Cellular functions of cGAS-STING signaling

Cyclic GMP-AMP (cGAMP) synthase (cGAS) senses misplaced genomic, mito-chondrial, and microbial double-stranded DNA (dsDNA) to synthesize 2 & PRIME;3 & PRIME;-cGAMP that mobilizes stimulator of interferon genes (STING) to unleash innate immune responses, constituting a ubiquitous and effective surveillance system against tissue damage and pathogen invasion. However, imbalanced cGAS-STING signaling tethers considerably in infectious, autoimmune, malignant, fibrotic, and neurodegenerative diseases. Recently, multifaceted roles for cGAS-STING signaling at the cellular scale have emerged; these include autoph-agy, translation, metabolism homeostasis, cellular condensation, DNA damage repair, senescence, and cell death. These dominances adaptively shape cellu-lar physiologies and impact disease pathogenesis. However, understanding how DNA sensing-initiated responses trigger these diverse cellular processes remains an outstanding challenge. In this review we discuss recent develop-ments of cellular physiological states controlled by cGAS-STING machinery, as well as their disease relevance and underlying mechanisms, canonical or non-canonical. Ultimately, exploiting these cellular functions and mechanisms may represent promising targets for disease therapeutics.