Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells
Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells
复制标题
乳酰化驱动的 METTL3 介导的 RNA m6A 修饰促进肿瘤浸润骨髓细胞的免疫抑制
DOI：
10.1016/j.molcel.2022.02.033
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发表时间：
2022-05-05
期刊：
影响因子：
16
通讯作者：
Wang, Qingqing
中科院分区：
文献类型：
--
作者：
Xiong, Jia;He, Jia;Wang, Qingqing
肿瘤浸润髓样细胞（TIM）是参与肿瘤免疫逃逸的重要细胞群，其功能受多种表观遗传机制调节。RNA N-6-甲基腺苷（m（6）A）修饰在控制TIM功能中的精确调控模式仍然知之甚少。我们的研究表明，TIMs中甲基转移酶样3（methyltransferase-like 3，肌L3）表达的增加与结肠癌患者的不良预后相关，并且肌L3的髓样缺陷减弱了小鼠肿瘤的生长。在TIM中，m（6）A-YTHDF 1轴介导了m（6）A对JAK 1 mRNA的修饰，增强了JAK 1蛋白的翻译效率和随后STAT 3的磷酸化。在肿瘤微环境中积累的乳酸盐通过H3 K18乳酸化有效诱导TIM中的胃L3上调。有趣的是，我们在胃L3的锌指结构域中鉴定了两个乳酰化修饰位点，这是胃L3捕获靶RNA所必需的。我们的结果强调了乳酰化驱动的胃L3介导的RNA m（6）A修饰对于促进TIM的免疫抑制能力的重要性。
Tumor-infiltrating myeloid cells (TIMs) are crucial cell populations involved in tumor immune escape, and their functions are regulated by multiple epigenetic mechanisms. The precise regulation mode of RNA N-6-methyladenosine (m(6)A) modification in controlling TIM function is still poorly understood. Our study revealed that the increased expression of methyltransferase-like 3 (METTL3) in TIMs was correlated with the poor prognosis of colon cancer patients, and myeloid deficiency of METTL3 attenuated tumor growth in mice. METTL3 mediated m(6)A modification on Jak1 mRNA in TIMs, the m(6)A-YTHDF1 axis enhanced JAK1 protein translation efficiency and subsequent phosphorylation of STAT3. Lactate accumulated in tumor microenvironment potently induced METTL3 upregulation in TIMs via H3K18 lactylation. Interestingly, we identified two lactylation modification sites in the zinc-finger domain of METTL3, which was essential for METTL3 to capture target RNA. Our results emphasize the importance of lactylation-driven METTL3-mediated RNA m(6)A modification for promoting the immunosuppressive capacity of TIMs.