Journal Article

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

Wulczyn, F. Gregory, König, Julian, Raj, Timsse, Wang, Yinhu, Pan, Wenliang, Urlaub, Henning, Kang, Hyun-Seo, Hoefig, Kai P., Feske, Stefan, Wurst, Wolfgang, Giesert, Florian, Xu, Meng, Tsokos, George C., Adler, Barbara, Hohn, Christine, Sattler, Michael, Straub, Tobias, Ziętara, Natalia, Feederle, Regina, Łyszkiewicz, Marcin, Ito-Kureha, Taku, Chernev, Aleksandar, Heissmeyer, Vigo, Kisielow, Jan, Daniel, Carolin

2024

Overview

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 Ca 2+ 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. Regulation of thymocyte development by RNA-binding proteins is not fully characterized. Here the authors show the RBP ARPP21 interacting with the Rag1 3’-UTR to promote Rag1 expression, TCR rearrangement and an increased diversity of the TCR repertoire and that ARPP21 is down regulated by TCR stimulation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 3' Untranslated regions / 631/250/1619/554/1775 / 631/250/1620/1840 / 631/250/2152/1566/2493 / 631/250/2152/2497 / 631/250/249 / 96 / 96/31 / Animals / Calcium ions / Calcium signalling / Cell Differentiation - genetics / Down-regulation / Gene expression / Humanities and Social Sciences / Lymphocytes / Lymphocytes T / Mice / multidisciplinary / Phenotypes / Phosphorylation / Proteasomes / Proteins / RAG1 protein / Receptors, Antigen, T-Cell - genetics / Receptors, Antigen, T-Cell - metabolism / RNA, Messenger - genetics / RNA, Messenger - metabolism / RNA-binding protein / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Science / Science (multidisciplinary) / STIM1 protein / T cell receptors / Thymocytes / Thymocytes - metabolism / Thymus Gland - metabolism / Transcriptomes / Uridine