaperones, including members of the Hsp27, Hsp40/70, and Hsp90 families, as well as the chaperonin complex Hsp60/10 have an established role in mitochondrial protein import and folding. The "Chaperone Code" describes the regulation of chaperone activity by dynamic post-translational modifications; however, little is known about the post-translational regulation of mitochondrial chaperones. Dissecting the regulation of chaperone function is essential for understanding their differential regulation in pathogenic conditions and the potential development of efficacious therapeutic strategies. Here, we summarize the recent literature on post-translational regulation of mitochondrial chaperones, the consequences for mitochondrial function, and potential implications for disease.
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Affiliation(s)
- R Felipe Perez
- Department of Urology, Upstate Medical University, Syracuse, NY, USA
| | - Gianna Mochi
- Department of Urology, Upstate Medical University, Syracuse, NY, USA; Department of Biochemistry & Molecular Biology, Upstate Medical University, Syracuse, NY, USA; Upstate Cancer Center, State University of New York, Upstate Medical University, Syracuse, NY, USA
| | - Ariba Khan
- Department of Urology, Upstate Medical University, Syracuse, NY, USA
| | - Mark Woodford
- Department of Urology, Upstate Medical University, Syracuse, NY, USA; Department of Biochemistry & Molecular Biology, Upstate Medical University, Syracuse, NY, USA; Upstate Cancer Center, State University of New York, Upstate Medical University, Syracuse, NY, USA.
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4
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Kinger S, Jagtap YA, Kumar P, Choudhary A, Prasad A, Prajapati VK, Kumar A, Mehta G, Mishra A. Proteostasis in neurodegenerative diseases. Adv Clin Chem 2024; 121:270-333. [PMID: 38797543 DOI: 10.1016/bs.acc.2024.04.002] [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] [Indexed: 05/29/2024]
Abstract
Proteostasis is essential for normal function of proteins and vital for cellular health and survival. Proteostasis encompasses all stages in the "life" of a protein, that is, from translation to functional performance and, ultimately, to degradation. Proteins need native conformations for function and in the presence of multiple types of stress, their misfolding and aggregation can occur. A coordinated network of proteins is at the core of proteostasis in cells. Among these, chaperones are required for maintaining the integrity of protein conformations by preventing misfolding and aggregation and guide those with abnormal conformation to degradation. The ubiquitin-proteasome system (UPS) and autophagy are major cellular pathways for degrading proteins. Although failure or decreased functioning of components of this network can lead to proteotoxicity and disease, like neuron degenerative diseases, underlying factors are not completely understood. Accumulating misfolded and aggregated proteins are considered major pathomechanisms of neurodegeneration. In this chapter, we have described the components of three major branches required for proteostasis-chaperones, UPS and autophagy, the mechanistic basis of their function, and their potential for protection against various neurodegenerative conditions, like Alzheimer's, Parkinson's, and Huntington's disease. The modulation of various proteostasis network proteins, like chaperones, E3 ubiquitin ligases, proteasome, and autophagy-associated proteins as therapeutic targets by small molecules as well as new and unconventional approaches, shows promise.
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Affiliation(s)
- Sumit Kinger
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, India
| | - Yuvraj Anandrao Jagtap
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, India
| | - Prashant Kumar
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, India
| | - Akash Choudhary
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, India
| | - Amit Prasad
- School of Biosciences and Bioengineering, Indian Institute of Technology Mandi, Mandi, Himachal Pradesh, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Dhaula Kuan, New Delhi, India
| | - Amit Kumar
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, Madhya Pradesh, India
| | - Gunjan Mehta
- Department of Biotechnology, Indian Institute of Technology Hyderabad, Telangana, India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, India.
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5
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Schroeder HT, De Lemos Muller CH, Heck TG, Krause M, Homem de Bittencourt PI. The dance of proteostasis and metabolism: Unveiling the caloristatic controlling switch. Cell Stress Chaperones 2024; 29:175-200. [PMID: 38331164 PMCID: PMC10939077 DOI: 10.1016/j.cstres.2024.02.002] [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: 09/15/2023] [Revised: 02/02/2024] [Accepted: 02/04/2024] [Indexed: 02/10/2024] Open
Abstract
The heat shock response (HSR) is an ancient and evolutionarily conserved mechanism designed to restore cellular homeostasis following proteotoxic challenges. However, it has become increasingly evident that disruptions in energy metabolism also trigger the HSR. This interplay between proteostasis and energy regulation is rooted in the fundamental need for ATP to fuel protein synthesis and repair, making the HSR an essential component of cellular energy management. Recent findings suggest that the origins of proteostasis-defending systems can be traced back over 3.6 billion years, aligning with the emergence of sugar kinases that optimized glycolysis around 3.594 billion years ago. This evolutionary connection is underscored by the spatial similarities between the nucleotide-binding domain of HSP70, the key player in protein chaperone machinery, and hexokinases. The HSR serves as a hub that integrates energy metabolism and resolution of inflammation, further highlighting its role in maintaining cellular homeostasis. Notably, 5'-adenosine monophosphate-activated protein kinase emerges as a central regulator, promoting the HSR during predominantly proteotoxic stress while suppressing it in response to predominantly metabolic stress. The complex relationship between 5'-adenosine monophosphate-activated protein kinase and the HSR is finely tuned, with paradoxical effects observed under different stress conditions. This delicate equilibrium, known as caloristasis, ensures that cellular homeostasis is maintained despite shifting environmental and intracellular conditions. Understanding the caloristatic controlling switch at the heart of this interplay is crucial. It offers insights into a wide range of conditions, including glycemic control, obesity, type 2 diabetes, cardiovascular and neurodegenerative diseases, reproductive abnormalities, and the optimization of exercise routines. These findings highlight the profound interconnectedness of proteostasis and energy metabolism in cellular function and adaptation.
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Affiliation(s)
- Helena Trevisan Schroeder
- Laboratory of Cellular Physiology (FisCel) Department of Physiology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Carlos Henrique De Lemos Muller
- Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX), Department of Physiology, ICBS, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil
| | - Thiago Gomes Heck
- Post Graduate Program in Integral Health Care (PPGAIS-UNIJUÍ/UNICRUZ/URI), Regional University of Northwestern Rio Grande Do Sul State (UNIJUI) and Post Graduate Program in Mathematical and Computational Modeling (PPGMMC), UNIJUI, Ijuí, Rio Grande do Sul, Brazil
| | - Mauricio Krause
- Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX), Department of Physiology, ICBS, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil
| | - Paulo Ivo Homem de Bittencourt
- Laboratory of Cellular Physiology (FisCel) Department of Physiology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
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6
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Storey JM, Storey KB. Chaperone proteins: universal roles in surviving environmental stress. Cell Stress Chaperones 2023; 28:455-466. [PMID: 36441380 PMCID: PMC10469148 DOI: 10.1007/s12192-022-01312-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/07/2022] [Accepted: 11/08/2022] [Indexed: 11/29/2022] Open
Abstract
Chaperone proteins have crucial roles to play in all animal species and are involved in mediating both the folding of newly synthesized peptides into their mature conformation, the refolding of misfolded proteins, and the trafficking of proteins between subcellular compartments. These highly conserved proteins have particularly important roles to play in dealing with disruptions of the proteome as a result of environmental stress since abiotic factors, including temperature, pressure, oxygen, water availability, and pollutants can readily disrupt the conformation and/or function of all types of proteins, e.g., enzymes, transporters, and structural proteins. The current review provides an update on recent advances in understanding the roles and responses of chaperones in aiding animals to deal with environmental stress, offering new information on chaperone action in supporting survival strategies including torpor, hibernation, anaerobiosis, estivation, and cold/freeze tolerance among both vertebrate and invertebrate species.
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Affiliation(s)
- Janet M Storey
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada
| | - Kenneth B Storey
- Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada.
