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Xu, M. ; Ito-Kureha, T.* ; Kang, H.-S. ; Chernev, A.* ; Raj, T.* ; Hoefig, K.P. ; Hohn, C.* ; Giesert, F. ; Wang, Y.* ; Pan, W.* ; Ziętara, N.* ; Straub, T.* ; Feederle, R. ; Daniel, C. ; Adler, B.* ; König, J.* ; Feske, S.* ; Tsokos, G.C.* ; Wurst, W. ; Urlaub, H.* ; Sattler, M. ; Kisielow, J.* ; Wulczyn, F.G.* ; Łyszkiewicz, M. ; Heissmeyer, V.

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

Nat. Commun. 15:2194 (2024)
Publ. Version/Full Text DOI PMC
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Gene Rearrangement; V(d)j Recombinase; T-cells; Alpha; Assignment; Repress; Roquin
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 15, Issue: 1, Pages: , Article Number: 2194 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Abteilung für Molekulare Immunregulation (AMIR)
Institute of Structural Biology (STB)
Institute of Developmental Genetics (IDG)
CF Monoclonal Antibodies (CF-MAB)
Type 1 Diabetes Immunology (TDI)
Grants PHS NIH
German Research Foundation
Wilhelm Sander
Krebshilfe
China Postdoctoral Council program of the Helmholtz Association (OCPC)