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

  • Mol Cell. 2016 Oct 6;64(1):105-119. doi: 10.1016/j.molcel.2016.08.025.
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
Affiliations
  • 1. Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, PRC.
  • 2. Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, PRC; School of Life Sciences, Zhengzhou University, Zhengzhou 450001, Henan, PRC.
  • 3. Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; Institute of Biosciences and Technology, Texas A&M University, Health Science Center, Houston, TX 77030, USA.
  • 4. Institute of Biosciences and Technology, Texas A&M University, Health Science Center, Houston, TX 77030, USA.
  • 5. Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, PRC; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510275, PRC. Electronic address: [email protected].
  • 6. Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; Institute of Biosciences and Technology, Texas A&M University, Health Science Center, Houston, TX 77030, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA. Electronic address: [email protected].
  • 7. Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, PRC; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University, Guangzhou 510275, PRC. Electronic address: [email protected].
PMID: 27666593 DOI: 10.1016/j.molcel.2016.08.025
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.