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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Sayaka Aizawa & Toru Okamoto & Yukari Sugiyama & Takahisa Kouwaki & Ayano Ito & Tatsuya Suzuki & Chikako Ono & Takasuke Fukuhara & Masahiro Yamamoto & Masayasu Okochi & Nobuhiko Hiraga & Michio Imamur, 2016. "TRC8-dependent degradation of hepatitis C virus immature core protein regulates viral propagation and pathogenesis," Nature Communications, Nature, vol. 7(1), pages 1-12, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11379
    DOI: 10.1038/ncomms11379
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