Abstract 812: Processing of core protein by signal peptide peptidase participates in propagation and pathogenesis of hepatitis C virus

Abstract

Abstract Hepatitis C virus (HCV) is a major causative agent of chronic liver diseases including steatosis, cirrhosis and hepatocellular carcinoma (HCC). The HCV core protein is cleaved off from a precursor polyprotein by a signal peptidase and then further processed by signal peptide peptidase (SPP) within the transmembrane region. However, the biological significance of the processing of HCV core protein by SPP remains largely unknown. Transgenic mice expressing HCV core protein exhibit insulin-resistance, steatosis and finally develop HCC, suggesting that core protein plays crucial roles in pathogenesis of HCV. In this study we have established SPP-knockout (KO) mice and cell lines to examine the roles of SPP on the propagation and pathogenesis of HCV. SPP KO mice were embryonic lethal at around E13.5, therefore we prepared SPP-KO mouse embryonic fibroblast cells (MEFs). In SPP-KO cells, HCV core protein was quickly degraded by proteasome and propagation of HCV was severely impaired. Treatment of cells with LY-411575, an inhibitor for SPP, also induced degradation of HCV core protein and suppressed the production of infectious HCV particles. PA28γ or E6AP, which had been reported to degrade core protein, were not involved in SPP-mediated degradation, suggesting the other mechanisms were involved in SPP-induced core protein degradation. Furthermore, oral administration of LY-411575 into HCV core transgenic mice reduced expression of core protein and cured insulin-resistance. The deletion of one allele of SPP gene in core transgenic mice led to impair the expression of core protein and cure insulin-resistance. These results suggest that SPP is a novel drug target for chronic hepatitis C through suppression of viral propagation and liver failures. Citation Format: Toru Okamoto, Sayaka Aizawa, Takahisa Kouwaki, Tatsuya Suzuki, Takasuke Fukuhara, Kohji Moriishi, Kazuhiko Koike, Yoshiharu Matsuura. Processing of core protein by signal peptide peptidase participates in propagation and pathogenesis of hepatitis C virus. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 812. doi:10.1158/1538-7445.AM2015-812