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1
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Wu X, Zhou Y, Lu Z, Zhang Y, Zhang T, Jiang Q. Cupric citrate supplementation improves growth performance, nutrient utilization, antioxidant capacity, and intestinal microbiota of broilers. Anim Biosci 2025; 38:530-538. [PMID: 39483018 PMCID: PMC11917449 DOI: 10.5713/ab.24.0382] [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: 06/06/2024] [Accepted: 09/21/2024] [Indexed: 11/03/2024] Open
Abstract
OBJECTIVE This study aimed to examine the impact of cupric citrate on broilers and compare it with the copper sulfate groups and a control group. METHODS A total of 360 1-day-old Ross 308 broilers were randomly assigned into 5 groups, each with 6 replicates of 12 broilers per treatment. The control group was fed a basal diet without any copper supplementation. In contrast, the other groups received basal diets supplemented with either 50 mg/kg (CS-50) or 100 mg/kg (CS-100) of copper in the form of copper sulfate, or 50 mg/kg (CC-50) or 100 mg/kg (CC-100) of copper in the form of cupric citrate, for a period of 42 days. RESULTS The results showed that copper supplementation affected the average daily gain (ADG) from day 1 to 21 (p = 0.026) and day 1 to 42 (p = 0.025) in a source-dependent manner. Copper source also influenced the energy digestibility (p = 0.004), with the CC-100 being the most effective treatment. Notably, birds in the CC-100 groups had significantly reduced concentrations of Escherichia coli (p<0.05) in the cecum, and the Lactobacillus in the ileum, compared to the control group. Dietary copper supplementation also increased the pH in the duodenum (p<0.05) irrespective of the sources and levels. In addition, the source of copper affected the activities of ceruloplasmin (p = 0.014) and CuZn superoxide dismutase (p = 0.025) in the serum, with the CC-100 group showing the highest levels of both enzymes. CONCLUSION Copper supplementation generally improves the growth, nutrient utilization, intestinal microflora, gastrointestinal pH, and antioxidant defences of broilers. Moreover, cupric citrate is as effective as copper sulfate even at equal or lower concentrations.
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Affiliation(s)
- Xuezhuang Wu
- College of Animal Science, Anhui Science and Technology University, Anhui 233100, China
| | - Yahao Zhou
- College of Animal Science, Anhui Science and Technology University, Anhui 233100, China
| | - Zhentao Lu
- College of Animal Science, Anhui Science and Technology University, Anhui 233100, China
| | - Yunting Zhang
- College of Animal Science, Anhui Science and Technology University, Anhui 233100, China
| | - Tietao Zhang
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun 130112, China
| | - Qingkui Jiang
- Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA
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2
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Liu C, Zhao K, Chen Y, Yao Y, Tang J, Wang J, Xu C, Yang Q, Zheng Y, Yuan Y, Sun H, Zhang Y, Zhou Y, Chen J, Wang Y, Wu C, Pei R, Chen X. Mitochondrial Glycerol-3-Phosphate Dehydrogenase Restricts HBV Replication via the TRIM28-Mediated Degradation of HBx. J Virol 2023; 97:e0058023. [PMID: 37166302 PMCID: PMC10231258 DOI: 10.1128/jvi.00580-23] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 04/21/2023] [Indexed: 05/12/2023] Open
Abstract
Hepatitis B virus (HBV) infection affects hepatic metabolism. Serum metabolomics studies have suggested that HBV possibly hijacks the glycerol-3-phosphate (G3P) shuttle. In this study, the two glycerol-3-phosphate dehydrogenases (GPD1 and GPD2) in the G3P shuttle were analyzed for determining their role in HBV replication and the findings revealed that GPD2 and not GPD1 inhibited HBV replication. The knockdown of GPD2 expression upregulated HBV replication, while GPD2 overexpression reduced HBV replication. Moreover, the overexpression of GPD2 significantly reduced HBV replication in hydrodynamic injection-based mouse models. Mechanistically, this inhibitory effect is related to the GPD2-mediated degradation of HBx protein by recruiting the E3 ubiquitin ligase TRIM28 and not to the alterations in G3P metabolism. In conclusion, this study revealed GPD2, a key enzyme in the G3P shuttle, as a host restriction factor in HBV replication. IMPORTANCE The glycerol-3-phosphate (G3P) shuttle is important for the delivery of cytosolic reducing equivalents into mitochondria for oxidative phosphorylation. The study analyzed two key components of the G3P shuttle and identified GPD2 as a restriction factor in HBV replication. The findings revealed a novel mechanism of GPD2-mediated inhibition of HBV replication via the recruitment of TRIM28 for degrading HBx, and the HBx-GPD2 interaction could be another potential therapeutic target for anti-HBV drug development.
