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

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

  • Nat Cell Biol. 2025 Aug;27(8):1342-1356. doi: 10.1038/s41556-025-01706-w.
Semih Can Akincilar # 1,  Kerem Fidan # 1,  Naveen Kumar 1,  Qin Feng Ng 1,  Prativa Majee 1,  Lele Wu 1,  Darryl J Y Han 2,  Claire Hian Tzer Chan 1,  Joelle Yi Heng Chua 1,  Khaireen Idzham 1,  Asami Oji 3,  Wei Jie Jonathan Lee 4 5 6,  Stefan H Oehlers 2,  Masahito Ikawa 3,  Vinay Tergaonkar 7 8
Affiliations

Affiliations

  • 1 Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
  • 2 A*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
  • 3 Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
  • 4 Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Republic of Singapore.
  • 5 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, MD6 Centre for Translational Medicine, Singapore, Republic of Singapore.
  • 6 Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore, Republic of Singapore.
  • 7 Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore. vinayt@imcb.a-star.edu.sg.
  • 8 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Republic of Singapore. vinayt@imcb.a-star.edu.sg.
  • # Contributed equally.
PMID: 40770487 DOI: 10.1038/s41556-025-01706-w
Abstract

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.

Figures
Products