TY - JOUR
T1 - Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation
AU - Jeltsch, Katharina M.
AU - Hu, Desheng
AU - Brenner, Sven
AU - Zöller, Jessica
AU - Heinz, Gitta A.
AU - Nagel, Daniel
AU - Vogel, Katharina U.
AU - Rehage, Nina
AU - Warth, Sebastian C.
AU - Edelmann, Stephanie L.
AU - Gloury, Renee
AU - Martin, Nina
AU - Lohs, Claudia
AU - Lech, Maciej
AU - Stehklein, Jenny E.
AU - Geerlof, Arie
AU - Kremmer, Elisabeth
AU - Weber, Achim
AU - Anders, Hans Joachim
AU - Schmitz, Ingo
AU - Schmidt-Supprian, Marc
AU - Fu, Mingui
AU - Holtmann, Helmut
AU - Krappmann, Daniel
AU - Ruland, Jürgen
AU - Kallies, Axel
AU - Heikenwalder, Mathias
AU - Heissmeyer, Vigo
N1 - Funding Information:
We thank H.-M. Jäck and J. Wittmann (Friedrich-Alexander-Universität Erlangen, Germany) for the cloned 3′ UTR of mouse Irf4; and D. Baumjohann for critical reading of the manuscript. Supported by the Deutsche Forschungsgemeinschaft (SFB 1054 TP-A03 and Z02 to V.H.; SFB 1054 TP-B01 to J.R.; SFB 1054 TP-A04 to D.K.; SFB 1054 TP-A02 to M.S.-S; GRK1202 to H.-J.A. and M.L.; SFB TR36 to M.H. and HO1116/5-2 to H.H.) the PCCC (M.H.), the Hofschneider Foundation (M.H.), Boehringer Ingelheim Fonds (G.A.H.) and The Federation of European Biochemical Societies (K.U.V.).
Publisher Copyright:
© 2014 Nature America, Inc. All rights reserved.
PY - 2014/10/25
Y1 - 2014/10/25
N2 - 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.
AB - 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.
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U2 - 10.1038/ni.3008
DO - 10.1038/ni.3008
M3 - Article
C2 - 25282160
AN - SCOPUS:84908209291
SN - 1529-2908
VL - 15
SP - 1079
EP - 1089
JO - Nature Immunology
JF - Nature Immunology
IS - 11
ER -