Nuclear cGAS regulates transcription to inhibit lipid metabolism and suppress cell growth

ABSTRACT: cGAS is a cytosolic DNA sensor essential for host defense against viral/bacterial infections. To prevent misactivation, nuclear cGAS is suppressed through nucleosome tethering or BAF binding. However, pathophysiological functions of nuclear cGAS beyond its role as an inactive enzyme remain unclear. We mapped the genome-wide cGAS localization and identify its association with AP-1 transcription factors through a novel TAD domain, operating independently of its established nucleosome binding or DNA binding ability. We demonstrated cGAS regulated LGALS3 transcription and expression, through inhibiting ACAA2 activity, reduced fatty acid oxidation and acetyl-CoA production, thereby lowering cholesterol levels. cGAS depletion increased cellular cholesterol to activate mTORC2/Akt signaling. This leads to increased cell size, enhanced tumor growth and resistance chemotherapy. Together, our study uncovers a novel nuclear cGAS function in governing transcriptome to link cell metabolism with tumor growth and therapy resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE342461 | GEO | 2026/08/26

REPOSITORIES: GEO