The odyssey of cGAS: From cytosol to nucleus

The cyclic GMP-AMP synthase (cGAS) is a widely recognized pattern recognition receptor responsible for detecting pathogenic DNA in the cytosol and inducing the production of type I interferon (IFN) to combat infections. The recently discovered nuclear localization of cGAS has changed the old dogma, illuminated a captivating dimension of innate immunity, and sparked many fundamental questions beyond the field of immunology. This review explores cGAS nuclear localization models, activation mechanisms, and biological significance. This expansion challenges the conventional understanding of cGAS and opens new avenues for scientific exploration, promising insights into cellular surveillance and potentially unveiling new therapeutic targets for immune disorders. [Display omitted] •cGAS is located in the nucleus and tethered to the chromatin.•Post-translational modifications regulate cGAS nuclear localization.•Chromatin tethering and phosphorylation inhibit nuclear cGAS activation.•Nuclear cGAS senses DNA virus HSV-1 infection.•Chromatin perturbation potentially activates nuclear cGAS.