Evolutionarily conserved role of telomerase reverse transcriptase in programming the microenvironment via regulation of the cGAS-STING pathway.

Telomerase holoenzyme maintains telomere length and regulates inflammation caused by telomeric DNA damage. However, beyond its role in telomere maintenance, the molecular function of telomerase in directly regulating inflammation remains unclear. Here we show that the reverse transcriptase component of telomerase, TERT, has a cell-type-specific role in directly regulating inflammation via the cytoplasmic cGAS-STING nucleic acid-sensing pathway. Using murine and zebrafish models of gut inflammation as well as human colitis and Crohn's disease samples, we demonstrate that this function of TERT is evolutionarily conserved. Using our knock-in TERTVAA mouse model where reverse-transcriptase-inactive TERT is driven by its endogenous loci, combined with molecular, pharmacological and single-cell approaches, we identify a myeloid subpopulation termed T-MAC wherein TERT enhances STING activation and initiates type 1 interferon responses independent of reverse transcriptase activity or telomere length. We highlight a role of TERT in directly regulating inflammation and provide a therapeutic rationale for targeting TERT beyond cancers.