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The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3’-UTR and promoting Rag1 mRNA expression

Author

Listed:
  • Meng Xu

    (Molecular Targets and Therapeutics Center, Helmholtz Zentrum München
    Huazhong University of Science and Technology)

  • Taku Ito-Kureha

    (Ludwig-Maximilians-Universität in Munich)

  • Hyun-Seo Kang

    (Helmholtz Zentrum München
    Technical University of Munich, TUM School of Natural Sciences, Department of Bioscience and Bavarian NMR Center (BNMRZ))

  • Aleksandar Chernev

    (Bioanalytical Mass Spectrometry)

  • Timsse Raj

    (Ludwig-Maximilians-Universität in Munich)

  • Kai P. Hoefig

    (Molecular Targets and Therapeutics Center, Helmholtz Zentrum München)

  • Christine Hohn

    (Ludwig-Maximilians-Universität in Munich)

  • Florian Giesert

    (Helmholtz Zentrum München)

  • Yinhu Wang

    (New York University, Grossman School of Medicine)

  • Wenliang Pan

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Natalia Ziętara

    (Ludwig-Maximilians-Universität in Munich
    Boehringer Ingelheim Pharma GmbH & Co. KG)

  • Tobias Straub

    (Faculty of Medicine, Ludwig-Maximilians-Universität in Munich)

  • Regina Feederle

    (German Research Center for Environmental Health)

  • Carolin Daniel

    (Helmholtz Diabetes Center at Helmholtz Zentrum München
    German Center for Diabetes Research (DZD)
    Division of Clinical Pharmacology, Department of Medicine IV, Ludwig-Maximilians-Universität München)

  • Barbara Adler

    (Ludwig-Maximilians-Universität in Munich)

  • Julian König

    (Institute of Molecular Biology (IMB))

  • Stefan Feske

    (New York University, Grossman School of Medicine)

  • George C. Tsokos

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Wolfgang Wurst

    (Helmholtz Zentrum München
    Technical University of Munich
    Munich Cluster of Systems Neurology (SyNergy)
    German Center for Neurodegenerative Diseases (DZNE) site Munich)

  • Henning Urlaub

    (Bioanalytical Mass Spectrometry
    University Medical Center Göttingen, Department of Clinical Chemistry, Bioanalytics Group
    Georg-August University Göttingen
    University of Göttingen)

  • Michael Sattler

    (Helmholtz Zentrum München
    Technical University of Munich, TUM School of Natural Sciences, Department of Bioscience and Bavarian NMR Center (BNMRZ))

  • Jan Kisielow

    (ETH Zürich
    Repertoire Immune Medicines (Switzerland) AG)

  • F. Gregory Wulczyn

    (Charite-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health)

  • Marcin Łyszkiewicz

    (Molecular Targets and Therapeutics Center, Helmholtz Zentrum München
    University Medical Center Ulm)

  • Vigo Heissmeyer

    (Molecular Targets and Therapeutics Center, Helmholtz Zentrum München
    Ludwig-Maximilians-Universität in Munich)

Abstract

The regulation of thymocyte development by RNA-binding proteins (RBPs) is largely unexplored. We identify 642 RBPs in the thymus and focus on Arpp21, which shows selective and dynamic expression in early thymocytes. Arpp21 is downregulated in response to T cell receptor (TCR) and Ca2+ signals. Downregulation requires Stim1/Stim2 and CaMK4 expression and involves Arpp21 protein phosphorylation, polyubiquitination and proteasomal degradation. Arpp21 directly binds RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. Analysis of the Arpp21–bound transcriptome reveals strong interactions with the Rag1 3′-UTR. Arpp21–deficient thymocytes show reduced Rag1 expression, delayed TCR rearrangement and a less diverse TCR repertoire. This phenotype is recapitulated in Rag1 3′-UTR mutant mice harboring a deletion of the Arpp21 response region. These findings show how thymocyte-specific Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until signals from the TCR terminate Arpp21 and Rag1 activities.

Suggested Citation

  • Meng Xu & Taku Ito-Kureha & Hyun-Seo Kang & Aleksandar Chernev & Timsse Raj & Kai P. Hoefig & Christine Hohn & Florian Giesert & Yinhu Wang & Wenliang Pan & Natalia Ziętara & Tobias Straub & Regina Fe, 2024. "The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3’-UTR and promoting Rag1 mRNA expression," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46371-z
    DOI: 10.1038/s41467-024-46371-z
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