The ubiquitin E3 ligase TRIM10 promotes STING aggregation and activation in the Golgi apparatus

Lingli Kong; Chao Sui; Tian Chen; Lei Zhang; Wei Zhao; Yi Zheng; Bingyu Liu; Xiaochen Cheng; Chengjiang Gao

doi:10.1016/j.celrep.2023.112306

The ubiquitin E3 ligase TRIM10 promotes STING aggregation and activation in the Golgi apparatus

Cell Rep. 2023 Apr 25;42(4):112306. doi: 10.1016/j.celrep.2023.112306. Epub 2023 Mar 26.

Authors

Lingli Kong¹, Chao Sui¹, Tian Chen², Lei Zhang¹, Wei Zhao³, Yi Zheng¹, Bingyu Liu¹, Xiaochen Cheng⁴, Chengjiang Gao⁵

Affiliations

¹ Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong 250012, P.R. China; Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China.
² Department of Pathogenic Biology, School of Biomedical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China.
³ Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong 250012, P.R. China; Department of Pathogenic Biology, School of Biomedical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China.
⁴ Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong 250012, P.R. China; Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China. Electronic address: chengxc@sdu.edu.cn.
⁵ Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong 250012, P.R. China; Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China. Electronic address: cgao@sdu.edu.cn.

PMID: 36972172
DOI: 10.1016/j.celrep.2023.112306

Abstract

STING is an endoplasmic reticulum-resident protein regulating innate immunity. After binding with cyclic guanosine monophosphate-AMP (cGAMP), STING translocates from the endoplasmic reticulum (ER) to the Golgi apparatus to stimulate TBK1 and IRF3 activation, leading to expression of type I interferon. However, the exact mechanism concerning STING activation remains largely enigmatic. Here, we identify tripartite motif 10 (TRIM10) as a positive regulator of STING signaling. TRIM10-deficient macrophages exhibit reduced type I interferon production upon double-stranded DNA (dsDNA) or cGAMP stimulation and decreased resistance to herpes simplex virus 1 (HSV-1) infection. Additionally, TRIM10-deficient mice are more susceptible to HSV-1 infection and exhibit faster melanoma growth. Mechanistically, TRIM10 associates with STING and catalyzes K27- and K29-linked polyubiquitination of STING at K289 and K370, which promotes STING trafficking from the ER to the Golgi apparatus, formation of STING aggregates, and recruitment of TBK1 to STING, ultimately enhancing the STING-dependent type I interferon response. Our study defines TRIM10 as a critical activator in cGAS-STING-mediated antiviral and antitumor immunity.

Keywords: CP: Cell biology; CP: Immunology; STING; TRIM10; innate immunity; polyubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA
Golgi Apparatus / metabolism
Herpes Simplex*
Immunity, Innate
Interferon Type I*
Intracellular Signaling Peptides and Proteins
Membrane Proteins / metabolism
Mice
Nucleotidyltransferases / metabolism
Tripartite Motif Proteins
Ubiquitin
Ubiquitin-Protein Ligases

Substances

DNA
Interferon Type I
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Nucleotidyltransferases
TRIM10 protein, mouse
Tripartite Motif Proteins
Ubiquitin
Ubiquitin-Protein Ligases
Sting1 protein, mouse