Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation

Katharina M. Jeltsch, Desheng Hu, Sven Brenner, Jessica Zöller, Gitta A. Heinz, Daniel Nagel, Katharina U. Vogel, Nina Rehage, Sebastian C. Warth, Stephanie L. Edelmann, Renee Gloury, Nina Martin, Claudia Lohs, Maciej Lech, Jenny E. Stehklein, Arie Geerlof, Elisabeth Kremmer, Achim Weber, Hans Joachim Anders, Ingo SchmitzMarc Schmidt-Supprian, Mingui Fu, Helmut Holtmann, Daniel Krappmann, Jürgen Ruland, Axel Kallies, Mathias Heikenwalder, Vigo Heissmeyer

Research output: Contribution to journalArticle

Abstract

Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (TFH cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the TH 17 subset of helper T cells in the lungs. Roquin inhibited TH 17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the TH 17 cell-promoting factors IL-6, ICOS, c-Rel, IRF4, IκBNS and IκB. This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance TH 17 differentiation.

Original languageEnglish (US)
Pages (from-to)1079-1089
Number of pages11
JournalNature Immunology
Volume15
Issue number11
DOIs
StatePublished - Oct 25 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Jeltsch, K. M., Hu, D., Brenner, S., Zöller, J., Heinz, G. A., Nagel, D., Vogel, K. U., Rehage, N., Warth, S. C., Edelmann, S. L., Gloury, R., Martin, N., Lohs, C., Lech, M., Stehklein, J. E., Geerlof, A., Kremmer, E., Weber, A., Anders, H. J., ... Heissmeyer, V. (2014). Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation. Nature Immunology, 15(11), 1079-1089. https://doi.org/10.1038/ni.3008