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

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.

SUBMITTER: Aizawa S

PROVIDER: S-EPMC4857398 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Aizawa Sayaka S Okamoto Toru T Sugiyama Yukari Y Kouwaki Takahisa T Ito Ayano A Suzuki Tatsuya T Ono Chikako C Fukuhara Takasuke T Yamamoto Masahiro M Okochi Masayasu M Hiraga Nobuhiko N Imamura Michio M Chayama Kazuaki K Suzuki Ryosuke R Shoji Ikuo I Moriishi Kohji K Moriya Kyoji K Koike Kazuhiko K Matsuura Yoshiharu Y

Nature communications 20160504

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 ...[more]

PMID: 27142248

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

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

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