NLRC4 promotes the cGAS‐STING signaling pathway by facilitating CBL‐mediated K63‐linked polyubiquitination of TBK1
Rongzhao Zhang, Wenxian Yang, Huifang Zhu, Jingbo Zhai, Mengzhou Xue, Chunfu Zheng
Abstract
Abstract TANK‐binding kinase 1 (TBK1) is crucial in producing type Ⅰ interferons (IFN‐Ⅰ) that play critical functions in antiviral innate immunity. The tight regulation of TBK1, especially its activation, is very important. Here we identify NLRC4 as a positive regulator of TBK1. Ectopic expression of NLRC4 facilitates the activation of the IFN‐β promoter, the mRNA levels of IFN‐β , ISG54 , and ISG56 , and the nuclear translocation of interferon regulatory factor 3 induced by cGAS and STING. Consistently, under herpes simplex virus‐1 (HSV‐1) infection, knockdown or knockout of NLRC4 in BJ cells and primary peritoneal macrophages from Nlrc4 ‐deficient ( Nlrc4 −/− ) mice show attenuated Ifn‐β , Isg54 , and Isg56 mRNA transcription, TBK1 phosphorylation, and augmented viral replications. Moreover, Nlrc4 −/− mice show higher mortality upon HSV‐1 infection. Mechanistically, NLRC4 facilitates the interaction between TBK1 and the E3 ubiquitin ligase CBL to enhance the K63‐linked polyubiquitination of TBK1. Our study elucidates a previously uncharacterized function for NLRC4 in upregulating the cGAS‐STING signaling pathway and antiviral innate immunity.