TRC8-dependent degradation of hepatitis C virus immature core protein regulates viral propagation and pathogenesis.

Sayaka Aizawa,Ryosuke Suzuki,Kazuaki Chayama,Toru Okamoto,Takasuke Fukuhara,Masayasu Okochi,Yoshiharu Matsuura,Kazuhiko Koike,Kohji Moriishi,Kyoji Moriya,Ayano Ito,Masahiro Yamamoto,Nobuhiko Hiraga,Chikako Ono,Yukari Sugiyama,Takahisa Kouwaki,Ikuo Shoji,Michio Imamura,Tatsuya Suzuki

doi:10.1038/ncomms11379

Abstract

Signal-peptide peptidase (SPP) is an intramembrane protease that participates in the production of the mature core protein of hepatitis C virus (HCV). Here we show that SPP inhibition reduces the production of infectious HCV particles and pathogenesis. The immature core protein produced in SPP-knockout cells or by treatment with an SPP inhibitor is quickly degraded by the ubiquitin–proteasome pathway. Oral administration of the SPP inhibitor to transgenic mice expressing HCV core protein (CoreTg) reduces the expression of core protein and ameliorates insulin resistance and liver steatosis. Moreover, the haploinsufficiency of SPP in CoreTg has similar effects. TRC8, an E3 ubiquitin ligase, is required for the degradation of the immature core protein. The expression of the HCV core protein alters endoplasmic reticulum (ER) distribution and induces ER stress in SPP/TRC8 double-knockout cells. These data suggest that HCV utilizes SPP cleavage to circumvent the induction of ER stress in host cells.

Highlights

Signal-peptide peptidase (SPP) is an intramembrane protease that participates in the production of the mature core protein of hepatitis C virus (HCV)
We found that the immature HCV core protein produced in SPP gene-knockout (SPPKO) cells or cells treated with an SPP inhibitor was quickly degraded by the ubiquitin– proteasome pathway
We demonstrated that the administration of an SPP inhibitor to CoreTg and single-allele deletion of SPP genes in CoreTg reduced the expression of the core protein and ameliorated insulin resistance and liver steatosis

Summary

Introduction

Signal-peptide peptidase (SPP) is an intramembrane protease that participates in the production of the mature core protein of hepatitis C virus (HCV). The expression of the HCV core protein alters endoplasmic reticulum (ER) distribution and induces ER stress in SPP/TRC8 double-knockout cells. These data suggest that HCV utilizes SPP cleavage to circumvent the induction of ER stress in host cells. The recovery of either SPP or TRC8 expression abrogated the induction of ER stress in SPP/TRC8DKO cells, suggesting that the immature HCV core protein retained in the ER membrane induces ER stress. Our data indicate that the inhibition of SPP activity induces the production of the immature HCV core protein, and TRC8 is involved in the degradation of the immature core protein by the proteasome to circumvent the induction of ER stress

Methods

Results

Conclusion