Cyclic GMP-AMP synthase (cGAS) is an essential DNA virus sensor that triggers type I interferon (IFN) signaling by producing cGAMP to initiate antiviral immunity. However, post-translational regulation of cGAS remains largely unknown. We report that K48-linked ubiquitination of cGAS is a recognition signal for p62-depdendent selective autophagic degradation. The induction of TRIM14 by type I IFN accelerates cGAS stabilization by recruiting USP14 to cleave the ubiquitin chains of cGAS at lysine (K) 414. Knockout of TRIM14 impairs herpes simplex virus type 1 (HSV-1)-triggered antiviral responses in a cGAS-dependent manner. Due to impaired type I IFN production, Trim14 mice are highly susceptible to lethal HSV-1 infection. Taken together, our findings reveal a positive feedback loop of cGAS signaling generated by TRIM14-USP14 and provide insights into the crosstalk between autophagy and type I IFN signaling in innate immunity.

The noncanonical NF‐κB signaling pathway plays a critical role in a variety of biological functions including chronic inflammation and tumorigenesis. Activation of noncanonical NF‐κB signaling largely relies on the abundance as well as the processing of the NF‐κB family member p100/p52. Here, TRIM14 is identified as a novel positive regulator of the noncanonical NF‐κB signaling pathway. TRIM14 promotes noncanonical NF‐κB activation by targeting p100/p52 in vitro and in vivo. Furthermore, a mechanistic study shows that TRIM14 recruits deubiquitinase USP14 to cleave the K63‐linked ubiquitin chains of p100/p52 at multiple sites, thereby preventing p100/p52 from cargo receptor p62‐mediated autophagic degradation. TRIM14 deficiency in mice significantly impairs noncanonical NF‐κB‐mediated inflammatory responses as well as acute colitis and colitis‐associated colon cancer development. Taken together, these findings establish the TRIM14‐USP14 axis as a crucial checkpoint that controls noncanonical NF‐κB signaling and highlight the crosstalk between autophagy and innate immunity.