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-κB 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 IKKα/β and TBK1/IKKɛ, 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.

转录因子p65和IRF3在诱导细胞抗病毒反应中起关键作用。p65和IRF3的磷酸化是其活性所必需的，并且构成了关键的检查要点。在这里，我们报道病毒感染诱导了INKIT的上调，INKIT是NF-κB和IRF3的抑制剂，可通过阻断p65和IRF3的磷酸化来限制先天的抗病毒反应。INKIT过表达抑制病毒诱导的p65和IRF3磷酸化以及下游基因的表达。相反，敲除或敲除INKIT具有相反的效果：Inkit ^-/-与野生型小鼠相比，小鼠产生的I型干扰素和促炎细胞因子水平升高，并且对致命病毒感染的抵抗力更高。INKIT与IKKα/β和TBK1 /IKKɛ相互作用，损害p65和IRF3的募集和磷酸化。病毒感染诱导了IKK在Ser58介导的IKK介导的磷酸化，导致其与IKK分离。因此，我们的发现揭示了INKIT作为先天抗病毒反应的调节剂。