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

被引：43

作者：

Aizawa, Sayaka ^{[1
]}

Okamoto, Toru ^{[1
]}

Sugiyama, Yukari ^{[1
]}

Kouwaki, Takahisa ^{[1
]}

Ito, Ayano ^{[1
]}

Suzuki, Tatsuya ^{[1
]}

Ono, Chikako ^{[1
]}

Fukuhara, Takasuke ^{[1
]}

Yamamoto, Masahiro ^{[2
]}

Okochi, Masayasu ^{[3
]}

Hiraga, Nobuhiko ^{[4
]}

Imamura, Michio ^{[4
]}

Chayama, Kazuaki ^{[4
]}

Suzuki, Ryosuke ^{[5
]}

Shoji, Ikuo ^{[6
]}

Moriishi, Kohji ^{[7
]}

Moriya, Kyoji ^{[8
]}

Koike, Kazuhiko ^{[8
]}

Matsuura, Yoshiharu ^{[1
]}

机构：

[1] Osaka Univ, Dept Mol Virol, Osaka 5650871, Japan

[2] Osaka Univ, Microbial Dis Res Inst, Dept Immunoparasitol, Osaka 5650871, Japan

[3] Osaka Univ, Dept Integrated Med, Neuropsychiat & Neurochem, Osaka 5650871, Japan

[4] Hiroshima Univ, Sch Med, Dept Med & Mol Sci, Hiroshima 7348551, Japan

[5] Natl Inst Infect Dis, Dept Virol 2, Tokyo 1628640, Japan

[6] Kobe Univ, Grad Sch Med, Ctr Infect Dis, Div Infect Dis Control, Kobe, Hyogo 6500017, Japan

[7] Univ Yamanashi, Fac Med, Dept Microbiol, Yamanashi 4093898, Japan

[8] Univ Tokyo, Grad Sch Med, Dept Gastroenterol, Tokyo 1138655, Japan

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

SIGNAL PEPTIDE PEPTIDASE; JAPANESE-ENCEPHALITIS-VIRUS; INTRAMEMBRANE PROTEOLYSIS; HEPATOCELLULAR-CARCINOMA; LOCALIZATION; REPLICATION; DISLOCATION; DOWNSTREAM; ACTIVATION; PA28-GAMMA;

D O I：

10.1038/ncomms11379

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 HCVcore 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.

引用

页数：12

共 57 条

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