Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their 
cooperatively repressed targets to promote T(H)17 differentiation

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

doi:10.1038/ni.3008

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Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation

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Schmidt-Supprian, Marc
Schmidt-Supprian, Marc / Molecular Immunology and Signaltransduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Jeltsch, K. M., Hu, D., Brenner, S., Zöller, J., Heinz, G. A., Nagel, D., et al. (2014). Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation. NATURE IMMUNOLOGY, 15(11), 1079-1089. doi:10.1038/ni.3008.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0024-457A-F

Abstract

Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (T-FH 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 T(H)17 subset of helper T cells in the lungs. Roquin inhibited T(H)17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the T(H)17 cell promoting factors IL-6, ICOS, c-Rel, IRF4, I kappa BNS and I kappa B zeta. 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 T(H)17 differentiation.