GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation.
GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation.
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GP73 通过促进 MAVS 和 TRAF6 降解来抑制宿主先天免疫反应以促进病毒复制
DOI：
10.1371/journal.ppat.1006321
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发表时间：
2017-04
期刊：
影响因子：
6.7
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Zhang X;Zhu C;Wang T;Jiang H;Ren Y;Zhang Q;Wu K;Liu F;Liu Y;Wu J
丙型肝炎病毒（HCV）感染是慢性肝病和肝细胞癌（HCC）的主要原因，高尔基体蛋白73（GP 73）是肝病和HCC的血清生物标志物。然而，GP 73调节HCV感染的潜在机制在很大程度上是未知的。在这里，我们发现，GP 73作为一种新的负调节宿主先天免疫，以促进HCV感染。在HCV感染患者血清、原代人肝细胞（PHH）和人肝癌细胞中，GP 73表达被激活，并通过线粒体抗病毒信号蛋白（MAVS）、TNF受体相关因子6（TRAF 6）和丝裂原活化蛋白激酶/细胞外调节蛋白激酶（MEK/ERK）途径与干扰素β（IFN-β）的产生相关。详细的研究表明，HCV感染激活MAVS，MAVS又通过TRAF相互作用基序（TIM）招募TRAF 6，TRAF 6随后通过卷曲螺旋结构域直接招募GP 73至MAVS。GP 73与MAVS和TRAF 6结合后，通过蛋白酶体依赖性途径促进MAVS和TRAF 6的降解。此外，GP 73还减弱了IFN-β启动子、IFN刺激的反应元件（ISRE）和核因子κB（NF-κB）启动子，并下调IFN-β、IFN-λ1、白细胞介素-6（IL-6）和IFN刺激的基因56（ISG 56），导致宿主先天免疫受到抑制。最后，GP 73的敲低下调Huh 7-MAVSR细胞和原代人肝细胞（PHH）中的HCV感染和复制，但这种抑制在Huh 7-MAVSR细胞中被GP 73 m4（突变体GP 73抵抗GP 73-shRNA#4）拯救，表明GP 73促进HCV感染。总之，我们证明了GP 73作为先天免疫的负调节剂，通过与MAVS/TRAF 6相互作用并促进MAVS/TRAF 6降解来促进HCV感染。本研究为HCV感染机制和发病机制提供了新的认识，提示GP 73是防治HCV相关疾病的一个潜在的抗病毒新靶点。
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.