title: GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation.
abstract: Hepatitis C virus (HCV) infection is a leading cause of chronic liver diseases and hepatocellular carcinoma (HCC) and Golgi protein 73 (GP73) is a serum biomarker for liver diseases and HCC. However, the mechanism underlying GP73 regulates HCV infection is largely unknown. Here, we revealed that GP73 acts as a novel negative regulator of host innate immunity to facilitate HCV infection. GP73 expression is activated and correlated with interferon-beta (IFN-β) production during HCV infection in patients' serum, primary human hepatocytes (PHHs) and human hepatoma cells through mitochondrial antiviral signaling protein (MAVS), TNF receptor-associated factor 6 (TRAF6) and mitogen-activated protein kinase kinase/extracellular regulated protein kinase (MEK/ERK) pathway. Detailed studies revealed that HCV infection activates MAVS that in turn recruits TRAF6 via TRAF-interacting-motifs (TIMs), and TRAF6 subsequently directly recruits GP73 to MAVS via coiled-coil domain. After binding with MAVS and TRAF6, GP73 promotes MAVS and TRAF6 degradation through proteasome-dependent pathway. Moreover, GP73 attenuates IFN-β promoter, IFN-stimulated response element (ISRE) and nuclear factor κB (NF-κB) promoter and down-regulates IFN-β, IFN-λ1, interleukin-6 (IL-6) and IFN-stimulated gene 56 (ISG56), leading to the repression of host innate immunity. Finally, knock-down of GP73 down-regulates HCV infection and replication in Huh7-MAVSR cells and primary human hepatocytes (PHHs), but such repression is rescued by GP73m4 (a mutant GP73 resists to GP73-shRNA#4) in Huh7-MAVSR cells, suggesting that GP73 facilitates HCV infection. Taken together, we demonstrated that GP73 acts as a negative regulator of innate immunity to facilitate HCV infection by interacting with MAVS/TRAF6 and promoting MAVS/TRAF6 degradation. This study provides new insights into the mechanism of HCV infection and pathogenesis, and suggests that GP73 is a new potential antiviral target in the prevention and treatment of HCV associated diseases.
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China.
authors.forename: Xuewu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China.
authors.forename: Chengliang
authors.initials: C
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China.
authors.forename: Tianci
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China.
authors.forename: Kailang
authors.initials: K
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China.
authors.forename: Yingle
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, P. R. China.
authors.forename: Jianguo
authors.identifier: http://orcid.org/0000-0002-8326-2895
authors.initials: J
authors.lastname: Wu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000998:Antiviral Agents / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002460:Cell Line; D016174:Hepacivirus / Q000302:isolation & purification*; D006526:Hepatitis C / Q000378:metabolism / Q000821:virology; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D007372:Interferons / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000821:virology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D014779:Virus Replication / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; C410824:GOLM1 protein, human; C505371:MAVS protein, human; D008565:Membrane Proteins; D048029:TNF Receptor-Associated Factor 6; D016899:Interferon-beta; D007372:Interferons