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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)
Verlagsversion DOI PMC
Open Access Gold
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Gene Rearrangement; V(d)j Recombinase; T-cells; Alpha; Assignment; Repress; Roquin
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 15, Heft: 1, Seiten: , Artikelnummer: 2194 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Molecular Immune Regulation (AMIR)
Institute of Structural Biology (STB)
Institute of Developmental Genetics (IDG)
Research Unit Type 1 Diabetes Immunology (TDI)
POF Topic(s) 30203 - Molecular Targets and Therapies
30204 - Cell Programming and Repair
30201 - Metabolic Health
Forschungsfeld(er) Immune Response and Infection
Enabling and Novel Technologies
Genetics and Epidemiology
Helmholtz Diabetes Center
PSP-Element(e) G-501712-001
G-503000-001
G-500500-001
G-502191-001
Förderungen PHS NIH
German Research Foundation
Wilhelm Sander
Krebshilfe
China Postdoctoral Council program of the Helmholtz Association (OCPC)
DOI 10.1038/s41467-024-46371-z
WOS ID 001183186200011
Scopus ID 85187421700
PubMed ID 38467629
Erfassungsdatum 2024-05-08
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