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Affiliation(s)
- Canyu Liu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Kaitao Zhao
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Yingshan Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yongxuan Yao
- Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou, China
| | - Jielin Tang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
- Guangzhou Laboratory, Guangzhou, China
| | - Jingjing Wang
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Chonghui Xu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Qi Yang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
- Guangzhou Laboratory, Guangzhou, China
| | - Yi Zheng
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yifei Yuan
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Hao Sun
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yongli Zhang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
| | - Yuan Zhou
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
| | | | - Yun Wang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
| | - Chunchen Wu
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rongjuan Pei
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
| | - Xinwen Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China
- Guangzhou Laboratory, Guangzhou, China
- Guangzhou Medical University, Guangzhou, China
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DNA Repair Factor Poly(ADP-Ribose) Polymerase 1 Is a Proviral Factor in Hepatitis B Virus Covalently Closed Circular DNA Formation. J Virol 2022; 96:e0058522. [DOI: 10.1128/jvi.00585-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
The biogenesis and eradication of HBV cccDNA have been a research priority in recent years. In this study, we identified the DNA repair factor PARP1 as a host factor required for the HBV
de novo
cccDNA formation.
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4
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Saad HKM, Abd Rahman AA, Ab Ghani AS, Taib WRW, Ismail I, Johan MF, Al-Wajeeh AS, Al-Jamal HAN. Activation of STAT and SMAD Signaling Induces Hepcidin Re-Expression as a Therapeutic Target for β-Thalassemia Patients. Biomedicines 2022; 10:biomedicines10010189. [PMID: 35052868 PMCID: PMC8773737 DOI: 10.3390/biomedicines10010189] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 01/27/2023] Open
Abstract
Iron homeostasis is regulated by hepcidin, a hepatic hormone that controls dietary iron absorption and plasma iron concentration. Hepcidin binds to the only known iron export protein, ferroportin (FPN), which regulates its expression. The major factors that implicate hepcidin regulation include iron stores, hypoxia, inflammation, and erythropoiesis. When erythropoietic activity is suppressed, hepcidin expression is hampered, leading to deficiency, thus causing an iron overload in iron-loading anemia, such as β-thalassemia. Iron overload is the principal cause of mortality and morbidity in β-thalassemia patients with or without blood transfusion dependence. In the case of thalassemia major, the primary cause of iron overload is blood transfusion. In contrast, iron overload is attributed to hepcidin deficiency and hyperabsorption of dietary iron in non-transfusion thalassemia. Beta-thalassemia patients showed marked hepcidin suppression, anemia, iron overload, and ineffective erythropoiesis (IE). Recent molecular research has prompted the discovery of new diagnostic markers and therapeutic targets for several diseases, including β-thalassemia. In this review, signal transducers and activators of transcription (STAT) and SMAD (structurally similar to the small mothers against decapentaplegic in Drosophila) pathways and their effects on hepcidin expression have been discussed as a therapeutic target for β-thalassemia patients. Therefore, re-expression of hepcidin could be a therapeutic target in the management of thalassemia patients. Data from 65 relevant published experimental articles on hepcidin and β-thalassemia between January 2016 and May 2021 were retrieved by using PubMed and Google Scholar search engines. Published articles in any language other than English, review articles, books, or book chapters were excluded.
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Affiliation(s)
- Hanan Kamel M. Saad
- School of Biomedicine, Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Kuala Nerus 21300, Terengganu, Malaysia; (H.K.M.S.); (W.R.W.T.); (I.I.)
| | - Alawiyah Awang Abd Rahman
- Pathology Department, Hospital Sultanah Nur Zahirah, Kuala Terengganu 20400, Terengganu, Malaysia; (A.A.A.R.); (A.S.A.G.)
| | - Azly Sumanty Ab Ghani
- Pathology Department, Hospital Sultanah Nur Zahirah, Kuala Terengganu 20400, Terengganu, Malaysia; (A.A.A.R.); (A.S.A.G.)
| | - Wan Rohani Wan Taib
- School of Biomedicine, Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Kuala Nerus 21300, Terengganu, Malaysia; (H.K.M.S.); (W.R.W.T.); (I.I.)
| | - Imilia Ismail
- School of Biomedicine, Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Kuala Nerus 21300, Terengganu, Malaysia; (H.K.M.S.); (W.R.W.T.); (I.I.)
| | - Muhammad Farid Johan
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelatan, Malaysia;
| | | | - Hamid Ali Nagi Al-Jamal
- School of Biomedicine, Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Kuala Nerus 21300, Terengganu, Malaysia; (H.K.M.S.); (W.R.W.T.); (I.I.)
