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 and Yoshiharu Matsuura ()
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Sayaka Aizawa: Osaka University
Toru Okamoto: Osaka University
Yukari Sugiyama: Osaka University
Takahisa Kouwaki: Osaka University
Ayano Ito: Osaka University
Tatsuya Suzuki: Osaka University
Chikako Ono: Osaka University
Takasuke Fukuhara: Osaka University
Masahiro Yamamoto: Research Institute for Microbial Diseases, Osaka University
Masayasu Okochi: Neuropsychiatry and Neurochemistry, Osaka University
Nobuhiko Hiraga: Hiroshima University School of Medicine
Michio Imamura: Hiroshima University School of Medicine
Kazuaki Chayama: Hiroshima University School of Medicine
Ryosuke Suzuki: National Institute of Infectious Diseases
Ikuo Shoji: Center for Infectious Diseases, Kobe University Graduate School of Medicine
Kohji Moriishi: Faculty of Medicine, University of Yamanashi
Kyoji Moriya: Graduate School of Medicine, The University of Tokyo
Kazuhiko Koike: Graduate School of Medicine, The University of Tokyo
Yoshiharu Matsuura: Osaka University

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11379

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