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7
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Lao S, Xiong S, Fang Q, Ye G. Identification and functional analysis of αB-crystallins in Pteromalus puparum. Front Physiol 2023; 14:1214835. [PMID: 37520833 PMCID: PMC10382227 DOI: 10.3389/fphys.2023.1214835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 07/06/2023] [Indexed: 08/01/2023] Open
Abstract
Heat shock proteins, including αB-crystallins (CRYAB), are pivotal in cellular defense mechanisms and stress response. This study presents a comprehensive investigation of heat shock proteins (HSPs), with a specific focus on the CRYAB family, within the genome of Pteromalus puparum. The analysis encompasses the identification of these proteins, exploration of their phylogenetic relationships, examination of conserved domains, and evaluation of their response to high temperature conditions. A total of 46 HSPs were identified in the P. puparum genome, and the differential expression of mRNA at 35°C and 25°C drew attention to five genes belonging to the CRYAB family, namely, PpCRYAB-1 to PpCRYAB-5. The conservation level of CRYAB family genes across different species was observed to be relatively modest. Through genome-wide screening of 22 species representing six insect orders, a total of 235 CRYAB proteins were identified, with P. puparum harboring eight CRYAB proteins, indicative of a moderate abundance compared to other species. Intriguingly, evolutionary analysis highlighted PpCRYAB-4 with potentially intricate differentiation in comparison to other members of the CRYAB family. Furthermore, RNA interference (RNAi) results demonstrated significant regulatory effects on adult lifespan under heat stress at 35°C for PpCRYAB-4 and PpCRYAB-5. These findings lay a groundwork for future investigations into stress resistance mechanisms in parasitic wasps, providing fresh insights for the study of insect resilience amidst the backdrop of global climate change.
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Estébanez B, Amaro-Gahete FJ, Gil-González C, González-Gallego J, Cuevas MJ, Jiménez-Pavón D. Influence of 12-Week Concurrent Training on Exosome Cargo and Its Relationship with Cardiometabolic Health Parameters in Men with Obesity. Nutrients 2023; 15:3069. [PMID: 37447395 DOI: 10.3390/nu15133069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/04/2023] [Accepted: 07/05/2023] [Indexed: 07/15/2023] Open
Abstract
Exosome release varies depending on the physiological state of the cell, so they could play a fundamental role in obesity, the biggest pandemic in today's societies. The beneficial effects that physical activity has both on weight and cardiovascular parameters may be mediated by exosomes released in response to exercise. Thus, we aimed (I) to study the influence of a 12-week CT intervention on exosome cargo modifications in men with obesity and (II) to determine whether changes in exosomes after the intervention were related to changes in cardiometabolic health parameters in our cohorts. An experimental, controlled design was performed in twelve (nine with valid data) adult male obese patients (mean values: 41.6 years old, 97.6 kg and 32.4 kg/m2) who were randomly divided into a control group (n = 4) and a training group (n = 5), which completed 36 sessions of CT (concurrent training) for 12 weeks. Before and after the training period, cardiometabolic health parameters were evaluated and blood samples to measure exosomes and proteins were drawn. No changes were observed in the levels of any exosomal markers and proteins; however, associations of changes between CD81 and both fat mass and weight, Flot-1 and VO2max, HSP70 and both CRP and left ventricle diastolic diameter or CD14 and leptin were found (all p ≤ 0.05). Although the current CT was not able to clearly modify the exosome cargo, a certain medium to large clinical effect was manifested considering the nature of this study. Moreover, the associations found between the promoted changes in cardiometabolic parameters and exosome-carried proteins could indicate a relationship to be considered for future treatments in patients with obesity.
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Affiliation(s)
- Brisamar Estébanez
- Institute of Biomedicine (IBIOMED), University of León, 24071 León, Spain
| | - Francisco J Amaro-Gahete
- Department of Physical Education and Sports, Faculty of Sports Science, Sport and Health University Research Institute (iMUDS), 18016 Granada, Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Instituto de Investigación Biosanitaria, ibs.Granada, 18012 Granada, Spain
| | - Cristina Gil-González
- MOVE-IT Research Group, Department of Physical Education, Faculty of Education Sciences, University of Cadiz, 11519 Cádiz, Spain
- Biomedical Research and Innovation Institute of Cádiz (INiBICA), 11519 Cádiz, Spain
| | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), University of León, 24071 León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
| | - María J Cuevas
- Institute of Biomedicine (IBIOMED), University of León, 24071 León, Spain
| | - David Jiménez-Pavón
- MOVE-IT Research Group, Department of Physical Education, Faculty of Education Sciences, University of Cadiz, 11519 Cádiz, Spain
- Biomedical Research and Innovation Institute of Cádiz (INiBICA), 11519 Cádiz, Spain
- CIBER of Frailty and Healthy Aging (CIBERFES), 28029 Madrid, Spain
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Esfahanian N, Knoblich CD, Bowman GA, Rezvani K. Mortalin: Protein partners, biological impacts, pathological roles, and therapeutic opportunities. Front Cell Dev Biol 2023; 11:1028519. [PMID: 36819105 PMCID: PMC9932541 DOI: 10.3389/fcell.2023.1028519] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 01/23/2023] [Indexed: 02/05/2023] Open
Abstract
Mortalin (GRP75, HSPA9A), a heat shock protein (HSP), regulates a wide range of cellular processes, including cell survival, growth, and metabolism. The regulatory functions of mortalin are mediated through a diverse set of protein partners associated with different cellular compartments, which allows mortalin to perform critical functions under physiological conditions, including mitochondrial protein quality control. However, alteration of mortalin's activities, its abnormal subcellular compartmentalization, and its protein partners turn mortalin into a disease-driving protein in different pathological conditions, including cancers. Here, mortalin's contributions to tumorigenic pathways are explained. Pathology information based on mortalin's RNA expression extracted from The Cancer Genome Atlas (TCGA) transcriptomic database indicates that mortalin has an independent prognostic value in common tumors, including lung, breast, and colorectal cancer (CRC). Subsequently, the binding partners of mortalin reported in different cellular models, from yeast to mammalian cells, and its regulation by post-translational modifications are discussed. Finally, we focus on colorectal cancer and discuss how mortalin and its tumorigenic downstream protein targets are regulated by a ubiquitin-like protein through the 26S proteasomal degradation machinery. A broader understanding of the function of mortalin and its positive and negative regulation in the formation and progression of human diseases, particularly cancer, is essential for developing new strategies to treat a diverse set of human diseases critically associated with dysregulated mortalin.
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Abioja M, Logunleko M, Majekodunmi B, Adekunle E, Shittu O, Odeyemi A, Nwosu E, Oke O, Iyasere O, Abiona J, Williams T, James I, Smith O, Daramola J. Roles of Candidate Genes in the Adaptation of Goats to Heat Stress: A Review. Small Rumin Res 2022. [DOI: 10.1016/j.smallrumres.2022.106878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Tustumi F, Agareno GA, Galletti RP, da Silva RBR, Quintas JG, Sesconetto LDA, Szor DJ, Wolosker N. The Role of the Heat-Shock Proteins in Esophagogastric Cancer. Cells 2022; 11:2664. [PMID: 36078072 PMCID: PMC9454628 DOI: 10.3390/cells11172664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 08/24/2022] [Accepted: 08/25/2022] [Indexed: 01/05/2023] Open
Abstract
Heat-shock proteins (HSPs) are a family of proteins that have received considerable attention over the last several years. They have been classified into six prominent families: high-molecular-mass HSP, 90, 70, 60, 40, and small heat shock proteins. HSPs participate in protein folding, stability, and maturation of several proteins during stress, such as in heat, oxidative stress, fever, and inflammation. Due to the immunogenic host's role in the combat against cancer cells and the role of the inflammation in the cancer control or progression, abnormal expression of these proteins has been associated with many types of cancer, including esophagogastric cancer. This study aims to review all the evidence concerning the role of HSPs in the pathogenesis and prognosis of esophagogastric cancer and their potential role in future treatment options. This narrative review gathers scientific evidence concerning HSPs in relation to esophagus and gastric cancer. All esophagogastric cancer subtypes are included. The role of HSPs in carcinogenesis, prognostication, and therapy for esophagogastric cancer are discussed. The main topics covered are premalignant conditions for gastric cancer atrophic gastritis, Barrett esophagus, and some viral infections such as human papillomavirus (HPV) and Epstein-Barr virus (EBV). HSPs represent new perspectives on the development, prognostication, and treatment of esophagogastric cancer.
