TREX1 exonuclease in immunity and disease

Abstract Three-prime repair exonuclease 1 (TREX1) is the major 3′ to 5′ DNA exonuclease in mammals and plays an essential role in preserving immune homeostasis by controlling cytosolic DNA sensing. By degrading excess self and foreign DNA, TREX1 limits aberrant activation of the cGAS–STING (cyclic GMP-AMP synthase – stimulator of interferon genes) pathway and downstream type I interferon responses. Loss-of-function mutations in TREX1 underlie a spectrum of interferon-driven autoimmune and autoinflammatory syndromes, demonstrating its role as a key regulator of immune tolerance. Beyond autoimmunity, recent discoveries have uncovered critical roles for TREX1 in shaping tumor immunogenicity and modulating antiviral defense through regulation of DNA-sensing pathways. In this review, we summarize current insights into the evolutionary origin, structural mechanisms, and functional repertoire of TREX1 in innate immunity. We further discuss how dysregulation of TREX1 contributes to disease and highlight emerging strategies to therapeutically modulate TREX1 activity in cancer and interferonopathies.