PDF(Pubmed)
Abstract：
Type I interferons play a fundamental role in innate host defense against viral infections by eliciting the induction of an antiviral gene program that serves to inhibit viral replication. Activation of type I interferon is regulated by the IRF3 transcription factor, which undergoes phosphorylation-dependent activation by the upstream kinase, TBK1, during viral infection. However, the mechanisms by which TBK1 achieves activation to support signaling to IRF3 remain incompletely understood. Here we identified the E3 ubiquitin ligase, tripartite motif containing 28 (TRIM28), as a positive regulator of type I interferon activation by facilitating TBK1 signaling. Genetic deletion of TRIM28 via CRISPR-Cas9 editing resulted in impaired type I interferon activation upon both RNA and DNA virus challenge, corresponding with increased susceptibility to virus infections in TRIM28 knockout cells. Mechanistically, TRIM28 interacted with TBK1 and mediated the assembly of K63-linked ubiquitin chains onto TBK1, a post-translational modification shown to augment TBK1 signal transmission events. TRIM28 knockout cells further displayed defective TBK1 phosphorylation and complex assembly with IRF3, resulting in impaired IRF3 phosphorylation. Altogether, our data demonstrate TBK1 to be a novel substrate for TRIM28 and identify TRIM28 as an essential regulatory factor in controlling innate antiviral immune responses.
摘要：
I型干扰素通过引发用于抑制病毒复制的抗病毒基因程序的诱导,在针对病毒感染的先天宿主防御中起基本作用。I型干扰素的激活受IRF3转录因子的调控，它经历上游激酶的磷酸化依赖性激活，TBK1，在病毒感染期间。然而,TBK1实现激活以支持IRF3信令的机制仍未完全了解。在这里，我们确定了E3泛素连接酶，包含28的三方基序（TRIM28），通过促进TBK1信号传导作为I型干扰素激活的正调节因子。通过CRISPR-Cas9编辑的TRIM28基因缺失导致RNA和DNA病毒攻击后I型干扰素激活受损，与TRIM28敲除细胞对病毒感染的易感性增加相对应。机械上,TRIM28与TBK1相互作用，并介导K63连接的泛素链组装到TBK1上，这是一种翻译后修饰，可增强TBK1信号传递事件。TRIM28敲除细胞进一步显示有缺陷的TBK1磷酸化和与IRF3的复合组装，导致IRF3磷酸化受损。总之,我们的数据表明TBK1是TRIM28的新型底物,并确定TRIM28是控制先天抗病毒免疫反应的重要调节因子.
