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Rosenlehner, T.* ; Pennavaria, S.* ; Akçabozan, B.* ; Jahani, S.* ; O'Neill, T.J. ; Krappmann, D. ; Straub, T.* ; Kranich, J.* ; Obst, R.*

Reciprocal regulation of mTORC1 signaling and ribosomal biosynthesis determines cell cycle progression in activated T cells.

Sci. Signal. 17:eadi8753 (2024)

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Open Access Green as soon as Postprint is submitted to ZB.

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Ribosomal biosynthesis in nucleoli is an energy-demanding process driven by all RNA polymerases and hundreds of auxiliary proteins. We investigated how this process is regulated in activated T lymphocytes by T cell receptor (TCR) signals and the multiprotein complexes mTORC1 and mTORC2, both of which contain the kinase mTOR. Deficiency in mTORC1 slowed the proliferation of T cells, with further delays in each consecutive division, an effect not seen with deficiency in mTORC2. mTORC1 signaling was stimulated by components of conventional TCR signaling, and, reciprocally, TCR sensitivity was decreased by mTORC1 inhibition. The substantial increase in the amount of RNA per cell induced by TCR activation was reduced by 50% by deficiency in mTORC1, but not in mTORC2 or in S6 kinases 1 and 2, which are activated downstream of mTORC1. RNA-seq data showed that mTORC1 deficiency reduced the abundance of all RNA biotypes, although rRNA processing was largely intact in activated T cells. Imaging cytometry with FISH probes for nascent pre-rRNA revealed that deletion of mTORC1, but not that of mTORC2, reduced the number and expansion of nucleolar sites of active transcription. Protein translation was consequently decreased by 50% in the absence of mTORC1. Inhibiting RNA polymerase I blocked not only proliferation but also mTORC1 signaling. Our data show that TCR signaling, mTORC1 activity, and ribosomal biosynthesis in the nucleolus regulate each other during biomass production in clonally expanding T cells.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Rna-polymerase-i; Protein S6 Phosphorylation; Mammalian Target; Phosphatidylinositol 3-kinase; Dynamic Regulation; Rapamycin; Transcription; Differentiation; Inactivation; Metabolism

ISSN (print) / ISBN 1945-0877

e-ISSN 1937-9145

Journal Science Signaling

Quellenangaben Volume: 17, Issue: 859, Article Number: eadi8753

Publisher American Association for the Advancement of Science (AAAS)

Publishing Place 1200 New York Ave, Nw, Washington, Dc 20005 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Signaling and Translation (SAT)

Grants Deutsche Krebshilfe grant
German Research