- Correspondence: ; Tel.: +60-1747-29012
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5
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Lin J, Li J, Xie P, Han Y, Yu D, Chen J, Zhang X. Hepatitis B virus middle surface antigen loss promotes clinical variant persistence in mouse models. Virulence 2021; 12:2868-2882. [PMID: 34738866 PMCID: PMC8632123 DOI: 10.1080/21505594.2021.1999130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Hepatitis B virus (HBV) middle surface antigen (MHBs) mutation or deletion occurs in patients with chronic HBV infection. However, the functional role of MHBs in HBV infection is still an enigma. Here, we reported that 7.33% (11/150) isolates of CHB patients had MHBs start codon mutations compared with 0.00% (0/146) in acute hepatitis B (AHB) patients. Interestingly, MHBs loss accounted for 11.88% (126/1061) isolates from NCBI GenBank, compared with 0.09% (1/1061) and 0.00% (0/1061) for HBV large surface antigen (LHBs) loss and HBV small surface antigen (SHBs) loss, respectively. One persistent HBV clone of genotype B (B56, MHBs loss) from a CHB patient was hydrodynamically injected into BALB/c mice. B56 persisted for >70 weeks in BALB/c mice, whereas B56 with restored MHBs (B56M+) was quickly cleared within 28 days. Serum cytokine assays demonstrated that CXCL1, CXCL2, IL-6 and IL-33 were significantly increased during rapid HBV clearance in B56M+ mice. Furthermore, the enhancers and promoters of B56 were proved to be required for B56 persistence in mice. Ablating MHBs expression improved the persistence of a new clone (HBV1.3, genotype B) which was recreated by using enhancers and promoters of B56. These data demonstrated that MHBs deletion can promote the persistence of specific HBV variants in a hydrodynamic mouse model. MHBs re-expression restored a rapid clearance of HBV, which was accompanied by cytokine responses including the elevation of CXCL1, CXCL2, IL-6 and IL-33.
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Affiliation(s)
- Junyu Lin
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Li
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peilin Xie
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Han
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Demin Yu
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jia Chen
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinxin Zhang
- Department of Infectious Diseases, Research Laboratory of Clinical Virology, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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6
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Zhao K, Ke Z, Hu H, Liu Y, Li A, Hua R, Guo F, Xiao J, Zhang Y, Duan L, Yan XF, Gao YG, Liu B, Xia Y, Li Y. Structural Basis and Function of the N Terminus of SARS-CoV-2 Nonstructural Protein 1. Microbiol Spectr 2021; 9:e0016921. [PMID: 34132580 PMCID: PMC8552758 DOI: 10.1128/spectrum.00169-21] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 05/12/2021] [Indexed: 11/20/2022] Open
Abstract
Nonstructural protein 1 (Nsp1) of severe acute respiratory syndrome coronaviruses (SARS-CoVs) is an important pathogenic factor that inhibits host protein translation by means of its C terminus. However, its N-terminal function remains elusive. Here, we determined the crystal structure of the N terminus (amino acids [aa] 11 to 125) of SARS-CoV-2 Nsp1 at a 1.25-Å resolution. Further functional assays showed that the N terminus of SARS-CoVs Nsp1 alone loses the ability to colocalize with ribosomes and inhibit protein translation. The C terminus of Nsp1 can colocalize with ribosomes, but its protein translation inhibition ability is significantly weakened. Interestingly, fusing the C terminus of Nsp1 with enhanced green fluorescent protein (EGFP) or other proteins in place of its N terminus restored the protein translation inhibitory ability to a level equivalent to that of full-length Nsp1. Thus, our results suggest that the N terminus of Nsp1 is able to stabilize the binding of the Nsp1 C terminus to ribosomes and act as a nonspecific barrier to block the mRNA channel, thus abrogating host mRNA translation.
