Kim Min Soo, Kim Sunghoon, Myung Heejoon
Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Yong-In, Gyung-Gi Do, Korea.
Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Korea.
PLoS One. 2014 May 9;9(5):e96302. doi: 10.1371/journal.pone.0096302. eCollection 2014.
Hepatitis C virus (HCV) causes chronic hepatitis leading to liver fibrosis and autoimmune diseases. AIMP1/p43 is a multifunctional protein initially known as a cofactor of aminoacyl tRNA synthetase complex. Its function includes negative regulation of TGF-β signaling and suppression of Lupus-like autoimmune disease by inhibition of surface expression of gp96. HCV E2 was shown to directly interact with AIMP1/p43 by GST pulldown assay and coimmunoprecipitation. Their subcellular colocalization was observed in an immunofluorescence confocal microscopy. We showed that HCV E2 led to degradation of AIMP1/p43 in two ways. First, in the presence of HCV E2, endogenous AIMP1/p43 was shown to be degraded in an ubiquitin-dependent proteasome pathway. Second, grp78, an ER chaperone, was shown to interact with and stabilize AIMP1/p43. And HCV E2 inhibited this interaction leading to reduction of cellular AIMP1/p43. The degradation of AIMP1/p43 by HCV E2 resulted in increase of TGF-β signaling and cell surface expression of gp96. Thus we suggest that these are novel mechanisms responsible for liver fibrosis and autoimmune diseases caused by HCV.
丙型肝炎病毒（HCV）会引发慢性肝炎，进而导致肝纤维化和自身免疫性疾病。AIMP1/p43是一种多功能蛋白，最初被认为是氨酰tRNA合成酶复合体的辅助因子。其功能包括对转化生长因子-β（TGF-β）信号传导的负调控以及通过抑制gp96的表面表达来抑制狼疮样自身免疫性疾病。通过谷胱甘肽-S-转移酶（GST）下拉试验和免疫共沉淀表明，HCV E2可直接与AIMP1/p43相互作用。在免疫荧光共聚焦显微镜下观察到了它们的亚细胞共定位。我们发现HCV E2通过两种方式导致AIMP1/p43降解。首先，在存在HCV E2的情况下，内源性AIMP1/p43显示在泛素依赖性蛋白酶体途径中被降解。其次，内质网伴侣蛋白grp78显示与AIMP1/p43相互作用并使其稳定。而HCV E2抑制这种相互作用，导致细胞内AIMP1/p43减少。HCV E2导致的AIMP1/p43降解致使TGF-β信号传导增加以及gp96的细胞表面表达增加。因此，我们认为这些是由HCV引起的肝纤维化和自身免疫性疾病的新机制。
