cGAS phase separation inhibits TREX1-mediated DNA degradation and enhances cytosolic DNA sensing

Cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA is critical for the immune response to cancer and pathogen infection. Here, we discover that cGAS-DNA phase separation is required to resist negative regulation and allow efficient sensing of immunostimulatory DNA. We map the molecular determinants of cGAS condensate formation and demonstrate that phase separation functions to limit activity of the cytosolic exonuclease TREX1. Mechanistically, phase separation forms a selective environment that suppresses TREX1 catalytic function and restricts DNA degradation to an outer shell at the droplet periphery. We identify a TREX1 mutation associated with the severe autoimmune disease Aicardi-Goutieres syndrome that increases penetration of TREX1 into the repressive droplet interior and specifically impairs degradation of phase-separated DNA. Our results define a critical function of cGAS-DNA phase separation and reveal a molecular mechanism that balances cytosolic DNA degradation and innate immune activation.

Automated summary

The phase separation of cGAS-DNA is critical for efficient sensing of immunostimulatory DNA, as it limits the activity of the cytosolic exonuclease TREX1. This selective environment suppresses TREX1 function and restricts DNA degradation, balancing cytosolic DNA degradation and innate immune activation.