NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance
NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance
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DOI：
10.1016/j.cmet.2023.07.009
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发表时间：
2023-10-03
期刊：
影响因子：
29
通讯作者：
Lin，Hui-Kuan
中科院分区：
文献类型：
--
作者：
Chen，Tingjin;Xu，Zhi-Gang;Lin，Hui-Kuan
已知葡萄糖代谢协调肿瘤发生。葡萄糖是否作为一种信号分子直接调节癌蛋白活性的肿瘤发生仍然难以捉摸。在这里，我们报告说，葡萄糖是一个辅因子结合甲基转移酶NSUN 2在氨基酸1-28，以促进NSUN 2寡聚化和激活。NSUN 2激活维持了整体m5 C RNA甲基化，包括TREX 2，并稳定TREX 2以限制胞质dsDNA积累和cGAS/STING激活，从而促进肿瘤发生和抗PD-L1免疫治疗抗性。葡萄糖结合缺陷或破坏葡萄糖/NSUN 2相互作用的NSUN 2突变体消除了NSUN 2活性和TREX 2诱导，导致cGAS/STING激活以用于致癌抑制。引人注目的是，葡萄糖/NSUN 2/TREX 2轴的遗传缺失通过cGAS/STING活化促进细胞凋亡和CD 8 +T细胞浸润来抑制肿瘤发生并克服那些冷肿瘤中的抗PD-L1免疫疗法抗性。我们的研究将NSUN 2鉴定为直接葡萄糖传感器，其被葡萄糖激活通过维持TREX 2表达以使cGAS/STING失活来驱动肿瘤发生和免疫治疗抗性。
Glucose metabolism is known to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Here, we report that glucose is a cofactor binding to methyltransferase NSUN2 at amino acid 1–28 to promote NSUN2 oligomerization and activation. NSUN2 activation maintains global m5C RNA methylation, includingTREX2, and stabilizesTREX2to restrict cytosolic dsDNA accumulation and cGAS/STING activation for promoting tumorigenesis and anti-PD-L1 immunotherapy resistance. An NSUN2 mutant defective in glucose binding or disrupting glucose/NSUN2 interaction abolishes NSUN2 activity and TREX2 induction leading to cGAS/STING activation for oncogenic suppression. Strikingly, genetic deletion of the glucose/NSUN2/TREX2 axis suppresses tumorigenesis and overcomes anti-PD-L1 immunotherapy resistance in those cold tumors through cGAS/STING activation to facilitate apoptosis and CD8+T cell infiltration. Our study identifies NSUN2 as a direct glucose sensor whose activation by glucose drives tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation.