N6-adenosine methylation of mRNAs requires Wtap expression and controls T cell receptor signaling and survival

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; Heissmeyer, Vigo

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N6-adenosine methylation of mRNAs requires Wtap expression and controls T cell receptor signaling and survival

Ito-Kureha, Taku ORCID Institute for Immunology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität in Munich, Planegg-Martinsried, Germany
Leoni, Cristina ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Borland, Kayla Department of Chemistry, Ludwig-Maximilians-Universität in Munich, Munich, Germany
Cantini, Giulia Research Unit Molecular Immune Regulation, Helmholtz Zentrum München, Munich, Germany - Institute for Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
Bataclan, Marian ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Metzger, Rebecca N. Institute for Immunology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität in Munich, Planegg-Martinsried, Germany
Ammann, Gregor ORCID Department of Chemistry, Ludwig-Maximilians-Universität in Munich, Munich, Germany
Krug, Anne B. ORCID Institute for Immunology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität in Munich, Planegg-Martinsried, Germany
Marsico, Annalisa Institute for Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
Kaiser, Stefanie Department of Chemistry, Ludwig-Maximilians-Universität in Munich, Munich, Germany - Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Frankfurt am Main, Germany
Canzar, Stefan ORCID Gene Center, Ludwig-Maximilians-Universität in Munich, Munich, Germany
Feske, Stefan Department of Pathology, New York University School of Medicine, New York, NY, USA
Monticelli, Silvia ORCID Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
König, Julian ORCID Institute of Molecular Biology, Mainz, Germany
Heissmeyer, Vigo ORCID Institute for Immunology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität in Munich, Planegg-Martinsried, Germany - Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Frankfurt am Main, Germany

2021

Submitted to:

Nature Immunology. - 2021

English 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 mRNA modification affecting splicing, translation and stability of transcripts. Here, we describe the Wtap protein as essential for m6A methyltransferase complex function and reveal its crucial role in TCR signaling. 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 (SOCE) activity and diminished survival of T cells. These findings uncover how m6A modification impacts on TCR signal transduction and determines activation and survival of T cells.

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