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Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T17 differentiation

Jeltsch, KM; Hu, D; Brenner, S; Zoller, J; Heinz, GA; Nagel, D; Vogel, KU; Rehage, N; Warth, SC; Edelmann, SL; Gloury, R; Martin, N; Lohs, C; Lech, M; Stehklein, JE; Geerlof, A; Kremmer, E; Weber, A; Anders, HJ; Schmitz, I; Schmidt-Supprian, M; Fu, M; Holtmann, H; Krappmann, D; Ruland, J; Kallies, A; Heikenwalder, M; Heissmeye, V
Nat Immunol
Journal Article
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 TH17 subset of helper T cells in the lungs. Roquin inhibited TH17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the TH17 cell-promoting factors IL-6, ICOS, c-Rel, IRF4, IkappaBNS and IkappaBzeta. 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 TH17 differentiation.
Molecular Immunology
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Creation Date 2014-10-13 02:21:50 Last Modified 2015-09-29 03:29:40