The function of Wtap in N ⁶-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. N⁶-methyladenosine (m⁶A) 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 m⁶A methyltransferase complex function and reveal its crucial role in TCR signaling in mouse T cells. Wtap and m⁶A 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 m⁶A 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 m⁶A modification impacts on TCR signal transduction and determines activation and survival of T cells.