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