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Nat Immunol. 2014 Nov;15(11):1079-89. doi: 10.1038/ni.3008. Epub 2014 Oct 5.

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

Author information

1
1] Institute for Immunology, Ludwig-Maximilians-Universität München, Munich, Germany. [2] Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
2
Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
3
Institute for Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
4
Institute of Toxicology and Pharmacology, Research Unit Cellular Signal Integration, Helmholtz Zentrum München, Neuherberg, Germany.
5
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
6
Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.
7
Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.
8
Institute for Surgical Pathology, University Hospital, Zürich, Switzerland.
9
1] Helmholtz Centre for Infection Research, Braunschweig, Germany. [2] Institute for Molecular and Clinical Immunology, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany.
10
Max Planck Institute of Biochemistry, Martinsried, Germany.
11
Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
12
Institute of Biochemistry, Hannover Medical School, Hannover, Germany.
13
Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

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, 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.

PMID:
25282160
DOI:
10.1038/ni.3008
[Indexed for MEDLINE]

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