mTOR signaling promotes rapid m6A mRNA methylation to regulate NK-cell activation and effector functions

IF 8.1 1区 医学 Q1 IMMUNOLOGY Cancer immunology research Pub Date : 2024-04-19 DOI:10.1158/2326-6066.cir-23-0339
Meng Meng, Zhaoyang Zhong, Liang Song, Zhaohui Zhang, Xiaofeng Yin, Xiqiang Xie, Lei Tian, Wei Wu, Yao Yang, Yafei Deng, Hongyan Peng, Shuting Wu, Guanghe Ran, Yuqing Lin, Qiangqiang Lai, Qinghua Bi, Fulin Yan, Yan Ji, Yang Wang, Xiaohui Li, Ping Yi, Jianhua Yu, Youcai Deng
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Abstract

Natural killer (NK) cells can be rapidly activated in response to cytokines during host defense against malignant cells or viral infection. However, it remains unclear what mechanisms precisely and rapidly regulate the expression of the numerous genes involved in activating NK cells. In this study, we discovered that NK-cell N6-methyladenosine (m6A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment. Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double knockout of METTL3/14 significantly impacted NK-cell homeostasis, maturation, and antitumor immunity. This suggests a cooperative role of METTL3 and METTL14 in regulating NK-cell development and effector functions. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m6A methylation. Furthermore, inhibiting mTOR complex 1 (mTORC1) activation prevented m6A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine (SAM) supplementation. Collectively, we have unraveled crucial roles for rapid m6A mRNA methylation downstream of the mTORC1–SAM signal axis in regulating NK-cell activation and effector functions.
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mTOR 信号促进 m6A mRNA 快速甲基化,从而调控 NK 细胞的活化和效应功能
在宿主抵御恶性细胞或病毒感染的过程中,自然杀伤(NK)细胞可在细胞因子的作用下被迅速激活。然而,目前仍不清楚是什么机制精确而快速地调控了参与激活 NK 细胞的众多基因的表达。在这项研究中,我们发现 NK 细胞 N6-甲基腺苷(m6A)甲基化水平在 NK 细胞短期激活后迅速上调,并在肿瘤微环境中被抑制。甲基转移酶样3(METTL3)或METTL14的缺失会适度影响NK细胞的稳态,而METTL3/14的双基因敲除则会显著影响NK细胞的稳态、成熟和抗肿瘤免疫。这表明METTL3和METTL14在调控NK细胞发育和效应功能方面发挥着协同作用。利用甲基化 RNA 免疫沉淀测序(MeRIP-seq),我们证明了参与 NK 细胞效应功能的基因,如 Prf1 和 Gzmb,直接被 m6A 甲基化修饰。此外,抑制 mTOR 复合物 1(mTORC1)的活化可阻止 NK 细胞活化时 m6A 甲基化水平的升高,而补充 S-腺苷蛋氨酸(SAM)可恢复这种情况。总之,我们揭示了 mTORC1-SAM 信号轴下游的快速 m6A mRNA 甲基化在调节 NK 细胞活化和效应功能中的关键作用。
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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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