Cellular functions of cGAS-STING signaling

HighlightsCyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling possesses widespread interferon-independent activities, and controls diverse cellular functions.cGAS-STING signaling also controls autophagy, translation, metabolism, condensation, senescence, cell death, and fibrotic and neurodegenerative diseases.Versatile cellular functions of cGAS-STING are mediated by canonical and a few noncanonical pathways.Dysfunction of cGAS-STING-mediated cellular functions and noncanonical signaling underlie disease pathogenesis.AbstractCyclic GMP-AMP (cGAMP) synthase (cGAS) senses misplaced genomic, mitochondrial, and microbial double-stranded DNA (dsDNA) to synthesize 2′3′-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 autophagy, translation, metabolism homeostasis, cellular condensation, DNA damage repair, senescence, and cell death. These dominances adaptively shape cellular 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 developments of cellular physiological states controlled by cGAS-STING machinery, as well as their disease relevance and underlying mechanisms, canonical or noncanonical. Ultimately, exploiting these cellular functions and mechanisms may represent promising targets for disease therapeutics.