Immature Core protein of hepatitis C virus induces an unfolded protein response through inhibition of ERAD-L in a yeast model system

Shota Takahashi, Naoko Sato, Junichi Kikuchi, Hideaki Kakinuma, Jun Okawa, Yukiko Masuyama, Singo Iwasa, Hayato Irokawa, Gi Wook Hwang, Akira Naganuma, Michinori Kohara, Shusuke Kuge

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2 Citations (Scopus)

Abstract

The structural protein Core of hepatitis C virus (HCV), a cytosolic protein, induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in hepatocytes, and is responsible for the pathogenesis of persistent HCV infection. Using yeast as a model system, we evaluated mechanisms underlying Core-induced interference of ER homeostasis and UPR, and found that UPR is induced by the immature Core (aa 1–191, Core191) but not by the mature Core (aa 1–177, Core177). Interestingly, Core191 inhibits both ERAD-L, a degradation system responsible for misfolded/unfolded proteins in the ER lumen, and ERAD-M, a degradation system responsible for proteins carrying a misfolded/unfolded region in the ER membrane. In contrast, Core177 inhibits ERAD-M but not ERAD-L. In addition, requirement of an unfolded protein sensor in the ER lumen suggested that inhibition of ERAD-L is probably responsible for Core191-dependent UPR activation. These results implicate inadequate maturation of Core as a trigger for induction of ER stress and UPR.

Original languageEnglish
Pages (from-to)160-173
Number of pages14
JournalGenes to Cells
Volume22
Issue number2
DOIs
Publication statusPublished - 2017 Feb 1

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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    Takahashi, S., Sato, N., Kikuchi, J., Kakinuma, H., Okawa, J., Masuyama, Y., Iwasa, S., Irokawa, H., Hwang, G. W., Naganuma, A., Kohara, M., & Kuge, S. (2017). Immature Core protein of hepatitis C virus induces an unfolded protein response through inhibition of ERAD-L in a yeast model system. Genes to Cells, 22(2), 160-173. https://doi.org/10.1111/gtc.12464