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

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 Feederle, Carolin Daniel, Barbara Adler, Julian König, Stefan Feske, George C. Tsokos, Wolfgang Wurst, Henning Urlaub, Michael Sattler, Jan Kisielow (), F. Gregory Wulczyn (), Marcin Łyszkiewicz () and Vigo Heissmeyer ()
Additional contact information
Meng Xu: Molecular Targets and Therapeutics Center, Helmholtz Zentrum München
Taku Ito-Kureha: Ludwig-Maximilians-Universität in Munich
Hyun-Seo Kang: Helmholtz Zentrum München
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
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
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
Henning Urlaub: Bioanalytical Mass Spectrometry
Michael Sattler: Helmholtz Zentrum München
Jan Kisielow: ETH Zürich
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
Vigo Heissmeyer: Molecular Targets and Therapeutics Center, Helmholtz Zentrum München

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46371-z

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