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

Meixin Chen; Qingcai Meng; Yunfei Qin; Puping Liang; Peng Tan; Lian He; Yubin Zhou; Yongjun Chen; Junjiu Huang; Rong-Fu Wang; Jun Cui

doi:10.1016/j.molcel.2016.08.025

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. Epub 2016 Sep 22.

Authors

Meixin Chen¹, Qingcai Meng¹, Yunfei Qin², Puping Liang¹, Peng Tan³, Lian He⁴, Yubin Zhou⁴, Yongjun Chen¹, Junjiu Huang⁵, Rong-Fu Wang⁶, Jun Cui⁷

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.

MeSH terms

Animals
Autophagy / drug effects
Feedback, Physiological
HEK293 Cells
Herpes Simplex / genetics*
Herpes Simplex / immunology
Herpes Simplex / mortality
Herpes Simplex / virology
Herpesvirus 1, Human / growth & development
Herpesvirus 1, Human / immunology
Host-Pathogen Interactions
Humans
Immunity, Innate*
Interferon Type I / pharmacology
Intracellular Signaling Peptides and Proteins
Lung / drug effects
Lung / immunology
Lung / virology
Mice
Mice, Knockout
Nucleotidyltransferases / genetics*
Nucleotidyltransferases / immunology
Protein Processing, Post-Translational*
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Sequestosome-1 Protein / genetics*
Sequestosome-1 Protein / immunology
Signal Transduction
Survival Analysis
Trans-Activators / genetics*
Trans-Activators / immunology
Tripartite Motif Proteins
Ubiquitin Thiolesterase / antagonists & inhibitors
Ubiquitin Thiolesterase / deficiency
Ubiquitin Thiolesterase / genetics*

Substances

Interferon Type I
Intracellular Signaling Peptides and Proteins
RNA, Small Interfering
Sequestosome-1 Protein
Sqstm1 protein, mouse
Trans-Activators
Trim14 protein, mouse
Tripartite Motif Proteins
Usp14 protein, mouse
Nucleotidyltransferases
cGAS protein, mouse
Ubiquitin Thiolesterase