TREX1-induced chromosome fragmentation at the interface of innate immunity and genomic instability

Abstract

Abstract The cGAS-STING pathway, a crucial component of innate immunity, recognizes viral DNA in the cytosol. cGAS binds dsDNA and catalyzes the production of the second messenger cGAMP, resulting in the expression of Type I interferons and other pro-inflammatory genes. To prevent autoimmunity, activation of cGAS by cytosolic self-DNA is normally counteracted by the cytosolic nuclease TREX1. In many chromosomally instable cancers, cytosolic self-DNA accumulates as DNA bridges or micronuclei (MN), whose nuclear envelopes are prone to rupture, exposing contained DNA to the cytosol. cGAS activation at ruptured MN is implicated in anti-tumor immunity. However, mechanisms regulating cGAS activation at ruptured MN are yet unknown. Here, we show that TREX1 partially degrades chromosomal DNA in the cytosol to suppress cGAS activation. We observed localization of cGAS and TREX1 to ruptured MN and DNA bridges, strongly suggesting an unknown role for TREX1 in regulating cGAS activation in cancer. After induction of MN or DNA bridge formation, TREX1 KO causes dramatic increases in cGAMP production and cGAS-STING pathway signaling. Furthermore, ruptured MN exhibit TREX1-dependent DNA damage and ssDNA foci. TREX1 is bound to the ER, which is known to invade ruptured MN. We found that an ER binding mutant of TREX1 does not localize to MN anymore and was not able to rescue the TREX1 KO phenotype, suggesting a role for the ER to recruit TREX1 to MN. In summary, we propose that TREX1 enters MN as a consequence of nuclear envelope rupture to partially degrade DNA, thereby suppressing cGAS activation. By eliminating the immunogenic potential of these DNA species, TREX1 may dampen anti-tumor immunity and thereby help cancer cells escape the immune system.