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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Amino Acid Sequence
  • Animals
  • Binding Sites / immunology
  • Caspases / metabolism*
  • Cell Differentiation / immunology
  • Cell Line
  • Genes, rel / genetics
  • HEK293 Cells
  • Humans
  • Inducible T-Cell Co-Stimulator Protein / genetics
  • Interferon Regulatory Factors / genetics
  • Interleukin-6 / genetics
  • Intracellular Signaling Peptides and Proteins
  • Lung / immunology
  • Lung / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Proteins / genetics
  • RNA, Messenger / genetics
  • RNA-Binding Proteins / metabolism
  • Receptors, Antigen, T-Cell / immunology*
  • Ribonucleases / metabolism*
  • Sequence Alignment
  • Th17 Cells / cytology*
  • Th17 Cells / immunology
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Icos protein, mouse
  • IkappaBNS protein, mouse
  • Inducible T-Cell Co-Stimulator Protein
  • Interferon Regulatory Factors
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • Nfkbiz protein, mouse
  • Nuclear Proteins
  • Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Receptors, Antigen, T-Cell
  • interferon regulatory factor-4
  • Rc3h1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Ribonucleases
  • regnase-1, mouse
  • Caspases
  • Malt1 protein, mouse
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein