新加坡国立大学Vinay Tergaonkar小组取得一项新突破。他们的研究认为端粒酶逆转录酶通过调控cGAS-STING通路在微环境编程中的进化保守作用。相关论文于2025年8月6日发表在《自然—细胞生物学》杂志上。

本研究表明，端粒酶的逆转录酶组分TERT在通过细胞质cGAS-STING核酸感应途径直接调节炎症中具有细胞类型特异性作用。使用小鼠和斑马鱼的肠道炎症模型以及人类结肠炎和克罗恩病样本，该课题组证明了TERT的这种功能是进化保守的。使用他们的敲入tertwaa小鼠模型，其中逆转录酶失活的TERT由其内源性位点驱动，结合分子，药理学和单细胞方法，该课题组确定了称为T-MAC的髓系亚群，其中TERT增强STING激活并启动独立于逆转录酶活性或端粒长度的1型干扰素反应。该研究团队强调了TERT在直接调节炎症中的作用，并提供了除癌症外靶向TERT的治疗原理。

据悉，端粒酶全酶维持端粒长度并调节端粒DNA损伤引起的炎症。然而，除了在端粒维持中的作用外，端粒酶在直接调节炎症中的分子功能尚不清楚。

附：英文原文

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

Author: 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

Issue&Volume: 2025-08-06

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.

DOI: 10.1038/s41556-025-01706-w

Source: https://www.nature.com/articles/s41556-025-01706-w