TRIM69 potentiates the cGAS-STING signalling pathway by promoting STING ubiquitination.

The cytosolic sensor cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is in charge of cytosolic DNA sensing and, as a result, the production of 2'3' cyclic GMP-AMP (cGAMP), which acts as a second messange molecule to activate the stimulator of interferon genes (STING) and the type I interferon (IFN-I) signalling pathway. We demonstrated that the E3 ubiquitin ligase enzyme TRIM69-induced ubiquitination of STING is necessary for cGAS-STING-mediated IFN-I production during antiviral innate immunity. A direct connection between TRIM69 and STING is essential for the ability of TRIM69 to activate the K63-linked ubiquitination of STING, which results in a significant increase in dimerization and downstream activation of TBK1. These findings suggest that TRIM69 is a novel, positive regulatory protein of the cytosolic DNA-sensing pathway, promoting the cGAS-STING signalling pathway.