title: TRC8-dependent degradation of hepatitis C virus immature core protein regulates viral propagation and pathogenesis.
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.
authors.affiliation: Department of Molecular Virology, Osaka University, Osaka, 565-0871 Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Aizawa
authors.affiliation: Department of Molecular Virology, Osaka University, Osaka, 565-0871 Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: Department of Molecular Virology, Osaka University, Osaka, 565-0871 Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Sugiyama
authors.affiliation: Department of Molecular Virology, Osaka University, Osaka, 565-0871 Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kouwaki
authors.affiliation: Department of Molecular Virology, Osaka University, Osaka, 565-0871 Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Molecular Virology, Osaka University, Osaka, 565-0871 Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Virology, Osaka University, Osaka, 565-0871 Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Ono
authors.affiliation: Department of Molecular Virology, Osaka University, Osaka, 565-0871 Japan.
authors.forename: Takasuke
authors.initials: T
authors.lastname: Fukuhara
authors.affiliation: Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Neuropsychiatry and Neurochemistry, Department of Integrated Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Okochi
authors.affiliation: Department of Medicine and Molecular Science, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiraga
authors.affiliation: Department of Medicine and Molecular Science, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Imamura
authors.affiliation: Department of Medicine and Molecular Science, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Division of Infectious Diseases Control, Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Shoji
authors.affiliation: Department of Microbiology, Faculty of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Moriishi
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Moriya
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.affiliation: Department of Molecular Virology, Osaka University, Osaka, 565-0871 Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Matsuura
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D057895:Haploinsufficiency; D016174:Hepacivirus / Q000472:pathogenicity / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054884:Host-Pathogen Interactions; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D014758:Viral Core Proteins / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication
chemical_list: D025801:Ubiquitin; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D044767:Ubiquitin-Protein Ligases; D016282:Aspartic Acid Endopeptidases; C460085:signal peptide peptidase; D046988:Proteasome Endopeptidase Complex