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

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. How-ever, the exact mechanism concerning STING activation remains largely enigmatic. Here, we identify tripar-tite 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 associ-ates 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 recruit-ment of TBK1 to STING, ultimately enhancing the STING-dependent type I interferon response. Our study de-fines TRIM10 as a critical activator in cGAS-STING-mediated antiviral and antitumor immunity.

Automated summary

Researchers have identified TRIM10 as a positive regulator of STING signaling, showing that it enhances the STING-dependent type I interferon response by promoting STING aggregation and interaction with TBK1. TRIM10-deficient cells and mice are more susceptible to viral infections and exhibit faster melanoma growth.