New Frontiers on Intracellular cGAS Activation: Molecular Mechanisms, Cellular Signaling, and Therapeutic Strategies

Abstract

Cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a pivotal role in the innate immune system. As the primary DNA sensor in cells, cGAS binds to dsDNA in the cytoplasm and forms cGAS-DNA liquid-liquid phase separation (LLPS) and activates its catalytic activity. This activation triggers the cGAS-stimulator of interferon genes (STING) signaling pathway, establishing an efficient system for pathogen detection. Beyond pathogen surveillance, cGAS performs a diverse range of roles, involved in inflammatory response, metabolic homeostasis, DNA damage repair, and cell death. These biological functions regulate cellular physiological homeostasis and influence the occurrence and development of diseases. This review provides an overview of the structure, localization, and intracellular biological functions of the cGAS-STING signaling pathway and cGAS-DNA LLPS. Furthermore, we discuss their contribution to the development of tumors, autoimmune diseases, and inflammatory diseases and highlight the innovative strategies in modulating cGAS activity, either through activation or inhibition, as a promising therapeutic approach.

Keywords

Cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (cGAS-STING) / Liquid-liquid phase separation (LLPS) / Biological function / Disease

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