Cutting Edge: USP27X Deubiquitinates and Stabilizes the DNA Sensor cGAS to Regulate Cytosolic DNA-Mediated Signaling

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, catalyzes the formation of the second messenger 2'3'-cGAMP that binds to STING and triggers the type I IFN signaling. Activation of cGAS can be modulated by several protein posttranslational modifications, including ubiquitination. However, the cGAS activation regulated by protein deubiquitination remains poorly understood. In this study, we identified that deubiquitinase USP27X could interact with cGAS and cleave K48-linked polyubiquitination chains from cGAS, leading to cGAS stabilization. Consistently, knockout of Usp27x in mice macrophages resulted in an accelerated turnover of cGAS, decreased cGAMP production, phosphorylation of TBK1 and IRF3, and IFN-beta production. Furthermore, Usp27x knockout mice macrophages showed impaired innate antiviral responses against HSV type 1 infection. Our data suggest that USP27X is a novel regulator of the cGAS-STING cytosolic DNA sensing pathway.