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Affiliation(s)
- Kaitao Zhao
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Zunhui Ke
- Department of Blood Transfusion, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Hongbing Hu
- Department of Blood Transfusion, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Yahui Liu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Aixin Li
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Rong Hua
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Fangteng Guo
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Junfeng Xiao
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Zhang
- Faculty of Science (Medical Science), The University of Sydney, Sydney, New South Wales, Australia
| | - Ling Duan
- Department of Blood Transfusion, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Xin-Fu Yan
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Yong-Gui Gao
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Bing Liu
- BioBank, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, United Kingdom
| | - Yuchen Xia
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Yan Li
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Tongji-Rongcheng Center for Biomedicine, Huazhong University of Science and Technology, Wuhan, China
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Monette A, Mouland AJ. Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates. Viruses 2020; 12:E1179. [PMID: 33081049 PMCID: PMC7589941 DOI: 10.3390/v12101179] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/05/2020] [Accepted: 10/12/2020] [Indexed: 02/08/2023] Open
Abstract
Liquid-liquid phase separation (LLPS) is a rapidly growing research focus due to numerous demonstrations that many cellular proteins phase-separate to form biomolecular condensates (BMCs) that nucleate membraneless organelles (MLOs). A growing repertoire of mechanisms supporting BMC formation, composition, dynamics, and functions are becoming elucidated. BMCs are now appreciated as required for several steps of gene regulation, while their deregulation promotes pathological aggregates, such as stress granules (SGs) and insoluble irreversible plaques that are hallmarks of neurodegenerative diseases. Treatment of BMC-related diseases will greatly benefit from identification of therapeutics preventing pathological aggregates while sparing BMCs required for cellular functions. Numerous viruses that block SG assembly also utilize or engineer BMCs for their replication. While BMC formation first depends on prion-like disordered protein domains (PrLDs), metal ion-controlled RNA-binding domains (RBDs) also orchestrate their formation. Virus replication and viral genomic RNA (vRNA) packaging dynamics involving nucleocapsid (NC) proteins and their orthologs rely on Zinc (Zn) availability, while virus morphology and infectivity are negatively influenced by excess Copper (Cu). While virus infections modify physiological metal homeostasis towards an increased copper to zinc ratio (Cu/Zn), how and why they do this remains elusive. Following our recent finding that pan-retroviruses employ Zn for NC-mediated LLPS for virus assembly, we present a pan-virus bioinformatics and literature meta-analysis study identifying metal-based mechanisms linking virus-induced BMCs to neurodegenerative disease processes. We discover that conserved degree and placement of PrLDs juxtaposing metal-regulated RBDs are associated with disease-causing prion-like proteins and are common features of viral proteins responsible for virus capsid assembly and structure. Virus infections both modulate gene expression of metalloproteins and interfere with metal homeostasis, representing an additional virus strategy impeding physiological and cellular antiviral responses. Our analyses reveal that metal-coordinated virus NC protein PrLDs initiate LLPS that nucleate pan-virus assembly and contribute to their persistence as cell-free infectious aerosol droplets. Virus aerosol droplets and insoluble neurological disease aggregates should be eliminated by physiological or environmental metals that outcompete PrLD-bound metals. While environmental metals can control virus spreading via aerosol droplets, therapeutic interference with metals or metalloproteins represent additional attractive avenues against pan-virus infection and virus-exacerbated neurological diseases.
