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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

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