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Affiliation(s)
- Francisco Tustumi
- Department of Gastroenterology, Universidade de São Paulo, Av. Dr. Enéas Carvalho de Aguiar, 255, São Paulo 05403-000, SP, Brazil
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Gabriel Andrade Agareno
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Ricardo Purchio Galletti
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Rafael Benjamim Rosa da Silva
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Julia Grams Quintas
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Lucas de Abreu Sesconetto
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Daniel José Szor
- Department of Gastroenterology, Universidade de São Paulo, Av. Dr. Enéas Carvalho de Aguiar, 255, São Paulo 05403-000, SP, Brazil
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Nelson Wolosker
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
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Maiti S, Picard D. Cytosolic Hsp90 Isoform-Specific Functions and Clinical Significance. Biomolecules 2022; 12:1166. [PMID: 36139005 PMCID: PMC9496497 DOI: 10.3390/biom12091166] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 11/17/2022] Open
Abstract
The heat shock protein 90 (Hsp90) is a molecular chaperone and a key regulator of proteostasis under both physiological and stress conditions. In mammals, there are two cytosolic Hsp90 isoforms: Hsp90α and Hsp90β. These two isoforms are 85% identical and encoded by two different genes. Hsp90β is constitutively expressed and essential for early mouse development, while Hsp90α is stress-inducible and not necessary for survivability. These two isoforms are known to have largely overlapping functions and to interact with a large fraction of the proteome. To what extent there are isoform-specific functions at the protein level has only relatively recently begun to emerge. There are studies indicating that one isoform is more involved in the functionality of a specific tissue or cell type. Moreover, in many diseases, functionally altered cells appear to be more dependent on one particular isoform. This leaves space for designing therapeutic strategies in an isoform-specific way, which may overcome the unfavorable outcome of pan-Hsp90 inhibition encountered in previous clinical trials. For this to succeed, isoform-specific functions must be understood in more detail. In this review, we summarize the available information on isoform-specific functions of mammalian Hsp90 and connect it to possible clinical applications.
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Affiliation(s)
| | - Didier Picard
- Département de Biologie Moléculaire et Cellulaire, Université de Genève, Sciences III, Quai Ernest-Ansermet 30, CH-1211 Geneve, Switzerland
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Costa-Beber LC, Hirsch GE, Heck TG, Ludwig MS. Chaperone duality: the role of extracellular and intracellular HSP70 as a biomarker of endothelial dysfunction in the development of atherosclerosis. Arch Physiol Biochem 2022; 128:1016-1023. [PMID: 32293198 DOI: 10.1080/13813455.2020.1745850] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The 70-kDa heat shock proteins (HSP70) may provide relevant information about the endothelial dysfunction in cardiovascular diseases. Located in the intracellular milieu (iHSP70), they are essential chaperones that inhibit nuclear factor kappa B activation, stimulate nitric oxide production and superoxide dismutase activity, and inhibit apoptosis. However, under stressful conditions, HSP70 can be released into the extracellular medium (eHSP70) and act as an inflammatory mediator. Although studies have reported the vasoprotective role of iHSP70, the evidence regarding eHSP70 is contradictory. eHSP70 can activate NFκB and activator protein-1, thus stimulating the release of inflammatory cytokines and production of reactive oxygen species. Due to the antagonistic nature of HSP70 according to its location, the eHSP70/iHSP70 ratio (Heck index) has been proposed as a better marker of inflammatory status; however, more studies are required to confirm this hypothesis. Therefore, this review summarises studies that, together, describe the role of HSP70 in endothelial dysfunction.
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Affiliation(s)
- Lílian Corrêa Costa-Beber
- Research Group in Physiology, Postgraduate Program in Integral Attention to Health, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUI), Ijuí, Brazil
| | - Gabriela Elisa Hirsch
- Research Group in Physiology, Postgraduate Program in Integral Attention to Health, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUI), Ijuí, Brazil
| | - Thiago Gomes Heck
- Research Group in Physiology, Postgraduate Program in Integral Attention to Health, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUI), Ijuí, Brazil
| | - Mirna Stela Ludwig
- Research Group in Physiology, Postgraduate Program in Integral Attention to Health, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUI), Ijuí, Brazil
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Yong Y, Li J, Yu T, Fang B, Liu X, Yu Z, Ma X, Gooneratne R, El-Atye AA, Ju X. Overexpression of heat shock protein 70 induces apoptosis of intestinal epithelial cells in heat-stressed pigs: A proteomics approach. J Therm Biol 2022; 108:103289. [DOI: 10.1016/j.jtherbio.2022.103289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 06/11/2022] [Indexed: 12/28/2022]
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15
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Hsp90 in Human Diseases: Molecular Mechanisms to Therapeutic Approaches. Cells 2022; 11:cells11060976. [PMID: 35326427 PMCID: PMC8946885 DOI: 10.3390/cells11060976] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 02/04/2023] Open
Abstract
The maturation of hemeprotein dictates that they incorporate heme and become active, but knowledge of this essential cellular process remains incomplete. Studies on chaperon Hsp90 has revealed that it drives functional heme maturation of inducible nitric oxide synthase (iNOS), soluble guanylate cyclase (sGC) hemoglobin (Hb) and myoglobin (Mb) along with other proteins including GAPDH, while globin heme maturations also need an active sGC. In all these cases, Hsp90 interacts with the heme-free or apo-protein and then drives the heme maturation by an ATP dependent process before dissociating from the heme-replete proteins, suggesting that it is a key player in such heme-insertion processes. As the studies on globin maturation also need an active sGC, it connects the globin maturation to the NO-sGC (Nitric oxide-sGC) signal pathway, thereby constituting a novel NO-sGC-Globin axis. Since many aggressive cancer cells make Hbβ/Mb to survive, the dependence of the globin maturation of cancer cells places the NO-sGC signal pathway in a new light for therapeutic intervention. Given the ATPase function of Hsp90 in heme-maturation of client hemeproteins, Hsp90 inhibitors often cause serious side effects and this can encourage the alternate use of sGC activators/stimulators in combination with specific Hsp90 inhibitors for better therapeutic intervention.
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Beretta G, Shala AL. Impact of Heat Shock Proteins in Neurodegeneration: Possible Therapeutical Targets. Ann Neurosci 2022; 29:71-82. [PMID: 35875428 PMCID: PMC9305912 DOI: 10.1177/09727531211070528] [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: 07/29/2021] [Accepted: 10/24/2021] [Indexed: 01/20/2023] Open
Abstract
Human neurodegenerative diseases occur as a result of various factors. Regardless of the variety in the etiology of development, many of these diseases are characterized by the accumulation of pathological, misfolded proteins; hence, such diseases are considered as proteinopathies. While plenty of research study has been conducted in order to identify the pathophysiology of these proteinopathies, there is still a lack of understanding in terms of potential therapeutic targets. Molecular chaperones present the main workforce for cellular protection and stress response. Therefore, considering these functions, molecular chaperones present a promising target for research within the field of conformational diseases that arise from proteinopathies. Since the association between neurodegenerative disorders and their long-term consequences is well documented, the need for the development of new therapeutic strategies becomes even more critical. In this review, we summarized the molecular function of heat shock proteins and recent progress on their role, involvement, and other mechanisms related to neurodegeneration caused by different etiological factors. Based on the relevant scientific data, we will highlight the functional classification of heat shock proteins, regulatin, and their therapeutic potential for neurodegenerative disorders.