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Affiliation(s)
- Anne Monette
- Lady Davis Institute at the Jewish General Hospital, Montréal, QC H3T 1E2, Canada
| | - Andrew J. Mouland
- Lady Davis Institute at the Jewish General Hospital, Montréal, QC H3T 1E2, Canada
- Department of Medicine, McGill University, Montréal, QC H4A 3J1, Canada
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Gong A, Leitold S, Uhanova J, Minuk GY. Non-Wilson's Disease-Associated Hypoceruloplasminemia. J Clin Exp Hepatol 2020; 10:284-289. [PMID: 32655230 PMCID: PMC7335701 DOI: 10.1016/j.jceh.2019.11.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 11/17/2019] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION AND AIM Low serum ceruloplasmin levels can occur in patients without Wilson's disease (WD) liver disorders. When present, extensive, costly, and potentially harmful additional investigations for WD may be undertaken. The purpose of this study was to document the prevalence of low serum ceruloplasmin levels in adult patients without WD and describe the features commonly associated with this finding. MATERIALS AND METHODS Serum ceruloplasmin levels were measured by an enzymatic assay in 3040 adult patients attending an urban, liver diseases outpatient clinic. RESULTS A total of 122 (4.0%) patients without WD had serum ceruloplasmin levels less than the lower limit of normal documented at their initial visit. Their mean age was 44 ± 14 years, and 80 (66%) were men. The Model for End-stage Liver Disease (MELD) score was 9.0 ± 4.0. Approximately, one half (65/122, 53%) had underlying viral hepatitis (52% hepatitis B and 48% hepatitis C). When compared with 64 MELD-matched control patients with normal or elevated serum ceruloplasmin levels, there were no significant differences in liver enzyme/function tests, ferritin, creatinine values, or survival. However, the low serum ceruloplasmin cohort patients were younger (43 ± 14 versus 52 ± 13 years, p = 0.0002), less often men (66% vs. 88%, p = 0.001), and viral hepatitis was significantly more common (53% versus 27%, p = 0.0005). CONCLUSION Low serum ceruloplasmin levels were documented in 4.0% of adult patients without WD attending this urban liver diseases outpatient clinic. These patients tend to be younger, less often men, and more often have viral hepatitis as the underlying cause of their liver disease.
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Key Words
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- ASH, alcoholic steatohepatitis
- AST, aspartate aminotransferase
- Dx, diagnosis
- GGT, gamma-glutamyl transferase
- HBV, hepatitis B virus
- HCV, hepatitis C virus
- INR, international ratio of prothrombin times
- MELD, Model for End-stage Liver Disease
- NASH, nonalcoholic steatohepatitis
- T.Bili, total bilirubin
- WD, Wilson Disease
- ceruloplasmin
- hepatitis
- liver
- viral hepatitis
- wilson's disease
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Affiliation(s)
- Annie Gong
- Section of Hepatology, Department of Medicine, Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Samantha Leitold
- Section of Hepatology, Department of Medicine, Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Julia Uhanova
- Section of Hepatology, Department of Medicine, Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Gerald Y. Minuk
- Section of Hepatology, Department of Medicine, Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada,Department of Pharmacology and Therapeutics, Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada,Address for correspondence. Gerald Y. Minuk, Morberg Family Chair in Hepatology, University of Manitoba, John Buhler Research Centre, 715 McDermot Ave., Winnipeg, MB R3E 3P4, Canada.
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9
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Yuan Y, Zhao K, Yao Y, Liu C, Chen Y, Li J, Wang Y, Pei R, Chen J, Hu X, Zhou Y, Wu C, Chen X. HDAC11 restricts HBV replication through epigenetic repression of cccDNA transcription. Antiviral Res 2019; 172:104619. [PMID: 31600533 DOI: 10.1016/j.antiviral.2019.104619] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 09/18/2019] [Accepted: 10/05/2019] [Indexed: 12/12/2022]
Abstract
Hepatitis B virus (HBV) infection remains an important public health problem worldwide. Covalently closed circular DNA (cccDNA) exhibits as an individual minichromosome and is the molecular basis of HBV infection persistence and antiviral treatment failure. In the current study, we demonstrated that histone deacetylase 11 (HDAC11) inhibits HBV transcription and replication in HBV-transfected Huh7 cells. By using an HBV in vitro infection system, HDAC11 was found to affect the transcriptional activity of cccDNA but did not affect cccDNA production. Chromatin immunoprecipitation (ChIP) assays were utilized to analyze the epigenetic modifications of cccDNA. The results show that HDAC11 specifically reduced the acetylation level of cccDNA-bound histone H3 but did not affect that of histone H4. Furthermore, HDAC11 overexpression decreased the levels of cccDNA-bound acetylated H3K9 (H3K9ac) and H3K27 (H3K27ac). In conclusion, HDAC11 restricts HBV replication through epigenetic repression of cccDNA transcription. These findings reveal the novel role of HDAC11 in HBV infection, further broadening our knowledge regarding the functions of HDAC11 and the roles of HDACs in the epigenetic regulation of HBV cccDNA.
