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Free keywords:
NF-KAPPA-B; MESSENGER-RNA DECAY; HELPER T-CELLS; TRANSCRIPTION FACTOR;
PHARMACOLOGICAL INHIBITION; PROTEASE ACTIVITY; PROTECTS MICE; T-H-17
CELLS; ACTIVATION; AUTOIMMUNITY
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, I kappa BNS and I kappa B zeta. 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.