PDF(Pubmed)
Abstract：
The newly discovered zoonotic coronavirus swine acute diarrhea syndrome coronavirus (SADS-CoV) causes acute diarrhea, vomiting, dehydration, and high mortality rates in newborn piglets. Although SADS-CoV uses different strategies to evade the host\'s innate immune system, the specific mechanism(s) by which it blocks the interferon (IFN) response remains unidentified. In this study, the potential of SADS-CoV nonstructural proteins (nsp) to inhibit the IFN response was detected. The results determined that nsp1 was a potent antagonist of IFN response. SADS-CoV nsp1 efficiently inhibited signal transducer and activator of transcription 1 (STAT1) phosphorylation by inducing Janus kinase 1 (JAK1) degradation. Subsequent research revealed that nsp1 induced JAK1 polyubiquitination through K11 and K48 linkages, leading to JAK1 degradation via the ubiquitin-proteasome pathway. Furthermore, SADS-CoV nsp1 induced CREB-binding protein degradation to inhibit IFN-stimulated gene production and STAT1 acetylation, thereby inhibiting STAT1 dephosphorylation and blocking STAT1 transport out of the nucleus to receive antiviral signaling. In summary, the results revealed the novel mechanisms by which SADS-CoV nsp1 blocks the JAK-STAT signaling pathway via the ubiquitin-proteasome pathway. This study yielded valuable findings on the specific mechanism of coronavirus nsp1 in inhibiting the JAK-STAT signaling pathway and the strategies of SADS-CoV in evading the host\'s innate immune system.
摘要：
新发现的人畜共患冠状病毒猪急性腹泻综合征冠状病毒（SADS-CoV）引起急性腹泻，呕吐,脱水,新生仔猪死亡率高。虽然SADS-CoV使用不同的策略来逃避宿主的先天免疫系统，其阻断干扰素(IFN)应答的具体机制仍未确定。在这项研究中,检测到SADS-CoV非结构蛋白(nsp)抑制IFN应答的潜力.结果确定nsp1是IFN应答的有效拮抗剂。SADS-CoVnsp1通过诱导Janus激酶1（JAK1）降解有效抑制信号转导和转录激活因子1（STAT1）的磷酸化。随后的研究表明，nsp1通过K11和K48键诱导JAK1聚泛素化，通过泛素-蛋白酶体途径导致JAK1降解。此外，SADS-CoVnsp1诱导CREB结合蛋白（CBP）降解以抑制IFN刺激基因（ISG）的产生和STAT1乙酰化，从而抑制STAT1去磷酸化和阻断STAT1转运出核接受抗病毒信号。总之,研究结果揭示了SADS-CoVnsp1通过泛素-蛋白酶体通路阻断JAK-STAT信号通路的新机制.这项研究对冠状病毒nsp1抑制JAK-STAT信号通路的具体机制以及SADS-CoV逃避宿主先天性免疫系统的策略产生了有价值的发现。
