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Dynamic changes in tRNA modifications and abundance during T cell activation

Rak, Roni and Polonsky, Michal and Eizenberg-Magar, Inbal and Mo, Yufeng and Sakaguchi, Yuriko and Mizrahi, Orel and Nachshon, Aharon and Reich-Zeliger, Shlomit and Stern-Ginossar, Noam and Dahan, Orna and Suzuki, Tsutomu and Friedman, Nir and Pilpel, Yitzhak (2021) Dynamic changes in tRNA modifications and abundance during T cell activation. Proceedings of the National Academy of Sciences, 118 (42). Art. No. e2106556118. ISSN 0027-8424. PMCID PMC8594584. doi:10.1073/pnas.2106556118.

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The tRNA pool determines the efficiency, throughput, and accuracy of translation. Previous studies have identified dynamic changes in the tRNA (transfer RNA) supply and mRNA (messenger RNA) demand during cancerous proliferation. Yet dynamic changes may also occur during physiologically normal proliferation, and these are less well characterized. We examined the tRNA and mRNA pools of T cells during their vigorous proliferation and differentiation upon triggering their antigen receptor. We observed a global signature of switch in demand for codons at the early proliferation phase of the response, accompanied by corresponding changes in tRNA expression levels. In the later phase, upon differentiation, the response of the tRNA pool relaxed back to the basal level, potentially restraining excessive proliferation. Sequencing of tRNAs allowed us to evaluate their diverse base-modifications. We found that two types of tRNA modifications, wybutosine and ms2t6A, are reduced dramatically during T cell activation. These modifications occur in the anticodon loops of two tRNAs that decode “slippery codons,” which are prone to ribosomal frameshifting. Attenuation of these frameshift-protective modifications is expected to increase the potential for proteome-wide frameshifting during T cell proliferation. Indeed, human cell lines deleted of a wybutosine writer showed increased ribosomal frameshifting, as detected with an HIV gag-pol frameshifting site reporter. These results may explain HIV’s specific tropism toward proliferating T cells since it requires ribosomal frameshift exactly on the corresponding codon for infection. The changes in tRNA expression and modifications uncover a layer of translation regulation during T cell proliferation and expose a potential tradeoff between cellular growth and translation fidelity.

Item Type:Article
Related URLs:
URLURL TypeDescription Information ItemData ItemConsensus CDS (CCDS) project ItemGO project ItemMODOMICS database CentralArticle
Polonsky, Michal0000-0003-3871-460X
Eizenberg-Magar, Inbal0000-0001-6940-6226
Nachshon, Aharon0000-0003-2283-5220
Stern-Ginossar, Noam0000-0003-3583-5932
Dahan, Orna0000-0002-8096-5085
Friedman, Nir0000-0002-1078-3921
Additional Information:© 2021 National Academy of Sciences. Published under the PNAS license. Edited by Nahum Sonenberg, McGill University, Montreal, QC, Canada, and approved July 28, 2021 (received for review April 14, 2021). We thank the Y.P. and N.F. laboratory members Noa Hefetz-Aharon, Martin Mikl, Schraga Schwartz, and Daniel Douek for stimulating discussions. We also thank the European Research Council, the Israel Science Foundation, and the Israel Cancer Research Fund for grant support. Data Availability: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database (accession no. GSE165622) (66). Data sources are as follows: The coding sequences of Mus musculus were downloaded from the Consensus CDS (CCDS) project ( For classification of gene categories, defined gene categories by biological process were downloaded from the GO project (; to avoid too-small gene sets, we considered only those with at least 40 genes. Pathway lists were downloaded from mouseMine. For tRNA modifications, annotation of tRNA modifications were downloaded from the MODOMICS (9) database ( Author contributions: R.R., M.P., O.D., N.F., and Y.P. designed research; R.R., M.P., I.E.-M., Y.M., Y.S., O.M., and S.R.-Z., performed research; R.R. contributed new reagents/analytic tools; R.R., A.N., N.S.-G., and Y.P. analyzed data; and R.R., O.D., T.S., N.F., and Y.P. wrote the paper. The authors declare no competing interest. This article is a PNAS Direct Submission. This article contains supporting information online at
Funding AgencyGrant Number
European Research Council (ERC)UNSPECIFIED
Israel Science FoundationUNSPECIFIED
Israel Cancer Research FundUNSPECIFIED
Subject Keywords:transfer RNA; T cell activation; tRNA-modifications; HIV
Issue or Number:42
PubMed Central ID:PMC8594584
Record Number:CaltechAUTHORS:20211013-205829700
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Official Citation:Dynamic changes in tRNA modifications and abundance during T cell activation. Roni Rak, Michal Polonsky, Inbal Eizenberg-Magar, Yufeng Mo, Yuriko Sakaguchi, Orel Mizrahi, Aharon Nachshon, Shlomit Reich-Zeliger, Noam Stern-Ginossar, Orna Dahan, Tsutomu Suzuki, Nir Friedman, Yitzhak Pilpel. Proceedings of the National Academy of Sciences Oct 2021, 118 (42) e2106556118; DOI: 10.1073/pnas.2106556118
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111404
Deposited By: Tony Diaz
Deposited On:13 Oct 2021 21:25
Last Modified:12 Apr 2022 23:40

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