Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells

Essig, Katharina and Hu, Desheng and Guimaraes, Joao C. and Alterauge, Dominik and Edelmann, Stephanie and Raj, Timsse and Kranich, Jan and Behrens, Gesine and Heiseke, Alexander and Floess, Stefan and Klein, Juliane and Maiser, Andreas and Marschall, Susan and Hrabĕ de Angelis, Martin and Leonhardt, Heinrich and Calkhoven, Cornelis F. and Noessner, Elfriede and Brocker, Thomas and Huehn, Jochen and Krug, Anne B. and Zavolan, Mihaela and Baumjohann, Dirk and Heissmeyer, Vigo. (2017) Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells. Immunity, 47 (6). pp. 1067-1082.e12.

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Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17∼92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Bioinformatics (Zavolan)
UniBasel Contributors:Zavolan, Mihaela and Azevedo Salgado Guimaraes, Joao Carlos
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:19 Oct 2018 14:08
Deposited On:19 Oct 2018 14:08

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