RKIP and TBK1 form a positive feedback loop to promote type I interferon production in innateimmunity
RKIP and TBK1 form a positive feedback loop to promote type I interferon production in innateimmunity
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RKIP 和 TBK1 形成正反馈环，促进先天免疫中 I 型干扰素的产生
DOI：
10.15252/embj.201694060
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发表时间：
2016-12-01
期刊：
影响因子：
11.4
通讯作者：
Wang, Xiaojian
中科院分区：
文献类型：
--
作者：
Gu, Meidi;Liu, Zhiyong;Wang, Xiaojian
TANK结合激酶1（TBK1）活化是抗病毒先天免疫中I型干扰素产生的中心事件。然而，TBK1激活的调控机制仍不清楚。在这里，我们报告，Raf激酶抑制蛋白（RKIP）是必不可少的TBK1激活和I型干扰素的生产所引发的病毒感染。在病毒感染后，RKIP在丝氨酸109（S109）处被TBK1磷酸化。RKIP的磷酸化增强其与TBK1的相互作用，进而促进TBK1自身磷酸化。RKIP S109突变为丙氨酸消除了RKIP和TBK1之间的相互作用，以及RKIP的抗病毒功能。RKIP缺陷抑制细胞内双链RNA或DNA诱导的I型干扰素产生。一致地，RKIP缺陷使小鼠更容易受到水泡性口炎病毒（VSV）和单纯疱疹病毒（HSV）感染。这项研究揭示了RKIP和TBK1之间的一个以前未被认识到的正反馈回路，它对于抗病毒先天免疫中I型干扰素的产生至关重要。
TANK-binding kinase 1 (TBK1) activation is a central event in type I interferon production in anti-virus innate immunity. However, the regulatory mechanism underlying TBK1 activation remains unclear. Here we report that Raf kinase inhibitory protein (RKIP) is essential for TBK1 activation and type I interferon production triggered by viral infection. Upon viral infection, RKIP is phosphorylated at serine 109 (S109) by TBK1. Phosphorylation of RKIP enhances its interaction with TBK1 and in turn promotes TBK1 autophosphorylation. Mutation of RKIP S109 to alanine abrogates the interaction between RKIP and TBK1, and the anti-viral function of RKIP. RKIP deficiency inhibits intracellular double-stranded RNA- or DNA-induced type I interferon production. Consistently, RKIP deficiency renders the mice more susceptible to vesicular stomatitis virus (VSV) and herpes simplex virus (HSV) infections. This study reveals a previously unrecognized positive feedback loop between RKIP and TBK1 that is essential for type I interferon production in anti-viral innate immunity.