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Affiliation(s)
- Yifei Yuan
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Kaitao Zhao
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Yongxuan Yao
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Canyu Liu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Yingshan Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Jing Li
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; School of Pharmacy, Nankai University, Tianjin, China
| | - Yun Wang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Rongjuan Pei
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Jizheng Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Xue Hu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Yuan Zhou
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Chunchen Wu
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
| | - Xinwen Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
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10
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Lazarevic I, Banko A, Miljanovic D, Cupic M. Immune-Escape Hepatitis B Virus Mutations Associated with Viral Reactivation upon Immunosuppression. Viruses 2019; 11:v11090778. [PMID: 31450544 PMCID: PMC6784188 DOI: 10.3390/v11090778] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/21/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) reactivation occurs as a major complication of immunosuppressive therapy among persons who have recovered from acute hepatitis and those who have controlled chronic infection. Recent literature data emphasize the presence of a high degree of S gene variability in HBV isolates from patients who developed reactivation. In reactivated HBV, the most frequently detected mutations belong to the second loop of “a” determinant in HBsAg. These mutations were identified to be immune escape and responsible for vaccine- and diagnostic-escape phenomena. Their emergence clearly provides survival in the presence of a developed humoral immune response and is often associated with impaired serological diagnosis of HBV reactivation. The knowledge of their existence and roles can elucidate the process of reactivation and strongly highlights the importance of HBV DNA detection in monitoring all patients with a history of HBV infection who are undergoing immunosuppression. This review discusses the possible influence of the most frequently found immune-escape mutations on HBV reactivation.
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Affiliation(s)
- Ivana Lazarevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia.
| | - Ana Banko
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia
| | - Danijela Miljanovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia
| | - Maja Cupic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia
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11
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Wu C, Li B, Zhang X, Zhao K, Chen Y, Yuan Y, Liu Y, Chen R, Xu D, Chen X, Lu M. Complementation of Wild-Type and Drug-Resistant Hepatitis B Virus Genomes to Maintain Viral Replication and Rescue Virion Production under Nucleos(t)ide Analogs. Virol Sin 2019; 34:377-385. [PMID: 31218588 DOI: 10.1007/s12250-019-00143-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 05/14/2019] [Indexed: 02/06/2023] Open
Abstract
As the open reading frames of hepatitis B virus (HBV) genomes are overlapping, resistance mutations (MTs) in HBV polymerase may result in stop codon MTs in hepatitis B surface proteins, which are usually detected as a mixed population with wild-type (WT) HBV. The question was raised how the coexistence of nucleos(t)ide analogs (NAs) resistance MTs and WT sequences affects HBV replication. In the present study, HBV genomes with frequently detected reverse transcriptase (RT)/surface truncation MTs, rtA181T/sW172*, rtV191I/sW182* and rtM204I/sW196*, were phenotypically characterized alone or together with their WT counterparts in different ratios by transient transfection in the absence or presence of NAs. In the absence of NAs, RT/surface truncation MTs impaired the expression and secretion of HBV surface proteins, and had a dose-dependent negative effect on WT HBV virion secretion. However, in the presence of NAs, coexistence of MTs with WT maintained viral replication, and the presence of WT was able to rescue the production of MT HBV virions. Our findings reveal that complementation of WT and MT HBV genomes is highly effective under drug treatment.
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Affiliation(s)
- Chunchen Wu
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, China.,State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Baolin Li
- Institute of Virology, University Hospital of Essen, 45122, Essen, Germany
| | - Xiaoyong Zhang
- Institute of Virology, University Hospital of Essen, 45122, Essen, Germany
| | - Kaitao Zhao
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yingshan Chen
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yifei Yuan
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yan Liu
- Institute of Infectious Diseases and Liver Failure Research Center, Beijing 302 Hospital, Beijing, 100039, China
| | - Rongjuan Chen
- Institute of Infectious Diseases and Liver Failure Research Center, Beijing 302 Hospital, Beijing, 100039, China
| | - Dongping Xu
- Institute of Infectious Diseases and Liver Failure Research Center, Beijing 302 Hospital, Beijing, 100039, China
| | - Xinwen Chen
- State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
| | - Mengji Lu
- Institute of Virology, University Hospital of Essen, 45122, Essen, Germany.
