The Relationship Between GP73 And HCV Infection And The Function Of GP73 In Antiviral Innate Immunity

Hepatitis C virus (HCV) infection is one of the leading causes of chronic liver diseases and hepatocellular carcinoma (HCC). Golgi protein 73 (GP73), a resident Golgi membrane protein, is a novel promising serum biomarker for the diagnosis of liver diseases and HCC. Although several studies have demonstrated the molecular mechanisms between HCV infection, serum GP73 upregulation and HCC development, the exact function of GP73 remains largely unknown.In this study, we identified a previously undescribed function of GP73 as a negative regulator of virus-triggered innate immune responses. We found that HCV upregulates the expression and secretion of GP73, which correlates with the activation of interferon response, and knockdown of GP73 severely impairs HCV infection and replication. Further studies demonstrated that GP73 negatively regulates virus-triggered signaling. Upon virus infection, GP73 is recruited to the mitochondrial antiviral signaling protein/TNF receptor-associated factor 6 (MAVS/TRAF6) signalosome to inhibit the activation of interferon regulatory factor 3 (IRF3) and nuclear factor ?B (NF-?B) transcription factors, and the production of type ? interferons (IFNs) and proinflammatory cytokines. Furthermore, GP73 promotes the degradation of MAVS/TRAF6 signalosome through the proteasome-dependent pathways. On the other hand, we also found that GP73 can mediate the interaction of ApoE and HCV NS5A to promote HCV particle assembly and secretion.Conclusions:GP73 interacts with MAVS/TRAF6 signalosome and promotes its proteasome-dependent degradation to negatively regulate innate immune responses, consequently, facilitates HCV infection and replication. Furthermore, GP73 mediates the interaction of ApoE with HCV NS5A to promote viral particle secretion.