NLRC4 promotes the cGAS‐STING signaling pathway by facilitating CBL‐mediated K63‐linked polyubiquitination of TBK1

Abstract

AbstractTANK‐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.