2. Academic Validation
  3. TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses

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

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: hjunjiu@mail.sysu.edu.cn.
  • 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: rwang3@houstonmethodist.org.
  • 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: cuij5@mail.sysu.edu.cn.
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.

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