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Ito-Kureha, T.* ; Leoni, C.* ; Borland, K.* ; Cantini, G. ; Bataclan, M.* ; Metzger, R.N.* ; Ammann, G.* ; Krug, A.B.* ; Marsico, A. ; Kaiser, S.* ; Canzar, S.* ; Feske, S.* ; Monticelli, S.* ; König, J.* ; Heissmeyer, V.

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

Nat. Immunol. 23, 1208-1221 (2022)
Postprint DOI PMC
Open Access Green
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.
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Publication type Article: Journal article
Document type Scientific Article
Language english
Publication Year 2022
HGF-reported in Year 2022
ISSN (print) / ISBN 1529-2908
e-ISSN 1529-2916
Journal Nature Immunology
Quellenangaben Volume: 23, Issue: 8, Pages: 1208-1221 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Reviewing status Peer reviewed
Institute(s) Research Unit Molecular Immune Regulation (AMIR)
Institute of Computational Biology (ICB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
30205 - Bioengineering and Digital Health
Research field(s) Immune Response and Infection
Enabling and Novel Technologies
PSP Element(s) G-501712-001
G-503800-001
Grants Deutsche Forschungsgemeinschaft
DOI 10.1038/s41590-022-01268-1
WOS ID WOS:000829717100001
Scopus ID 85134689911
PubMed ID 35879451
Erfassungsdatum 2022-10-24
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