Aizawa Sayaka, Okamoto Toru, Sugiyama Yukari, Kouwaki Takahisa, Ito Ayano, Suzuki Tatsuya, Ono Chikako, Fukuhara Takasuke, Yamamoto Masahiro, Okochi Masayasu, Hiraga Nobuhiko, Imamura Michio, Chayama Kazuaki, Suzuki Ryosuke, Shoji Ikuo, Moriishi Kohji, Moriya Kyoji, Koike Kazuhiko, Matsuura Yoshiharu
Department of Molecular Virology, Osaka University, Osaka, 565-0871 Japan.
Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Nat Commun. 2016 May 4;7:11379. doi: 10.1038/ncomms11379.
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.
信号肽肽酶（SPP）是一种膜内蛋白酶，参与丙型肝炎病毒（HCV）成熟核心蛋白的产生。在此我们表明，抑制SPP可减少传染性HCV颗粒的产生及发病机制。在SPP基因敲除细胞中产生的或用SPP抑制剂处理后产生的未成熟核心蛋白会被泛素-蛋白酶体途径迅速降解。对表达HCV核心蛋白的转基因小鼠（CoreTg）口服SPP抑制剂可降低核心蛋白的表达，并改善胰岛素抵抗和肝脂肪变性。此外，CoreTg中SPP的单倍剂量不足也有类似作用。E3泛素连接酶TRC8是未成熟核心蛋白降解所必需的。HCV核心蛋白的表达会改变内质网（ER）分布，并在SPP/TRC8双基因敲除细胞中诱导ER应激。这些数据表明，HCV利用SPP切割来规避宿主细胞中ER应激的诱导。
