内输蛋白
核运输
核定位序列
细胞生物学
生物
核磷蛋白
病毒复制
核蛋白
STAT1
核孔
细胞核
病毒学
信号转导
转录因子
生物化学
细胞质
病毒
基因
作者
Yoichi Miyamoto,Yumi Itoh,Tatsuya Suzuki,Tomohisa Tanaka,Yusuke Sakai,Masaru Koido,Chiaki Hata,Caixia Wang,Mayumi Otani,Kohji Moriishi,Taro Tachibana,Yoichiro Kamatani,Yoshihiro Yoneda,Tomoyoshi Okamoto,Masahiro Oka
标识
DOI:10.1038/s42003-022-03427-4
摘要
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ORF6 is an antagonist of interferon (IFN)-mediated antiviral signaling, achieved through the prevention of STAT1 nuclear localization. However, the exact mechanism through which ORF6 prevents STAT1 nuclear trafficking remains unclear. Herein, we demonstrate that ORF6 directly binds to STAT1 with or without IFN stimulation, resulting in the nuclear exclusion of STAT1. ORF6 also recognizes importin α subtypes with different modes, in particular, high affinity to importin α1 but a low affinity to importin α5. Although ORF6 potentially disrupts the importin α/importin β1-mediated nuclear transport, thereby suppressing the nuclear translocation of the other classical nuclear localization signal-containing cargo proteins, the inhibitory effect of ORF6 is modest when compared with that of STAT1. The results indicate that the drastic nuclear exclusion of STAT1 is attributed to the specific binding with ORF6, which is a distinct strategy for the importin α1-mediated pathway. Combined with the results from a newly-produced replicon system and a hamster model, we conclude that SARS-CoV-2 ORF6 acts as a virulence factor via regulation of nucleocytoplasmic trafficking to accelerate viral replication, resulting in disease progression.
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