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Affiliation(s)
- Giangiacomo Beretta
- Department of Environmental Science and Policy, University of Milan, Milan, Italy
| | - Aida Loshaj Shala
- Department of Pharmacy, Faculty of Medicine, University Hasan Prishtina, Pristina, Kosovo
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Cantet JM, Yu Z, Ríus AG. Heat Stress-Mediated Activation of Immune-Inflammatory Pathways. Antibiotics (Basel) 2021; 10:antibiotics10111285. [PMID: 34827223 PMCID: PMC8615052 DOI: 10.3390/antibiotics10111285] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/09/2021] [Accepted: 10/12/2021] [Indexed: 12/23/2022] Open
Abstract
Physiological changes in animals exposed to elevated ambient temperature are characterized by the redistribution of blood toward the periphery to dissipate heat, with a consequent decline in blood flow and oxygen and nutrient supply to splanchnic tissues. Metabolic adaptations and gut dysfunction lead to oxidative stress, translocation of lumen contents, and release of proinflammatory mediators, activating a systemic inflammatory response. This review discusses the activation and development of the inflammatory response in heat-stressed models.
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De Maio A, Hightower L. The interaction of heat shock proteins with cellular membranes: a historical perspective. Cell Stress Chaperones 2021; 26:769-783. [PMID: 34478113 PMCID: PMC8413713 DOI: 10.1007/s12192-021-01228-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 01/09/2023] Open
Abstract
The interaction of heat shock proteins (HSP) with cellular membranes has been an enigmatic process, initially observed by morphological studies, inferred during the purification of HSP70s, and confirmed after the detection of these proteins on the surface of cancer cells and their insertion into artificial lipid bilayers. Today, the association of several HSP with lipid membranes is well established. However, the mechanisms for membrane insertion have been elusive. There is conclusive evidence indicating that HSP70s have a great selectivity for negatively charged phospholipids, whereas other HSP have a broader spectrum of lipid specificity. HSP70 also oligomerizes upon membrane insertion, forming ion conductance channels. The functional role of HSP70 lipid interactions appears related to membrane stabilization that may play a role during cell membrane biogenesis. They could also play a role as membrane chaperones as well as during endocytosis, microautophagy, and signal transduction. Moreover, HSP membrane association is a key component in the extracellular export of these proteins. The presence of HSP70 on the surface of cancer cells and its interaction with lysosome membranes have been envisioned as potential therapeutic targets. Thus, the biology and function of HSP membrane association are reaching a new level of excitement. This review is an attempt to preserve the recollection of the pioneering contributions of many investigators that have participated in this endeavor.
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Affiliation(s)
- Antonio De Maio
- Department of Surgery, Division of Trauma, Critical Care, Burns, and Acute Care Surgery, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
- Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
- Center for Investigations of Health and Education Disparities, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
| | - Lawrence Hightower
- Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, 06269, USA
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19
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Prahlad V. The discovery and consequences of the central role of the nervous system in the control of protein homeostasis. J Neurogenet 2020; 34:489-499. [PMID: 32527175 PMCID: PMC7736053 DOI: 10.1080/01677063.2020.1771333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 05/14/2020] [Indexed: 12/30/2022]
Abstract
Organisms function despite wide fluctuations in their environment through the maintenance of homeostasis. At the cellular level, the maintenance of proteins as functional entities at target expression levels is called protein homeostasis (or proteostasis). Cells implement proteostasis through universal and conserved quality control mechanisms that surveil and monitor protein conformation. Recent studies that exploit the powerful ability to genetically manipulate specific neurons in C. elegans have shown that cells within this metazoan lose their autonomy over this fundamental survival mechanism. These studies have uncovered novel roles for the nervous system in controlling how and when cells activate their protein quality control mechanisms. Here we discuss the conceptual underpinnings, experimental evidence and the possible consequences of such a control mechanism. PRELUDE: Whether the detailed examination of parts of the nervous system and their selective perturbation is sufficient to reconstruct how the brain generates behavior, mental disease, music and religion remains an open question. Yet, Sydney Brenner's development of C. elegans as an experimental organism and his faith in the bold reductionist approach that 'the understanding of wild-type behavior comes best after the discovery and analysis of mutations that alter it', has led to discoveries of unexpected roles for neurons in the biology of organisms.
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Affiliation(s)
- Veena Prahlad
- Department of Biology, Aging Mind and Brain Initiative, University of Iowa, Iowa City, IA, USA
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
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20
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Camacho Benítez A, Vasconcellos R, Lombide P, Viotti H, Pérez W, Cazales N, Cavestany D, Martin GB, Pedrana G. Heat shock protein HSP90 immunoexpression in equine endometrium during oestrus, dioestrus and anoestrus. Anat Histol Embryol 2020; 50:50-57. [PMID: 32776605 DOI: 10.1111/ahe.12598] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 06/30/2020] [Accepted: 07/08/2020] [Indexed: 11/30/2022]
Abstract
Heat shock proteins play a crucial role in cellular development, proliferation, differentiation and apoptosis. Heat shock protein 90 (HSP90) has been localised in the human endometrium, where its immunoexpression changes during the menstrual cycle. Similar studies have not been done for the equid species, so the present study aimed to describe endometrial HSP90 immunoexpression in mare endometrium. Endometrial biopsies were formalin-fixed and paraffin-embedded, and sections were stained with haematoxylin-eosin in preparation for HSP90 immunohistochemistry. Immunostaining and morphometric analyses were performed on the epithelial lining, endometrial glands and connective stroma during oestrus, dioestrus phase and anoestrus period (n = 7 per phase or period). Immunoexpression was localised in the basal region of the epithelial cells lining the lumen. Immunoexpression was greater during oestrus than during either dioestrus or anoestrus. During anoestrus, there was little immunostaining in the endometrium, suggesting that HSP90 is involved in the functional modulation of sex steroid receptors in cyclic mares. Indeed, the function of HSP90 as a chaperone in the folding of proteins, such as steroid receptors, might explain the greater intensity of immunostaining during the oestrus and dioestrus phases, compared the anoestrus period. We conclude that, in the mare, HSP90 plays a role in endometrial function and that further studies are needed to test whether it is important in pathological conditions as endometritis.
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Affiliation(s)
- Ana Camacho Benítez
- Histología y Embriología, Biociencias, Facultad de Veterinaria, Universidad de la República, Montevideo, Uruguay
| | - Rossana Vasconcellos
- Histología y Embriología, Biociencias, Facultad de Veterinaria, Universidad de la República, Montevideo, Uruguay
| | - Paula Lombide
- Histología y Embriología, Biociencias, Facultad de Veterinaria, Universidad de la República, Montevideo, Uruguay
| | - Helen Viotti
- Histología y Embriología, Biociencias, Facultad de Veterinaria, Universidad de la República, Montevideo, Uruguay
| | - William Pérez
- Anatomía, Biociencias, Facultad de Veterinaria, Universidad de la República, Montevideo, Uruguay
| | - Nicolás Cazales
- Centro de Posgrados, Facultad de Veterinaria, Universidad de la República, Montevideo, Uruguay
| | - Daniel Cavestany
- Centro de Posgrados, Facultad de Veterinaria, Universidad de la República, Montevideo, Uruguay
| | - Graeme B Martin
- School of Agriculture and Environment, University of Western Australia, Crawley, WA, Australia.,Faculty of Science, UWA School of Agriculture and Environment, University of Western Australia, Perth, Australia
| | - Graciela Pedrana
- Histología y Embriología, Biociencias, Facultad de Veterinaria, Universidad de la República, Montevideo, Uruguay
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21
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Advances in DNA Repair-Emerging Players in the Arena of Eukaryotic DNA Repair. Int J Mol Sci 2020; 21:ijms21113934. [PMID: 32486270 PMCID: PMC7313471 DOI: 10.3390/ijms21113934] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 05/27/2020] [Accepted: 05/29/2020] [Indexed: 12/17/2022] Open
Abstract
Genomic DNA is constantly damaged by factors produced during natural metabolic processes as well as agents coming from the external environment. Considering such a wide array of damaging agents, eukaryotic cells have evolved a DNA damage response (DRR) that opposes the influence of deleterious factors. Despite the broad knowledge regarding DNA damage and repair, new areas of research are emerging. New players in the field of DDR are constantly being discovered. The aim of this study is to review current knowledge regarding the roles of sirtuins, heat shock proteins, long-noncoding RNAs and the circadian clock in DDR and distinguish new agents that may have a prominent role in DNA damage response and repair.
