Ubiquitination of cGAS by TRAF6 regulates anti-DNA viral innate immune responses

cGAS-STING (stimulator of interferon genes) signaling is crucial for the recognition of cytoplasmic double-stranded DNA by host cells and consequently activating innate immune response by promoting the production cGAMP and type I interferon. However, it remains elusive how the cGAS enzymatic activity is regulated dynamically. In this study, we identified TRAF6 as a regulator of cGAS mediated anti-viral innate immunity. Our data showed that either ectopic expression or knockdown of TRAF6 modulates the double strand DNA induced expression of interferon-responsive genes. Mechanistically, TRAF6 specifically promotes cGAS activation by targeting cGAS for ubiquitination. Knockdown of TRAF6 results in a decrease in cGAS-induced IFNβ production when cells were infected with herpes simplex virus-1 (HSV-1). Together, our data identified TRAF6 as a positive regulator of cGAS-STING pathway by regulating cGAS activity.