Publication in detail

Nat Commun. 2016 May 4;7:11379. doi: 10.1038/ncomms11379.

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

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

Osaka University, Osaka, 565-0871, Japan. Hiroshima University School of Medicine, Hiroshima 734-8551, Japan. National Institute of Infectious Diseases, Tokyo 162-8640, Japan. Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. University of Yamanashi, Yamanashi 409-3898, Japan. The University of Tokyo, Tokyo 113-8655, Japan.

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.

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