cGAS, an innate dsDNA sensor with multifaceted functions

Cyclic GMP-AMP synthase (cGAS) functions as a pivotal intracellular sensor for the innate immune sensing of double-stranded DNA (dsDNA), monitoring those nucleic acids from foreign and endogenous sources. Upon assembling into cellular condensates with dsDNA and regulators, cGAS synthesizes 2′3′-cGAMP that activates the downstream STING signaling. This activation triggers a variety of intracellular responses, including autophagy, mRNA translation, interferon signaling, and inflammatory responses. Context-dependently, cGAS resides in diverse cellular compartments, including the nucleus, micronuclei, plasma membrane, and organelle surfaces. Beyond its DNA-sensing role, cGAS can play complex roles in these locations, such as DNA damage repairing, membrane restoration, chromatin condensation, angiogenesis, and aging regulation. This comprehensive review summarizes recent advances in the activation, regulation, and pharmacological management of cGAS, focusing on its molecular mechanisms, post-translational modifications (PTMs), and therapeutic interventions. The functional implications of cGAS in various disease contexts, including infectious diseases, autoinflammatory diseases, autoimmune diseases, aging, and cancers, are also covered.