Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway

Upon DNA stimulation, cyclic GMP-AMP synthase (cGAS) synthesizes the second messenger cyclic GMP-AMP (cGAMP) that binds to the STING, triggering antiviral interferon-β (IFN-β) production. However, it has remained undetermined how hosts regulate cGAS enzymatic activity after the resolution of DNA immunogen. Here, we show that Akt kinase plays a negative role in cGAS-mediated anti-viral immune response. Akt phosphorylated the S291 or S305 residue of the enzymatic domain of mouse or human cGAS, respectively, and this phosphorylation robustly suppressed its enzymatic activity. Consequently, expression of activated Akt led to the reduction of cGAMP and IFN-β production and the increase of herpes simplex virus 1 replication, whereas treatment with Akt inhibitor augmented cGAS-mediated IFN-β production. Furthermore, expression of the phosphorylation-resistant cGAS S291A mutant enhanced IFN-β production upon DNA stimulation, HSV-1 infection, and vaccinia virus infection. Our study identifies an Akt kinase-mediated checkpoint to fine-tune hosts’ immune responses to DNA stimulation. [Display omitted] •Akt-mediated phosphorylation robustly suppresses cGAS enzymatic activity•Akt-mediated phosphorylation changes cytokine production and HSV-1 replication•Akt phosphorylation-resistant cGAS enhances IFN-β production upon virus infection Although a robust cGAS-mediated antiviral response is essential for controlling viral infection, this response must be metered to avoid excessive production of cytokines. Seo et al. show that Akt phosphorylates cGAS and dampens its enzymatic activity as well as anti-viral activity in response to DNA stimulation and DNA virus infection.