Induction of INKIT by Viral Infection Negatively Regulates Antiviral Responses through Inhibiting Phosphorylation of p65 and IRF3
Induction of INKIT by Viral Infection Negatively Regulates Antiviral Responses through Inhibiting Phosphorylation of p65 and IRF3
复制标题
病毒感染诱导 INKIT 通过抑制 p65 和 IRF3 磷酸化负调节抗病毒反应
DOI：
10.1016/j.chom.2017.06.013
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发表时间：
2017-07-12
影响因子：
30.3
通讯作者：
Huang, Zan
中科院分区：
文献类型：
--
作者：
Lu, Bin;Ren, Yujie;Huang, Zan
转录因子p65和IRF 3在诱导细胞抗病毒反应中起关键作用。p65和IRF 3的磷酸化是其活性所必需的，并且构成关键检查点。在这里，我们报告说，病毒感染诱导上调INKIT，抑制NF-κ B和IRF 3，限制先天性抗病毒反应，通过阻断磷酸化p65和IRF 3。INKIT过表达抑制病毒诱导的p65和IRF 3磷酸化和下游基因的表达。相比之下，敲除或敲除INKIT具有相反的效果：Inkit（-/-）小鼠产生的I型干扰素和促炎细胞因子水平升高，并且与野生型相比对致死性病毒感染更具抵抗力。INKIT与IKKa/B和TBK 1/IKK 3相互作用，损害p65和IRF 3的募集和磷酸化。病毒感染诱导IKK介导的INKIT在Ser 58的磷酸化，导致其从IKK中解离。因此，我们的研究结果揭示了INKIT作为先天性抗病毒反应的调节剂。
The transcription factors p65 and IRF3 play key roles in the induction of cellular antiviral responses. Phosphorylation of p65 and IRF3 is required for their activity and constitutes a key checkpoint. Here we report that viral infection induced upregulation of INKIT, an inhibitor for NF-kB and IRF3 that restricted innate antiviral responses by blocking phosphorylation of p65 and IRF3. INKIT overexpression inhibited virus-induced phosphorylation of p65 and IRF3 and expression of downstream genes. In contrast, knockdown or knockout of INKIT had the opposite effect: Inkit(-/-) mice produced elevated levels of type I interferons and proinflammatory cytokines and were more resistant to lethal viral infection compared to wild-type. INKIT interacted with IKKa/b and TBK1/IKK 3, impairing the recruitment and phosphorylation of p65 and IRF3. Viral infection induced IKK-mediated phosphorylation of INKIT at Ser58, resulting in its dissociation from the IKKs. Our findings thus uncover INKIT as a regulator of innate antiviral responses.