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

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Article number11379
JournalNature communications
Volume7
DOIs
Publication statusPublished - May 4 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Aizawa, S., Okamoto, T., Sugiyama, Y., Kouwaki, T., Ito, A., Suzuki, T., Ono, C., Fukuhara, T., Yamamoto, M., Okochi, M., Hiraga, N., Imamura, M., Chayama, K., Suzuki, R., Shoji, I., Moriishi, K., Moriya, K., Koike, K., & Matsuura, Y. (2016). TRC8-dependent degradation of hepatitis C virus immature core protein regulates viral propagation and pathogenesis. Nature communications, 7, [11379]. https://doi.org/10.1038/ncomms11379