Abstract
The cytosolic Three prime Repair EXonuclease 1 (TREX1) is a powerful DNA-degrading enzyme required for clearing cytosolic DNA to prevent aberrant inflammation and autoimmunity. In the absence of TREX1 activity, cytosolic DNA pattern recognition receptors of the innate immune system are constitutively activated by undegraded TREX1 substrates. This triggers a chronic inflammatory response in humans expressing mutant TREX1 alleles, eliciting a spectrum of rare autoimmune diseases dependent on the nature of the mutation. The precise origins of cytosolic DNA targeted by TREX1 continue to emerge, but DNA emerging from the nucleus or taken up by the cell could represent potential sources. In this Review, we explore the biochemical and immunological data supporting the role of TREX1 in suppressing cytosolic DNA sensing, and discuss the possibility that TREX1 may contribute to maintenance of genome integrity.