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12
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RNA-Binding Motif Protein 24 (RBM24) Is Involved in Pregenomic RNA Packaging by Mediating Interaction between Hepatitis B Virus Polymerase and the Epsilon Element. J Virol 2019; 93:JVI.02161-18. [PMID: 30626666 DOI: 10.1128/jvi.02161-18] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Accepted: 12/18/2018] [Indexed: 12/14/2022] Open
Abstract
Encapsidation of pregenomic RNA (pgRNA) is a crucial step in hepatitis B virus (HBV) replication. Binding by viral polymerase (Pol) to the epsilon stem-loop (ε) on the 5'-terminal region (TR) of pgRNA is required for pgRNA packaging. However, the detailed mechanism is not well understood. RNA-binding motif protein 24 (RBM24) inhibits core translation by binding to the 5'-TR of pgRNA. Here, we demonstrate that RBM24 is also involved in pgRNA packaging. RBM24 directly binds to the lower bulge of ε via RNA recognition submotifs (RNPs). RBM24 also interacts with Pol in an RNA-independent manner. The alanine-rich domain (ARD) of RBM24 and the reverse transcriptase (RT) domain of Pol are essential for binding between RBM24 and Pol. In addition, overexpression of RBM24 increases Pol-ε interaction, whereas RBM24 knockdown decreases the interaction. RBM24 was able to rescue binding between ε and mutant Pol lacking ε-binding activity, further showing that RBM24 mediates the interaction between Pol and ε by forming a Pol-RBM24-ε complex. Finally, RBM24 significantly promotes the packaging efficiency of pgRNA. In conclusion, RBM24 mediates Pol-ε interaction and formation of a Pol-RBM24-ε complex, which inhibits translation of pgRNA and results in pgRNA packing into capsids/virions for reverse transcription and DNA synthesis.IMPORTANCE Hepatitis B virus (HBV) is a ubiquitous human pathogen, and HBV infection is a major global health burden. Chronic HBV infection is associated with the development of liver diseases, including fulminant hepatitis, hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. A currently approved vaccine can prevent HBV infection, and medications are able to reduce viral loads and prevent liver disease progression. However, current treatments rarely achieve a cure for chronic infection. Thus, it is important to gain insight into the mechanisms of HBV replication. In this study, we found that the host factor RBM24 is involved in pregenomic RNA (pgRNA) packaging and regulates HBV replication. These findings highlight a potential target for antiviral therapeutics of HBV infection.
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13
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Zhao K, Liu S, Chen Y, Yao Y, Zhou M, Yuan Y, Wang Y, Pei R, Chen J, Hu X, Zhou Y, Zhao H, Lu M, Wu C, Chen X. Upregulation of HBV transcription by sodium taurocholate cotransporting polypeptide at the postentry step is inhibited by the entry inhibitor Myrcludex B. Emerg Microbes Infect 2018; 7:186. [PMID: 30459339 PMCID: PMC6246608 DOI: 10.1038/s41426-018-0189-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 09/30/2018] [Accepted: 10/26/2018] [Indexed: 02/07/2023]
Abstract
Sodium taurocholate cotransporting polypeptide (NTCP) is a functional receptor for hepatitis B virus (HBV) entry. However, little is known regarding whether NTCP is involved in regulating the postentry steps of the HBV life cycle. Here, we found that NTCP expression upregulated HBV transcription at the postentry step and that the NTCP-targeting entry inhibitor Myrcludex B (MyrB) effectively suppressed HBV transcription both in an HBV in vitro infection system and in mice hydrodynamically injected with an HBV expression plasmid. Mechanistically, NTCP upregulated HBV transcription via farnesoid X receptor α (FxRα)-mediated activation of the HBV EN2/core promoter at the postentry step in a manner that was dependent on the bile acid (BA)-transport function of NTCP, which was blocked by MyrB. Our findings uncover a novel role for NTCP in the HBV life cycle and provide a reference for the use of novel NTCP-targeting entry inhibitors to suppress HBV infection and replication.
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Affiliation(s)
- Kaitao Zhao
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China.,University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Shuhui Liu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China.,University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Yingshan Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China.,University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Yongxuan Yao
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China.,University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Ming Zhou
- Shenzhen Xenotransplantation Research and Development Center, State and Local Joint Cancer Genome Clinical Application of Key Technology Laboratory, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, 518035, Shenzhen, China
| | - Yifei Yuan
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China.,University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Yun Wang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China
| | - Rongjuan Pei
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China
| | - Jizheng Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China
| | - Xue Hu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China
| | - Yuan Zhou
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China
| | - He Zhao
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China
| | - Mengji Lu
- Institute of Virology, University Hospital of Essen, 45147, Essen, Germany
| | - Chunchen Wu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China.
| | - Xinwen Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, 430071, Wuhan, China. .,University of Chinese Academy of Sciences, 100049, Beijing, China.