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22
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Genetically Modified Heat Shock Protein90s and Polyamine Oxidases in Arabidopsis Reveal Their Interaction under Heat Stress Affecting Polyamine Acetylation, Oxidation and Homeostasis of Reactive Oxygen Species. PLANTS 2019; 8:plants8090323. [PMID: 31484414 PMCID: PMC6783977 DOI: 10.3390/plants8090323] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 08/09/2019] [Accepted: 08/12/2019] [Indexed: 11/24/2022]
Abstract
One Sentence Summary Heat shock proteins90 (HSP90s) induce acetylation of polyamines (PAs) and interact with polyamine oxidases (PAOs) affecting oxidation of PAs and hydrogen peroxide (H2O2) homeostasis in Arabidopsis thaliana. Abstract The chaperones, heat shock proteins (HSPs), stabilize proteins to minimize proteotoxic stress, especially during heat stress (HS) and polyamine (PA) oxidases (PAOs) participate in the modulation of the cellular homeostasis of PAs and reactive oxygen species (ROS). An interesting interaction of HSP90s and PAOs was revealed in Arabidopsis thaliana by using the pLFY:HSP90RNAi line against the four AtHSP90 genes encoding cytosolic proteins, the T-DNA Athsp90-1 and Athsp90-4 insertional mutants, the Atpao3 mutant and pharmacological inhibitors of HSP90s and PAOs. Silencing of all cytosolic HSP90 genes resulted in several-fold higher levels of soluble spermidine (S-Spd), acetylated Spd (N8-acetyl-Spd) and acetylated spermine (N1-acetyl-Spm) in the transgenic Arabidopsis thaliana leaves. Heat shock induced increase of soluble-PAs (S-PAs) and soluble hydrolyzed-PAs (SH-PAs), especially of SH-Spm, and more importantly of acetylated Spd and Spm. The silencing of HSP90 genes or pharmacological inhibition of the HSP90 proteins by the specific inhibitor radicicol, under HS stimulatory conditions, resulted in a further increase of PA titers, N8-acetyl-Spd and N1-acetyl-Spm, and also stimulated the expression of PAO genes. The increased PA titers and PAO enzymatic activity resulted in a profound increase of PAO-derived hydrogen peroxide (H2O2) levels, which was terminated by the addition of the PAO-specific inhibitor guazatine. Interestingly, the loss-of-function Atpao3 mutant exhibited increased mRNA levels of selected AtHSP90 genes. Taken together, the results herein reveal a novel function of HSP90 and suggest that HSP90s and PAOs cross-talk to orchestrate PA acetylation, oxidation, and PA/H2O2 homeostasis.
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Lyon MS, Milligan C. Extracellular heat shock proteins in neurodegenerative diseases: New perspectives. Neurosci Lett 2019; 711:134462. [PMID: 31476356 DOI: 10.1016/j.neulet.2019.134462] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 08/23/2019] [Accepted: 08/24/2019] [Indexed: 01/20/2023]
Abstract
One pathological hallmark of neurodegenerative diseases and CNS trauma is accumulation of insoluble, hydrophobic molecules and protein aggregations found both within and outside cells. These may be the consequences of an inadequate or overburdened cellular response to stresses resulting from potentially toxic changes in extra- and intracellular environments. The upregulated expression of heat shock proteins (HSPs) is one example of a highly conserved cellular response to both internal and external stress. Intracellularly these proteins act as chaperones, playing vital roles in the folding of nascent polypeptides, the translocation of proteins between subcellular locations, and the disaggregation of misfolded or aggregated proteins in an attempt to maintain cellular proteostasis during both homeostatic and stressful conditions. While the predominant study of the HSPs has focused on their intracellular chaperone functions, it remains unclear if all neuronal populations can mount a complete stress response. Alternately, it is now well established that some members of this family of proteins can be secreted by nearby, non-neuronal cells to act in the extracellular environment. This review addresses the current literature detailing the use of exogenous and extracellular HSPs in the treatment of cellular and animal models of neurodegenerative disease. These findings offer a new measure of therapeutic potential to the HSPs, but obstacles must be overcome before they can be efficiently used in a clinical setting.
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Affiliation(s)
- Miles S Lyon
- Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States
| | - Carol Milligan
- Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.
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24
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Singh S, Tapadia MG. Molecular basis for efficacy of Guduchi and Madhuyashti feeding on different environmental stressors in Drosophila. Cell Stress Chaperones 2019; 24:549-565. [PMID: 30919212 PMCID: PMC6527653 DOI: 10.1007/s12192-019-00986-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 02/27/2019] [Accepted: 03/04/2019] [Indexed: 10/27/2022] Open
Abstract
Stressors of different kinds adversely affect life history parameters like growth, development, and reproduction. Organisms overcome the negative impact of environmental stressors and strive to reach a tolerant state through genetic and metabolic activities. Ayurvedic formulations are reported to have life trait benefitting properties which improve capacity to withstand stress and tolerate adverse conditions. Guduchi (Tinospora cordifolia) and Madhuyashti (Glycirrhiza glabra) Ayurvedic formulations are known to have immunomodulatory, intellect promoting, and adaptogenic properties, thus favoring good health and healthy aging. Present study investigates the efficacy of Guduchi and Madhuyashti in providing tolerance to different stresses and the underlying mechanisms using the Drosophila model. Drosophila larvae/flies fed on Guduchi or Madhuyashti were better thermo-protected, which correlated with increased expression of heat shock genes even without the heat shock. Guduchi or Madhuyashti feeding also increased antimicrobial peptide expression, thus providing better tolerance to pathogenic assaults. Feeding on Guduchi- or Madhuyashti- supplemented food also enhanced starvation and desiccation tolerance. However, neither of these formulations provided beneficial effects when grown under crowded conditions or when exposed to oxidative stressors.
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Affiliation(s)
- Surabhi Singh
- Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh India
| | - Madhu G. Tapadia
- Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh India
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Araujo TLS, Venturini G, Moretti AIS, Tanaka LY, Pereira AC, Laurindo FRM. Cell-surface HSP70 associates with thrombomodulin in endothelial cells. Cell Stress Chaperones 2019; 24:273-282. [PMID: 30645756 PMCID: PMC6363626 DOI: 10.1007/s12192-018-00964-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 04/26/2018] [Accepted: 12/14/2018] [Indexed: 10/27/2022] Open
Abstract
Heat shock protein-70 (HSP70) is crucial for proteostasis and displays cell-protective effects. Meanwhile, enhanced levels of cell-surface (cs) and secreted HSP70 paradoxically associate with pathologic cardiovascular conditions. However, mechanisms regulating csHSP70 pool are unknown. We hypothesized that total and csHSP70 expressions are modulated by hemodynamic forces, major contributors to endothelial pathophysiology. We also investigated whether thrombomodulin, a crucial thromboresistance cell-surface protein, is a csHSP70 target. We used proteomic/western analysis, confocal microscopy, and cs-biotinylation to analyze the pattern and specific characteristics of intracellular and csHSP70. HSP70 interaction with thrombomodulin was investigated by confocal colocalization, en face immunofluorescence, proximity assay, and immunoprecipitation. Thrombomodulin activity was assessed by measured protein C activation two-step assay. Our results show that csHSP70 pool in endothelial cells (EC) exhibits a peculiar cluster-like pattern and undergoes enhanced expression by physiological arterial-level laminar shear stress. Conversely, total and csHSP70 expressions were diminished under low shear stress, a known proatherogenic hemodynamic pattern. Furthermore, total HSP70 levels were decreased in aortic arch (associated with proatherogenic turbulent flow) compared with thoracic aorta (associated with atheroprotective laminar flow). Importantly, csHSP70 co-localized with thrombomodulin in cultured EC and aorta endothelium; proximity ligation assays and immunoprecipitation confirmed their physical interaction in EC. Remarkably, immunoneutralization of csHSP70 enhanced thrombomodulin activity in EC and aorta ex vivo. Overall, proatherogenic hemodynamic forces promote reduced total HSP70 expression, which might implicate in disturbed proteostasis; meanwhile, the associated decrease in cs-HSP70 pool associates with thromboresistance signaling. Cell-surface HSP70 (csHSP70) expression regulation and csHSP70 targets in vascular cells are unknown. We showed that HSP70 levels are shear stress-modulated and decreased under proatherogenic conditions. Remarkably, csHSP70 binds thrombomodulin and inhibits its activity in endothelial cells. This mechanism can potentially explain some deleterious effects previously associated with high extracellular HSP70 levels, as csHSP70 potentially could restrict thromboresistance and support thrombosis/inflammation in stress situations.
