Journal Article

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

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

2014

Overview

Mutations in the RNA-binding protein roquin-1 are known to result in humoral autoimmunity. Heissmeyer and colleagues show that MALT1 cleavage of roquin and regnase-1 downstream of TCR signaling releases cooperatively repressed targets to promote T H 17 cell differentiation 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, IκBNS and IκBζ. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13 / 13/51 / 38 / 38/90 / 42 / 631/250/2152/1566/2493 / 82 / 82/1 / 96 / 96/31 / Antigens / Autoimmunity / Biomedicine / Cell differentiation / Derepression / Genes / Helper cells / Immune response / Immunology / Inactivation / Infectious Diseases / Interferon regulatory factor 4 / Kinases / Lungs / Lymphocytes / Lymphocytes T / Microscopy / Mutation / Paracaspases / Pathology / Post-transcription / Postpartum period / Proteins / Repressors / RNA-binding protein / Transcription factors