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14
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Wu CC, Chen YS, Cao L, Chen XW, Lu MJ. Hepatitis B virus infection: Defective surface antigen expression and pathogenesis. World J Gastroenterol 2018; 24:3488-3499. [PMID: 30131655 PMCID: PMC6102499 DOI: 10.3748/wjg.v24.i31.3488] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/01/2018] [Accepted: 06/25/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health concern. HBV causes chronic infection in patients and can lead to liver cirrhosis, hepatocellular carcinoma, and other severe liver diseases. Thus, understanding HBV-related pathogenesis is of particular importance for prevention and clinical intervention. HBV surface antigens are indispensable for HBV virion formation and are useful viral markers for diagnosis and clinical assessment. During chronic HBV infection, HBV genomes may acquire and accumulate mutations and deletions, leading to the expression of defective HBV surface antigens. These defective HBV surface antigens have been found to play important roles in the progression of HBV-associated liver diseases. In this review, we focus our discussion on the nature of defective HBV surface antigen mutations and their contribution to the pathogenesis of fulminant hepatitis B. The relationship between defective surface antigens and occult HBV infection are also discussed.
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MESH Headings
- DNA, Viral/genetics
- DNA, Viral/isolation & purification
- Disease Progression
- Genome, Viral/genetics
- Hepatitis B Surface Antigens/genetics
- Hepatitis B Surface Antigens/immunology
- Hepatitis B Surface Antigens/metabolism
- Hepatitis B virus/genetics
- Hepatitis B virus/immunology
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/pathology
- Hepatitis B, Chronic/prevention & control
- Hepatitis B, Chronic/virology
- Humans
- Liver/immunology
- Liver/pathology
- Liver/virology
- Liver Failure, Acute/immunology
- Liver Failure, Acute/pathology
- Liver Failure, Acute/prevention & control
- Liver Failure, Acute/virology
- Mutation
- Virus Replication/genetics
- Virus Replication/immunology
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Affiliation(s)
- Chun-Chen Wu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, Hubei Province, China
| | - Ying-Shan Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, Hubei Province, China
| | - Liang Cao
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, Hubei Province, China
- Department of Microbiology and Immunology, Feinberg School of Medicine Northwestern University, Chicago, IL 60611, United States
| | - Xin-Wen Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, Hubei Province, China
| | - Meng-Ji Lu
- Institute of Virology, University Hospital of Essen, Essen 45122, Germany
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15
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Li Y, Sun Y, Sun F, Hua R, Li C, Chen L, Guo D, Mu J. Mechanisms and Effects on HBV Replication of the Interaction between HBV Core Protein and Cellular Filamin B. Virol Sin 2018; 33:162-172. [PMID: 29594956 DOI: 10.1007/s12250-018-0023-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 01/12/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is one of the major problems that threatens global health. There have been many studies on HBV, but the relationship between HBV and host factors is largely unexplored and more studies are needed to clarify these interactions. Filamin B is an actin-binding protein that acts as a cytoskeleton protein, and it is involved in cell development and several signaling pathways. In this study, we showed that filamin B interacted with HBV core protein, and the interaction promoted HBV replication. The interaction between filamin B and core protein was observed in HEK 293T, Huh7 and HepG2 cell lines by co-immunoprecipitation and co-localization immnofluoresence. Overexpression of filamin B increased the levels of HBV total RNAs and pre-genome RNA (pgRNA), and improved the secretion level of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). In contrast, filamin B knockdown inhibited HBV replication, decreased the level of HBV total RNAs and pgRNA, and reduced the secretion level of HBsAg and HBeAg. In addition, we found that filamin B and core protein may interact with each other via four blocks of argentine residues at the C-terminus of core protein. In conclusion, we identify filamin B as a novel host factor that can interact with core protein to promote HBV replication in hepatocytes. Our study provides new insights into the relationship between HBV and host factors and may provide new strategies for the treatment of HBV infection.
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Affiliation(s)
- Yilin Li
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yishuang Sun
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China
| | - Fuyun Sun
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Rong Hua
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Chenlin Li
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Lang Chen
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Deyin Guo
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China. .,School of Basic Medicine (Shenzhen), Sun Yat-sen University, Guangzhou, 510081, China.
| | - Jingfang Mu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
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