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Affiliation(s)
- Thaís L S Araujo
- Vascular Biology Laboratory, Heart Institute (InCor), University of São Paulo School of Medicine, Av. Enéas Carvalho Aguiar, 44, Annex II, 9th Floor, São Paulo, Brazil.
| | - Gabriela Venturini
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil
| | - Ana I S Moretti
- Vascular Biology Laboratory, Heart Institute (InCor), University of São Paulo School of Medicine, Av. Enéas Carvalho Aguiar, 44, Annex II, 9th Floor, São Paulo, Brazil
| | - Leonardo Y Tanaka
- Vascular Biology Laboratory, Heart Institute (InCor), University of São Paulo School of Medicine, Av. Enéas Carvalho Aguiar, 44, Annex II, 9th Floor, São Paulo, Brazil
| | - Alexandre Costa Pereira
- Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil
| | - Francisco R M Laurindo
- Vascular Biology Laboratory, Heart Institute (InCor), University of São Paulo School of Medicine, Av. Enéas Carvalho Aguiar, 44, Annex II, 9th Floor, São Paulo, Brazil
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Mazaira GI, Zgajnar NR, Lotufo CM, Daneri-Becerra C, Sivils JC, Soto OB, Cox MB, Galigniana MD. The Nuclear Receptor Field: A Historical Overview and Future Challenges. NUCLEAR RECEPTOR RESEARCH 2018; 5:101320. [PMID: 30148160 PMCID: PMC6108593 DOI: 10.11131/2018/101320] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
In this article we summarize the birth of the field of nuclear receptors, the discovery of untransformed and transformed isoforms of ligand-binding macromolecules, the discovery of the three-domain structure of the receptors, and the properties of the Hsp90-based heterocomplex responsible for the overall structure of the oligomeric receptor and many aspects of the biological effects. The discovery and properties of the subfamily of receptors called orphan receptors is also outlined. Novel molecular aspects of the mechanism of action of nuclear receptors and challenges to resolve in the near future are discussed.
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Affiliation(s)
- Gisela I. Mazaira
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (1428), Argentina
| | - Nadia R. Zgajnar
- Instituto de Biología y Medicina Experimental- CONICET. Buenos Aires (1428), Argentina
| | - Cecilia M. Lotufo
- Instituto de Biología y Medicina Experimental- CONICET. Buenos Aires (1428), Argentina
| | | | - Jeffrey C. Sivils
- Department of Biological Sciences and Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Olga B. Soto
- Department of Biological Sciences and Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Marc B. Cox
- Department of Biological Sciences and Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Mario D. Galigniana
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (1428), Argentina
- Instituto de Biología y Medicina Experimental- CONICET. Buenos Aires (1428), Argentina
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Martinez-Rossi NM, Bitencourt TA, Peres NTA, Lang EAS, Gomes EV, Quaresemin NR, Martins MP, Lopes L, Rossi A. Dermatophyte Resistance to Antifungal Drugs: Mechanisms and Prospectus. Front Microbiol 2018; 9:1108. [PMID: 29896175 PMCID: PMC5986900 DOI: 10.3389/fmicb.2018.01108] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 05/09/2018] [Indexed: 12/24/2022] Open
Abstract
Dermatophytes comprise pathogenic fungi that have a high affinity for the keratinized structures present in nails, skin, and hair, causing superficial infections known as dermatophytosis. A reasonable number of antifungal drugs currently exist on the pharmaceutical market to control mycoses; however, their cellular targets are restricted, and fungi may exhibit tolerance or resistance to these agents. For example, the stress caused by antifungal and cytotoxic drugs in sub-inhibitory concentrations promotes compensatory stress responses, with the over-expression of genes involved in cellular detoxification, drug efflux, and signaling pathways being among the various mechanisms that may contribute to drug tolerance. In addition, the ATP-binding cassette transporters in dermatophytes that are responsible for cellular efflux can act synergistically, allowing one to compensate for the absence of the other, revealing the complexity of drug tolerance phenomena. Moreover, mutations in genes coding for target enzymes could lead to substitutions in amino acids involved in the binding of antifungal agents, hindering their performance and leading to treatment failure. The relevance of each one of these mechanisms of resistance to fungal survival is hard to define, mainly because they can act simultaneously in the cell. However, an understanding of the molecular mechanisms involved in the resistance/tolerance processes, the identification of new antifungal targets, as well as the prospective of new antifungal compounds among natural or synthetic products, are expected to bring advances and new insights that facilitate the improvement or development of novel strategies for antifungal therapy.
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Affiliation(s)
- Nilce M Martinez-Rossi
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Tamires A Bitencourt
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Nalu T A Peres
- Department of Morphology, Federal University of Sergipe, Aracaju, Brazil
| | - Elza A S Lang
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Eriston V Gomes
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Natalia R Quaresemin
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Maíra P Martins
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Lucia Lopes
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Antonio Rossi
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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Moura CS, Lollo PCB, Morato PN, Amaya-Farfan J. Dietary Nutrients and Bioactive Substances Modulate Heat Shock Protein (HSP) Expression: A Review. Nutrients 2018; 10:nu10060683. [PMID: 29843396 PMCID: PMC6024325 DOI: 10.3390/nu10060683] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 05/21/2018] [Accepted: 05/23/2018] [Indexed: 01/06/2023] Open
Abstract
Interest in the heat shock proteins (HSPs), as a natural physiological toolkit of living organisms, has ranged from their chaperone function in nascent proteins to the remedial role following cell stress. As part of the defence system, HSPs guarantee cell tolerance against a variety of stressors, including exercise, oxidative stress, hyper and hypothermia, hyper and hypoxia and improper diets. For the past couple of decades, research on functional foods has revealed a number of substances likely to trigger cell protection through mechanisms that involve the induction of HSP expression. This review will summarize the occurrence of the most easily inducible HSPs and describe the effects of dietary proteins, peptides, amino acids, probiotics, high-fat diets and other food-derived substances reported to induce HSP response in animals and humans studies. Future research may clarify the mechanisms and explore the usefulness of this natural alternative of defense and the modulating mechanism of each substance.
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Affiliation(s)
- Carolina Soares Moura
- Protein Resources Laboratory, Food and Nutrition Department, Faculty of Food Engineering, University of Campinas (UNICAMP), Campinas 13083-862 São Paulo, Brazil.
| | | | - Priscila Neder Morato
- School of Health Sciences, Federal University of Grande Dourados, Dourados 79825-070, Mato Grosso do Sul, Brazil.
| | - Jaime Amaya-Farfan
- Protein Resources Laboratory, Food and Nutrition Department, Faculty of Food Engineering, University of Campinas (UNICAMP), Campinas 13083-862 São Paulo, Brazil.
