A Novel Transcript Isoform of TBK1 Negatively Regulates Type I IFN Production by Promoting Proteasomal Degradation of TBK1 and Lysosomal Degradation of IRF3.
A Novel Transcript Isoform of TBK1 Negatively Regulates Type I IFN Production by Promoting Proteasomal Degradation of TBK1 and Lysosomal Degradation of IRF3.
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TBK1 的新型转录亚型通过促进 TBK1 的蛋白酶体降解和 IRF3 的溶酶体降解来负调节 I 型 IFN 的产生
DOI：
10.3389/fimmu.2020.580864
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发表时间：
2020
影响因子：
7.3
通讯作者：
Chang MX
中科院分区：
文献类型：
--
作者：
Zhang J;Wu XM;Hu YW;Chang MX
TANK-BINDING KEK1(TANK-BINDING KEK1)是一种IKK相关的丝氨酸/苏氨酸激酶，在TLR和RLR信号通路诱导抗病毒I型干扰素(IFN)的过程中起着关键作用。在以前的研究中，我们通过靶向功能性的TBK1-IRF3复合体的形成，证明了斑马鱼的TBK1剪接异构体(TBK1_TV1和TBK1_TV2)是RLR抗病毒途径中的主要负调控因子。在本研究中，我们证明了第三种TBK1亚型(即TBK1_TV3)通过促进TBK1和IRF3的降解来抑制斑马鱼I型干扰素的产生。首先，TBK1_TV3的异位表达抑制了鲤鱼病毒诱导的I型干扰素反应的Poly(I：C)-和Spring病毒血症，也抑制了RIG-I、MDA5、MAVs、TBK1和IRF3刺激的干扰素启动子活性的上调。第二，TBK1_TV3靶向TBK1和IRF3，以抑制TBK1二聚体、TBK1-IRF3复合体和IRF3二聚体的形成。值得注意的是，TBK1_TV3通过泛素-蛋白酶体途径促进TBK1的降解，通过溶酶体途径促进IRF3的降解。进一步的分析表明，TBK1_TV3通过靶向TBK1的K251、K256和K271位点，促进了TBK1对K48连接泛素化的降解。总之，我们的结果提示了一种新的TBK1亚型介导的负调控机制，该机制用于平衡I型干扰素和ISGs的产生。
TANK-binding kinase 1 (TBK1), an IKK-related serine/threonine kinase, is pivotal for the induction of antiviral type I interferon (IFN) by TLR and RLR signaling pathways. In a previous study, we demonstrated that TBK1 spliced isoforms (TBK1_tv1 and TBK1_tv2) from zebrafish were dominant negative regulators in the RLR antiviral pathway by targeting the functional TBK1–IRF3 complex formation. In this study, we show that the third TBK1 isoform (namely TBK1_tv3) inhibits zebrafish type I IFN production by promoting TBK1 and IRF3 degradation. First, ectopic expression of TBK1_tv3 suppresses poly(I:C)- and Spring viremia of carp virus-induced type I IFN response, and also inhibits the up-regulation of IFN promoter activities stimulated by RIG-I, MDA5, MAVS, TBK1, and IRF3. Second, TBK1_tv3 targets TBK1 and IRF3 to impair the formation of TBK1 dimer, TBK1–IRF3 complex, and IRF3 dimer. Notably, TBK1_tv3 promotes the degradation of TBK1 through the ubiquitin–proteasome pathway and the degradation of IRF3 through the lysosomal pathway. Further analysis demonstrates that TBK1_tv3 promotes the degradation of TBK1 for K48-linked ubiquitination by targeting the K251, K256, and K271 sites of TBK1. Collectively, our results suggest a novel TBK1 isoform-mediated negative regulation mechanism, which serves to balance the production of type I IFN and ISGs.