TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses.
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.
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.
Meixin
M
Chen
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.
Qingcai
Q
Meng
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.
Yunfei
Y
Qin
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.
Puping
P
Liang
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.
Peng
P
Tan
Institute of Biosciences and Technology, Texas A&M University, Health Science Center, Houston, TX 77030, USA.
Lian
L
He
Institute of Biosciences and Technology, Texas A&M University, Health Science Center, Houston, TX 77030, USA.
Yubin
Y
Zhou
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.
Yongjun
Y
Chen
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.
Junjiu
J
Huang
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.
Rong-Fu
RF
Wang
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.
Jun
J
Cui
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D025461:Feedback, Physiological; D057809:HEK293 Cells; D006561:Herpes Simplex / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000821:virology; D018259:Herpesvirus 1, Human / Q000254:growth & development / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D009713:Nucleotidyltransferases / Q000235:genetics* / Q000276:immunology; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics* / Q000276:immunology; D000070584:Tripartite Motif Proteins; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; D009713:Nucleotidyltransferases; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; D015534:Trans-Activators; D000070584:Tripartite Motif Proteins; D043222:Ubiquitin Thiolesterase; C101343:Sqstm1 protein, mouse; C490593:Trim14 protein, mouse; C469268:Usp14 protein, mouse; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
TRIM14; USP14; autophagy; cGAS; p62; type I interferon (IFN) signaling