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Ikwegbue PC, Masamba P, Oyinloye BE, Kappo AP. Roles of Heat Shock Proteins in Apoptosis, Oxidative Stress, Human Inflammatory Diseases, and Cancer. Pharmaceuticals (Basel) 2017; 11:E2. [PMID: 29295496 PMCID: PMC5874698 DOI: 10.3390/ph11010002] [Citation(s) in RCA: 186] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 11/14/2017] [Accepted: 11/17/2017] [Indexed: 12/12/2022] Open
Abstract
Heat shock proteins (HSPs) play cytoprotective activities under pathological conditions through the initiation of protein folding, repair, refolding of misfolded peptides, and possible degradation of irreparable proteins. Excessive apoptosis, resulting from increased reactive oxygen species (ROS) cellular levels and subsequent amplified inflammatory reactions, is well known in the pathogenesis and progression of several human inflammatory diseases (HIDs) and cancer. Under normal physiological conditions, ROS levels and inflammatory reactions are kept in check for the cellular benefits of fighting off infectious agents through antioxidant mechanisms; however, this balance can be disrupted under pathological conditions, thus leading to oxidative stress and massive cellular destruction. Therefore, it becomes apparent that the interplay between oxidant-apoptosis-inflammation is critical in the dysfunction of the antioxidant system and, most importantly, in the progression of HIDs. Hence, there is a need to maintain careful balance between the oxidant-antioxidant inflammatory status in the human body. HSPs are known to modulate the effects of inflammation cascades leading to the endogenous generation of ROS and intrinsic apoptosis through inhibition of pro-inflammatory factors, thereby playing crucial roles in the pathogenesis of HIDs and cancer. We propose that careful induction of HSPs in HIDs and cancer, especially prior to inflammation, will provide good therapeutics in the management and treatment of HIDs and cancer.
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Affiliation(s)
- Paul Chukwudi Ikwegbue
- Biotechnology and Structural Biochemistry (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa.
| | - Priscilla Masamba
- Biotechnology and Structural Biochemistry (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa.
| | - Babatunji Emmanuel Oyinloye
- Biotechnology and Structural Biochemistry (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa.
- Department of Biochemistry, Afe Babalola University, PMB 5454, Ado-Ekiti 360001, Nigeria.
| | - Abidemi Paul Kappo
- Biotechnology and Structural Biochemistry (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa.
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Temperature stress and insect immunity. J Therm Biol 2017; 68:96-103. [DOI: 10.1016/j.jtherbio.2016.12.002] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 12/01/2016] [Accepted: 12/05/2016] [Indexed: 11/18/2022]
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The Potential Functions of Small Heat Shock Proteins in the Uterine Musculature during Pregnancy. ADVANCES IN ANATOMY, EMBRYOLOGY, AND CELL BIOLOGY 2017; 222:95-116. [PMID: 28389752 DOI: 10.1007/978-3-319-51409-3_5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The small heat shock protein B (HSPB) family is comprised of eleven members with many being induced by physiological stressors. In addition to being molecular chaperones, it is clear these proteins also play important roles in cell death regulation, cytoskeletal rearrangements, and immune system activation. These processes are important for the uterine smooth muscle or myometrium during pregnancy as it changes from a quiescent tissue, during the majority of pregnancy, to a powerful and contractile tissue at labor. The initiation and progression of labor within the myometrium also appears to require an inflammatory response as it is infiltrated by immune cells and it produces pro-inflammatory mediators. This chapter summarizes current knowledge on the expression of HSPB family members in the myometrium during pregnancy and speculates on the possible roles of these proteins during myometrial programming and transformation of the myometrium into a possible immune regulatory tissue.
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Martinez-Rossi NM, Jacob TR, Sanches PR, Peres NTA, Lang EAS, Martins MP, Rossi A. Heat Shock Proteins in Dermatophytes: Current Advances and Perspectives. Curr Genomics 2016; 17:99-111. [PMID: 27226766 PMCID: PMC4864838 DOI: 10.2174/1389202917666151116212437] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Revised: 07/02/2015] [Accepted: 07/13/2015] [Indexed: 11/29/2022] Open
Abstract
Heat shock proteins (HSPs) are proteins whose transcription responds rapidly to temperature shifts. They constitute a family of molecular chaperones, involved in the proper folding and stabilisation of proteins under physiological and adverse conditions. HSPs also assist in the protection and recovery of cells exposed to a variety of stressful conditions, including heat. The role of HSPs extends beyond chaperoning proteins, as they also participate in diverse cellular functions, such as the assembly of macromolecular complexes, protein transport and sorting, dissociation of denatured protein aggregates, cell cycle control, and programmed cell death. They are also important antigens from a variety of pathogens, are able to stimulate innate immune cells, and are implicated in acquired immunity. In fungi, HSPs have been implicated in virulence, dimorphic transition, and drug resistance. Some HSPs are potential targets for therapeutic strategies. In this review, we discuss the current understanding of HSPs in dermatophytes, which are a group of keratinophilic fungi responsible for superficial mycoses in humans and animals. Computational analyses were performed to characterise the group of proteins in these dermatophytes, as well as to assess their conservation and to identify DNA-binding domains (5′-nGAAn-3′) in the promoter regions of the hsp genes. In addition, the quantification of the transcript levels of few genes in a pacC background helped in the development of an extended model for the regulation of the expression of the hsp genes, which supports the participation of the pH-responsive transcriptional regulator PacC in this process.
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Affiliation(s)
- Nilce M Martinez-Rossi
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Tiago R Jacob
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Pablo R Sanches
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Nalu T A Peres
- Present address: Department of Morphology, Federal University of Sergipe, SE, Brazil
| | - Elza A S Lang
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Maíra P Martins
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Antonio Rossi
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
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Jacob TR, Peres NTA, Martins MP, Lang EAS, Sanches PR, Rossi A, Martinez-Rossi NM. Heat Shock Protein 90 (Hsp90) as a Molecular Target for the Development of Novel Drugs Against the Dermatophyte Trichophyton rubrum. Front Microbiol 2015; 6:1241. [PMID: 26617583 PMCID: PMC4639609 DOI: 10.3389/fmicb.2015.01241] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 10/26/2015] [Indexed: 01/14/2023] Open
Abstract
Treatment of fungal infections is difficult due to several reasons, such as side effects of drugs, emergence of resistant strains, and limited number of molecular targets for the drug compounds. In fungi, heat shock proteins (Hsps) have been implicated in several processes with the conserved molecular chaperone Hsp90 emerging as a potential target for antifungal therapy. It plays key cellular roles by eliciting molecular response to environmental changes, morphogenesis, antifungal resistance, and fungal pathogenicity. Here, we evaluated the transcription profiles of hsp genes of the most prevalent dermatophyte Trichophyton rubrum in response to different environmental challenges including nutrient availability, interaction with cells and molecules of the host tissue, and drug exposure. The results suggest that each Hsp responds to a specific stress condition and that the cohort of Hsps facilitates fungal survival under various environmental challenges. Chemical inhibition of Hsp90 resulted in increased susceptibility of the fungus to itraconazole and micafungin, and decreased its growth in human nails in vitro. Moreover, some hsp and related genes were modulated by Hsp90 at the transcriptional level. We are suggesting a role of Hsp90 in the pathogenicity and drug susceptibility of T. rubrum as well as the regulation of other Hsps. The synergism observed between the inhibition of Hsp90 and the effect of itraconazole or micafungin in reducing the fungal growth is of great interest as a novel and potential strategy to treat dermatophytoses.
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Affiliation(s)
- Tiago R Jacob
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto São Paulo, Brazil
| | - Nalu T A Peres
- Department of Morphology, Federal University of Sergipe Aracaju, Brazil
| | - Maíra P Martins
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto São Paulo, Brazil
| | - Elza A S Lang
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto São Paulo, Brazil
| | - Pablo R Sanches
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto São Paulo, Brazil
| | - Antonio Rossi
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto São Paulo, Brazil
| | - Nilce M Martinez-Rossi
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto São Paulo, Brazil
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Ivanova AA, Velichko AK, Kantidze OL, Razin SV. Heat stress induces formation of cytoplasmic granules containing HSC70 protein. DOKL BIOCHEM BIOPHYS 2015; 463:213-5. [PMID: 26335814 DOI: 10.1134/s1607672915040043] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Indexed: 11/22/2022]
Abstract
Using indirect immunofluorescence, in this study we showed that the constitutive heat shock protein HSC70 forms granule-like structures in the cytoplasm of human cells several days after the exposure to heat stress. It was shown that this effect is not the result of HSC70 overexpression under heat stress and is not due to the formation of hyperthermia-induced translational stress granules in the cytoplasm.
