Institute for Immunology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität in Munich, Planegg-Martinsried, Germany.
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
Nat Immunol. 2022 Aug;23(8):1208-1221. doi: 10.1038/s41590-022-01268-1. Epub 2022 Jul 25.
T cell antigen-receptor (TCR) signaling controls the development, activation and survival of T cells by involving several layers and numerous mechanisms of gene regulation. N-methyladenosine (mA) is the most prevalent messenger RNA modification affecting splicing, translation and stability of transcripts. In the present study, we describe the Wtap protein as essential for mA methyltransferase complex function and reveal its crucial role in TCR signaling in mouse T cells. Wtap and mA methyltransferase functions were required for the differentiation of thymocytes, control of activation-induced death of peripheral T cells and prevention of colitis by enabling gut RORγt regulatory T cell function. Transcriptome and epitranscriptomic analyses reveal that mA modification destabilizes Orai1 and Ripk1 mRNAs. Lack of post-transcriptional repression of the encoded proteins correlated with increased store-operated calcium entry activity and diminished survival of T cells with conditional genetic inactivation of Wtap. These findings uncover how mA modification impacts on TCR signal transduction and determines activation and survival of T cells.
T 细胞抗原受体 (TCR) 信号通过涉及几个层次和许多基因调控机制来控制 T 细胞的发育、激活和存活。N6-甲基腺苷 (mA) 是影响剪接、翻译和转录本稳定性的最普遍的信使 RNA 修饰。在本研究中，我们描述了 Wtap 蛋白是 mA 甲基转移酶复合物功能所必需的，并揭示了它在小鼠 T 细胞 TCR 信号中的关键作用。Wtap 和 mA 甲基转移酶功能对于胸腺细胞的分化、外周 T 细胞激活诱导死亡的控制以及通过使肠道 RORγt 调节性 T 细胞功能来预防结肠炎是必需的。转录组和外转录组分析表明，mA 修饰会使 Orai1 和 Ripk1 mRNA 不稳定。缺乏 Wtap 条件性基因缺失的 T 细胞中编码蛋白的转录后抑制缺失，与钙库操纵性钙内流活性增加和细胞存活减少相关。这些发现揭示了 mA 修饰如何影响 TCR 信号转导，并决定 T 细胞的激活和存活。
