Abstract:
A characteristic feature of COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is the dysregulated immune response with impaired type I and III interferon (IFN) expression and an overwhelming inflammatory cytokine storm. RIG-I-like receptors (RLRs) and cGAS-STING signaling pathways are responsible for sensing viral infection and inducing IFN production to combat invading viruses. Multiple proteins of SARS-CoV-2 have been reported to modulate the RLR signaling pathways to achieve immune evasion. Although SARS-CoV-2 infection also activates the cGAS-STING signaling by stimulating micronuclei formation during the process of syncytia, whether SARS-CoV-2 modulates the cGAS-STING pathway requires further investigation. Here, we screened 29 SARS-CoV-2-encoded viral proteins to explore the viral proteins that affect the cGAS-STING signaling pathway and found that SARS-CoV-2 open reading frame 10 (ORF10) targets STING to antagonize IFN activation. Overexpression of ORF10 inhibits cGAS-STING-induced interferon regulatory factor 3 phosphorylation, translocation, and subsequent IFN induction. Mechanistically, ORF10 interacts with STING, attenuates the STING-TBK1 association, and impairs STING oligomerization and aggregation and STING-mediated autophagy; ORF10 also prevents the endoplasmic reticulum (ER)-to-Golgi trafficking of STING by anchoring STING in the ER. Taken together, these findings suggest that SARS-CoV-2 ORF10 impairs the cGAS-STING signaling by blocking the translocation of STING and the interaction between STING and TBK1 to antagonize innate antiviral immunity.
摘要:
COVID-19是由严重急性呼吸道综合征冠状病毒2(SARS-CoV-2)感染引起的疾病的特征,是具有受损的I型和III型干扰素(IFN)表达和压倒性的炎性细胞因子风暴的失调的免疫应答。RIG-I样受体(RLR)和cGAS-STING信号通路负责感知病毒感染和诱导IFN产生以对抗入侵病毒。已经报道了SARS-CoV-2的多种蛋白质调节RLR信号传导途径以实现免疫逃避。尽管SARS-CoV-2感染也通过刺激合胞体过程中的微核形成来激活cGAS-STING信号传导,SARS-CoV-2是否调节cGAS-STING途径需要进一步研究。这里,我们筛选了29种SARS-CoV-2编码的病毒蛋白,以探索影响cGAS-STING信号通路的病毒蛋白,并发现SARS-CoV-2开放阅读框10(ORF10)靶向STING拮抗IFN激活。ORF10过表达抑制cGAS-STING诱导的干扰素调节因子3磷酸化,易位,和随后的IFN诱导。机械上,ORF10与STING交互,衰减STING-TBK1关联,并削弱STING寡聚化和聚集以及STING介导的自噬;ORF10还通过将STING锚定在ER中来防止STING的内质网(ER)到高尔基体运输。一起来看,这些发现表明,SARS-CoV-2ORF10通过阻断STING的易位以及STING与TBK1之间的相互作用来拮抗先天抗病毒免疫,从而损害cGAS-STING信号传导。