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Affiliation(s)
- A A Ivanova
- Institute of Gene Biology, Russian Academy of Sciences, ul. Vavilova 34/5, Moscow, 119334, Russia
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Pinsino A, Matranga V. Sea urchin immune cells as sentinels of environmental stress. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2015; 49:198-205. [PMID: 25463510 DOI: 10.1016/j.dci.2014.11.013] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 11/14/2014] [Accepted: 11/17/2014] [Indexed: 06/04/2023]
Abstract
Echinoderms, an ancient and very successful phylum of marine invertebrates, play a central role in the maintenance of ecosystem integrity and are constantly exposed to environmental pressure, including: predation, changes in temperature and pH, hypoxia, pathogens, UV radiation, metals, toxicants, and emerging pollutants like nanomaterials. The annotation of the sea urchin genome, so closely related to humans and other vertebrate genomes, revealed an unusually complex immune system, which may be the basis for why sea urchins can adapt to different marine environments and survive even in hazardous conditions. In this review, we give a brief overview of the morphological features and recognized functions of echinoderm immune cells with a focus on studies correlating stress and immunity in the sea urchin. Immune cells from adult Paracentrotus lividus, which have been introduced in the last fifteen years as sentinels of environmental stress, are valid tools to uncover basic molecular and regulatory mechanisms of immune responses, supporting their use in immunological research. Here we summarize laboratory and field studies that reveal the amenability of sea urchin immune cells for toxicological testing.
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Affiliation(s)
- Annalisa Pinsino
- Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "A. Monroy", Via Ugo La Malfa 153, 90146 Palermo, Italy.
| | - Valeria Matranga
- Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "A. Monroy", Via Ugo La Malfa 153, 90146 Palermo, Italy.
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Loshaj-Shala A, Poceva Panovska A, Brezovska K, Beretta G, Suturkova L, Apostolski S. Involvement of serum HSP 70 in Guillain-Barré Syndrome: An exploratory study and a review of current literature. MAKEDONSKO FARMACEVTSKI BILTEN 2015. [DOI: 10.33320/maced.pharm.bull.2015.61.01.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The evolutionary conserved family of heat shock proteins (HSP) is responsible for protecting cells against different types of stress. Although the levels of HSP can be readily measured in serum, the levels of HSP 70 in patients Guillain-Barre Syndrome (GBS) have not been studied before. To this aim we investigate whether patients with GBS (n=21) had altered serum HSP 70 levels compared to healthy controls (HC, n=9) and to patients affected by other immune disorders such as multifocal motor neuropathy (MMN, n=4) and chronic inflammatory demyelinating polyneuropathy (CIDP, n=6). The highest HSP 70 value (15.78 ± 1.72 ng/mL) was found in one patient in the GBS group, although we have found that serum HSP70 levels were significantly higher in 2 out of the 21 GBS patients (9.5%). Hence, it is of interest to underline that the patient with the highest HSP70 level, had also the best recovery rate. Моrе extensive research is required in order to support the hypothesis that HSP 70 serum concentration may be a useful biomarker for the prediction of remission outcome for GBS patients.
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Leão TL, da Fonseca FG. Subversion of cellular stress responses by poxviruses. World J Clin Infect Dis 2014; 4:27-40. [DOI: 10.5495/wjcid.v4.i4.27] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Revised: 07/26/2014] [Accepted: 09/10/2014] [Indexed: 02/06/2023] Open
Abstract
Cellular stress responses are powerful mechanisms that prevent and cope with the accumulation of macromolecular damage in the cells and also boost host defenses against pathogens. Cells can initiate either protective or destructive stress responses depending, to a large extent, on the nature and duration of the stressing stimulus as well as the cell type. The productive replication of a virus within a given cell places inordinate stress on the metabolism machinery of the host and, to assure the continuity of its replication, many viruses have developed ways to modulate the cell stress responses. Poxviruses are among the viruses that have evolved a large number of strategies to manipulate host stress responses in order to control cell fate and enhance their replicative success. Remarkably, nearly every step of the stress responses that is mounted during infection can be targeted by virally encoded functions. The fine-tuned interactions between poxviruses and the host stress responses has aided virologists to understand specific aspects of viral replication; has helped cell biologists to evaluate the role of stress signaling in the uninfected cell; and has tipped immunologists on how these signals contribute to alert the cells against pathogen invasion and boost subsequent immune responses. This review discusses the diverse strategies that poxviruses use to subvert host cell stress responses.
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Abstract
Ferruccio Ritossa wrote these lines only a few months before he died, as a preface to a book he wanted to write and that, unfortunately, we will never be able to read. It was to be the story of his life, an amazing story indeed. With this article, we want to take a picture of Ferruccio's life, a mosaic of events, facts, ideas, hopes, and memories linked in a way that they will not go away, even after "a stroll in our brain."
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Affiliation(s)
- Mauro Capocci
- />Unit of History of Medicine, Department of Medico-surgical Sciences and Biotechnologies, La Sapienza University of Rome, Rome, Italy
| | - M. Gabriella Santoro
- />Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy
| | - Lawrence E. Hightower
- />Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT USA
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Abstract
The expression of heat shock proteins (HSPs) is a basic and well-conserved cellular response to an array of stresses. These proteins are involved in the repair of cellular damage induced by the stress, which is necessary for the salutary resolution from the insult. Moreover, they confer protection from subsequent insults, which has been coined stress tolerance. Because these proteins are expressed in subcellular compartments, it was thought that their function during stress conditions was circumscribed to the intracellular environment. However, it is now well established that HSPs can also be present outside cells where they appear to display a function different than the well-understood chaperone role. Extracellular HSPs act as alert stress signals priming other cells, particularly of the immune system, to avoid the propagation of the insult and favor resolution. Because the majority of HSPs do not possess a secretory peptide signal, they are likely to be exported by a nonclassic secretory pathway. Different mechanisms have been proposed to explain the export of HSPs, including translocation across the plasma membrane and release associated with lipid vesicles, as well as the passive release after cell death by necrosis. Extracellular HSPs appear in various flavors, including membrane-bound and membrane-free forms. All of these variants of extracellular HSPs suggest that their interactions with cells may be quite diverse, both in target cell types and the activation signaling pathways. This review addresses some of our current knowledge about the release and relevance of extracellular HSPs.
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Velichko AK, Markova EN, Petrova NV, Razin SV, Kantidze OL. Mechanisms of heat shock response in mammals. Cell Mol Life Sci 2013; 70:4229-41. [PMID: 23633190 PMCID: PMC11113869 DOI: 10.1007/s00018-013-1348-7] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 04/12/2013] [Accepted: 04/15/2013] [Indexed: 12/28/2022]
Abstract
Heat shock (HS) is one of the best-studied exogenous cellular stresses. The cellular response to HS utilizes ancient molecular networks that are based primarily on the action of stress-induced heat shock proteins and HS factors. However, in one way or another, all cellular compartments and metabolic processes are involved in such a response. In this review, we aimed to summarize the experimental data concerning all aspects of the HS response in mammalian cells, such as HS-induced structural and functional alterations of cell membranes, the cytoskeleton and cellular organelles; the associated pathways that result in different modes of cell death and cell cycle arrest; and the effects of HS on transcription, splicing, translation, DNA repair, and replication.
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Affiliation(s)
- Artem K. Velichko
- Laboratory of Structural and Functional Organization of Chromosomes, Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia
| | - Elena N. Markova
- Laboratory of Structural and Functional Organization of Chromosomes, Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia
| | - Nadezhda V. Petrova
- Laboratory of Structural and Functional Organization of Chromosomes, Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia
- Department of Molecular Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Sergey V. Razin
- Laboratory of Structural and Functional Organization of Chromosomes, Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia
- Department of Molecular Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Omar L. Kantidze
- Laboratory of Structural and Functional Organization of Chromosomes, Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia
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