The function of Wtap in N-6-adenosine methylation of mRNAs controls T cell receptor signaling and survival of T cells

Ito-Kureha, Taku; Leoni, Cristina; Borland, Kayla; Cantini, Giulia; Bataclan, Marian; Metzger, Rebecca N.; Ammann, Gregor; Krug, Anne B.; Marsico, Annalisa; Kaiser, Stefanie; Canzar, Stefan; Feske, Stefan; Monticelli, Silvia; König, Julian und Heissmeyer, Vigo (2022): The function of Wtap in N-6-adenosine methylation of mRNAs controls T cell receptor signaling and survival of T cells. In: Nature Immunology, Bd. 23, Nr. 8: S. 1208-1221

Abstract

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 ROR gamma t(+) 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 Ca2+ entry in response to TCR ligation and decreased survival due to activation-induced cell death.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1529-2908
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 444891219
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 432656284
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 210592381
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 313381103