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

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

doi:10.1038/ncomms11379

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

Nat Commun. 2016 May 4:7:11379. doi: 10.1038/ncomms11379.

Authors

Sayaka Aizawa¹, Toru Okamoto¹, Yukari Sugiyama¹, Takahisa Kouwaki¹, Ayano Ito¹, Tatsuya Suzuki¹, Chikako Ono¹, Takasuke Fukuhara¹, Masahiro Yamamoto², Masayasu Okochi³, Nobuhiko Hiraga⁴, Michio Imamura⁴, Kazuaki Chayama⁴, Ryosuke Suzuki⁵, Ikuo Shoji⁶, Kohji Moriishi⁷, Kyoji Moriya⁸, Kazuhiko Koike⁸, Yoshiharu Matsuura¹

Affiliations

¹ Department of Molecular Virology, Osaka University, Osaka, 565-0871 Japan.
² Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
³ Neuropsychiatry and Neurochemistry, Department of Integrated Medicine, Osaka University, Osaka 565-0871, Japan.
⁴ Department of Medicine and Molecular Science, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.
⁵ Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
⁶ Division of Infectious Diseases Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
⁷ Department of Microbiology, Faculty of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
⁸ Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aspartic Acid Endopeptidases / genetics
Aspartic Acid Endopeptidases / metabolism
Disease Models, Animal
Endoplasmic Reticulum Stress / genetics
Fatty Liver / genetics
Fatty Liver / metabolism
Fatty Liver / pathology
Gene Expression Regulation
Haploinsufficiency
Hepacivirus / pathogenicity
Hepacivirus / physiology*
Hepatitis C / genetics*
Hepatitis C / metabolism
Hepatitis C / pathology
Host-Pathogen Interactions*
Humans
Insulin Resistance
Male
Mice
Mice, Transgenic
Proteasome Endopeptidase Complex / metabolism
Proteolysis
Signal Transduction
Ubiquitin / genetics
Ubiquitin / metabolism
Ubiquitin-Protein Ligases / genetics*
Ubiquitin-Protein Ligases / metabolism
Viral Core Proteins / genetics*
Viral Core Proteins / metabolism
Virus Replication*

Substances

Ubiquitin
Viral Core Proteins
nucleocapsid protein, Hepatitis C virus
Ubiquitin-Protein Ligases
Aspartic Acid Endopeptidases
signal peptide peptidase
Proteasome Endopeptidase Complex