Preprint

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
  • 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
  • Kellner, 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
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  • 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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  • English
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Biology, life sciences
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CC BY
Open access status
green
Identifiers
  • ARK ark:/12658/srd1325795
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https://n2t.net/ark:/12658/srd1325795
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