PDF(Pubmed)
Abstract：
Foot-and-mouth disease virus (FMDV) has developed various strategies to antagonize the host innate immunity. FMDV Lpro and 3Cpro interfere with type I IFNs through different mechanisms. The structural protein VP3 of FMDV degrades Janus kinase 1 to suppress IFN-γ signaling transduction. Whether non-structural proteins of FMDV are involved in restraining type II IFN signaling pathways is unknown. In this study, it was shown that FMDV replication was resistant to IFN-γ treatment after the infection was established and FMDV inhibited type II IFN induced expression of IFN-γ-stimulated genes (ISGs). We also showed for the first time that FMDV non-structural protein 3C antagonized IFN-γ-stimulated JAK-STAT signaling pathway by blocking STAT1 nuclear translocation. 3Cpro expression significantly reduced the ISGs transcript levels and palindromic gamma-activated sequences (GAS) promoter activity, without affecting the protein level, tyrosine phosphorylation, and homodimerization of STAT1. Finally, we provided evidence that 3C protease activity played an essential role in degrading KPNA1 and thus inhibited ISGs mRNA and GAS promoter activities. Our results reveal a novel mechanism by which an FMDV non-structural protein antagonizes host type II IFN signaling.
摘要：
口蹄疫病毒（FMDV）已经开发了各种策略来拮抗宿主的先天免疫。FMDVLpro和3Cpro通过不同的机制干扰I型IFN。FMDV的结构蛋白VP3降解Janus激酶1以抑制IFN-γ信号转导。FMDV的非结构蛋白是否参与抑制II型IFN信号通路尚不清楚。在这项研究中,研究表明，感染建立后，FMDV复制对IFN-γ治疗具有抗性，并且FMDV抑制II型IFN诱导的IFN-γ刺激基因（ISG）的表达。我们还首次显示FMDV非结构蛋白3C通过阻断STAT1核易位来拮抗IFN-γ刺激的JAK-STAT信号通路。3Cpro表达显着降低了ISGs转录水平和回文γ激活序列（GAS）启动子活性，在不影响蛋白质水平的情况下，酪氨酸磷酸化，和STAT1的同源二聚化。最后,我们提供的证据表明，3C蛋白酶活性在降解KPNA1中起着至关重要的作用，因此抑制了ISGsmRNA和GAS启动子的活性。我们的结果揭示了FMDV非结构蛋白拮抗宿主II型IFN信号的新机制。
