The function of Wtap in N6-adenosine methylation of mRNAs controls T cell receptor signaling and survival of T cells

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 6 -methyladenosine (m 6 A) 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 m 6 A methyltransferase complex function and reveal its crucial role in TCR signaling in mouse T cells. Wtap and m 6 A 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 m 6 A 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 m 6 A modification impacts on TCR signal transduction and determines activation and survival of T cells. Heissmeyer and colleagues show that TCR stimulation-induced cell death is controlled by N 6 -methyladenosine (m 6 A) modification of Orai1 and Ripk1 mRNAs. m 6 A is deposited by a ‘writer’ complex of Wtap and the N 6 -methyltransferase and bound by the ‘reader’ protein Ythdf2. T cells lacking Wtap exhibit enhanced Ca 2+ entry in response to TCR ligation and decreased survival due to activation-induced cell death.