TERC promotes cellular inflammatory response independent of telomerase
TERC promotes cellular inflammatory response independent of telomerase
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TERC 独立于端粒酶促进细胞炎症反应。
DOI：
10.1093/nar/gkz584
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发表时间：
2019-09-05
影响因子：
14.9
通讯作者：
Zhao, Yong
中科院分区：
文献类型：
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作者：
Liu, Haiying;Yang, Yiding;Zhao, Yong
TERC是端粒酶的RNA组分。然而，TERC在大多数人类终末分化细胞中也普遍表达，这些细胞不具有端粒酶活性。TERC在这些细胞中的功能在很大程度上是未知的。在这里，我们报告TERC通过以非端粒酶依赖的方式刺激NK-κ B通路来增强炎性细胞因子的表达和分泌。TERC在端粒酶阴性细胞中的异位表达改变了431个基因的表达，这些基因高度富集参与细胞免疫。我们使用先前确定的TERC的“结合基序”进行全基因组筛选，并确定了14个由TERC转录调控的基因。其中，有4个基因（LIN 37、TPRG 1 L、TYROBP和USP 16）被证实刺激NK-κ B通路的激活。从机制上讲，TERC通过形成RNA-DNA三链体与这些基因的启动子相关联，从而增强其转录。在体内，患有II型糖尿病和多发性硬化症等炎症相关疾病的患者中TERC和TERC靶基因（TYROBP、TPRG 1 L和USP 16）的表达水平上调。总的来说，这些结果揭示了TERC在刺激炎症反应方面的未知功能，并强调了TERC调节基因转录的新机制。TERC可能是开发抗炎治疗的新靶点。
TERC is an RNA component of telomerase. However, TERC is also ubiquitously expressed in most human terminally differentiated cells, which don't have telomerase activity. The function of TERC in these cells is largely unknown. Here, we report that TERC enhances the expression and secretion of inflammatory cytokines by stimulating NK-kappa B pathway in a telomerase-independent manner. The ectopic expression of TERC in telomerase-negative cells alters the expression of 431 genes with high enrichment of those involved in cellular immunity. We perform genome-wide screening using a previously identified 'binding motif' of TERC and identify 14 genes that are transcriptionally regulated by TERC. Among them, four genes (LIN37, TPRG1L, TYROBP and USP16) are demonstrated to stimulate the activation of NK-kappa B pathway. Mechanistically, TERC associates with the promoter of these genes through forming RNA-DNA triplexes, thereby enhancing their transcription. In vivo, expression levels of TERC and TERC target genes (TYROBP, TPRG1L and USP16) are upregulated in patients with inflammation-related diseases such as type II diabetes and multiple sclerosis. Collectively, these results reveal an unknown function of TERC on stimulating inflammatory response and highlight a new mechanism by which TERC modulates gene transcription. TERC may be a new target for the development of anti-inflammation therapeutics.