Akincilar Semih Can, Fidan Kerem, Kumar Naveen, Ng Qin Feng, Majee Prativa, Wu Lele, Han Darryl J Y, Chan Claire Hian Tzer, Chua Joelle Yi Heng, Idzham Khaireen, Oji Asami, Lee Wei Jie Jonathan, Oehlers Stefan H, Ikawa Masahito, Tergaonkar Vinay
Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
A*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
Nat Cell Biol. 2025 Aug 6. doi: 10.1038/s41556-025-01706-w.
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 TERT 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.
端粒酶全酶维持端粒长度并调节由端粒DNA损伤引起的炎症。然而，除了其在端粒维持中的作用外，端粒酶在直接调节炎症方面的分子功能仍不清楚。在这里，我们表明端粒酶的逆转录酶成分TERT通过细胞质cGAS-STING核酸感应途径在直接调节炎症中具有细胞类型特异性作用。使用肠道炎症的小鼠和斑马鱼模型以及人类结肠炎和克罗恩病样本，我们证明TERT的这一功能在进化上是保守的。使用我们的敲入TERT小鼠模型，其中逆转录酶失活的TERT由其内源基因座驱动，结合分子、药理学和单细胞方法，我们鉴定出一个称为T-MAC的髓系亚群，其中TERT增强STING激活并启动1型干扰素反应，而与逆转录酶活性或端粒长度无关。我们强调了TERT在直接调节炎症中的作用，并为针对癌症以外的TERT提供了治疗依据。
