TRC8-dependent degradation of hepatitis C virus immature core protein regulates viral propagation and pathogenesis.
TRC8-dependent degradation of hepatitis C virus immature core protein regulates viral propagation and pathogenesis.
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DOI：
10.1038/ncomms11379
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发表时间：
2016-05-04
影响因子：
16.6
通讯作者：
Matsuura Y
中科院分区：
文献类型：
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作者：
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
信号肽肽酶（SPP）是一种参与丙型肝炎病毒（HCV）成熟核心蛋白生成的膜内蛋白酶。本研究表明，抑制SPP可减少感染性HCV颗粒的产生和发病机制。SPP敲除细胞或SPP抑制剂处理产生的未成熟核心蛋白通过泛素-蛋白酶体途径迅速降解。对表达HCV核心蛋白（CoreTg）的转基因小鼠口服SPP抑制剂可降低核心蛋白的表达，改善胰岛素抵抗和肝脏脂肪变性。此外，CoreTg中SPP的单倍不足也有类似的影响。TRC8是一种E3泛素连接酶，是未成熟核心蛋白降解所必需的。HCV核心蛋白的表达改变了SPP/TRC8双敲除细胞内质网（ER）分布并诱导内质网应激。这些数据表明HCV利用SPP裂解来规避宿主细胞内质网应激的诱导。一种细胞蛋白酶，SPP，参与丙型肝炎病毒（HCV）成熟核心蛋白的生产。在这里，作者在小鼠模型中表明，SPP抑制通过E3泛素连接酶TRC8介导的未成熟核心蛋白的蛋白酶体降解来减少病毒的传播和发病。
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. A cellular protease, SPP, participates in production of the mature core protein of hepatitis C virus (HCV). Here, the authors show in mouse models that SPP inhibition reduces viral propagation and pathogenesis via proteasomal degradation of the immature core protein mediated by the E3 ubiquitin ligase TRC8.