title: Hepatitis B Virus X Protein Sensitizes TRAIL-Induced Hepatocyte Apoptosis by Inhibiting the E3 Ubiquitin Ligase A20.
abstract: Hepatitis B virus (HBV) infection causes hepatocyte death and liver damage, which may eventually lead to cirrhosis and liver cancer. Hepatitis B virus X protein (HBx) is a key antigen that is critically involved in HBV-associated liver diseases. However, the molecular basis for its pathogenesis, particularly in liver damage, has not been well defined. Herein, we report that HBx was able to enhance the susceptibility of hepatocytes to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Increased sensitivity to TRAIL was associated with HBx-induced upregulation of miR-125a, which, in turn, suppressed the expression of its putative target gene, A20 E3 ligase. Importantly, we demonstrate that the defective expression of A20 impaired the K63-linked polyubiquitination of caspase-8, which reciprocally enhanced the activation of caspase-8, the recruitment of Fas-associated death domain (FADD), and the formation of death-inducing signaling complex (DISC), thereby promoting HBx-mediated apoptotic signaling. Accordingly, antagonizing miR-125a or ectopically expressing A20 in hepatocytes abolished the pro-apoptotic effect of HBx. Conversely, the overexpression of miR-125a or knockdown of A20 mimicked HBx to enhance TRAIL susceptibility in hepatocytes. Thus, we establish, for the first time, a miR-125a/A20-initiated and caspase-8-targeted mechanism by which HBx modulates apoptotic signaling and increases hepatic susceptibility to the damaging agent, which might provide novel insight into HBV-related liver pathology.
authors.affiliation: Department of Basic Medical Science, Key Lab of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Affiliated Hospital of School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Changxin
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Basic Medical Science, Key Lab of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Basic Medical Science, Key Lab of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Basic Medical Science, Key Lab of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Ningtong
authors.initials: N
authors.lastname: Zhuang
authors.affiliation: Department of Basic Medical Science, Key Lab of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Dongjiu
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China.
authors.forename: Jianqin
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Basic Medical Science, Key Lab of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Liyun
authors.initials: L
authors.lastname: Shi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D025821:Polyubiquitin; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D053181:Caspase 8; D008239:Lysine