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. 2016 Oct 6;64(1):105-119.
doi: 10.1016/j.molcel.2016.08.025. Epub 2016 Sep 22.

TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses

Meixin Chen  1 , Qingcai Meng  1 , Yunfei Qin  2 , Puping Liang  1 , Peng Tan  3 , Lian He  4 , Yubin Zhou  4 , Yongjun Chen  1 , Junjiu Huang  5 , Rong-Fu Wang  6 , Jun Cui  7
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Free article

TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses

Meixin Chen et al. Mol Cell. .
Free article

Abstract

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.

Keywords: TRIM14; USP14; autophagy; cGAS; p62; type I interferon (IFN) signaling.

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