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Immature Core protein of hepatitis C virus induces an unfolded protein response through inhibition of ERAD ‐L in a yeast model system
Author(s) -
Takahashi Shota,
Sato Naoko,
Kikuchi Junichi,
Kakinuma Hideaki,
Okawa Jun,
Masuyama Yukiko,
Iwasa Singo,
Irokawa Hayato,
Hwang GiWook,
Naganuma Akira,
Kohara Michinori,
Kuge Shusuke
Publication year - 2017
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12464
Subject(s) - endoplasmic reticulum associated protein degradation , unfolded protein response , endoplasmic reticulum , biology , microbiology and biotechnology , cytosol , protein degradation , biochemistry , enzyme
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 .