glycoprotein-e2--hepatitis-c-virus and Autoimmune-Diseases

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.

Topics: Autoimmune Diseases; Blotting, Western; Cell Line, Tumor; Cell Membrane; Cytokines; Endoplasmic Reticulum Chaperone BiP; Heat-Shock Proteins; HEK293 Cells; Humans; Liver Cirrhosis; Membrane Glycoproteins; Microscopy, Fluorescence; Neoplasm Proteins; Proteasome Endopeptidase Complex; Protein Binding; Proteolysis; RNA Interference; RNA-Binding Proteins; Signal Transduction; Transforming Growth Factor beta; Up-Regulation; Viral Envelope Proteins