The E3 Deubiquitinase USP17 Is a Positive Regulator of Retinoic Acid-related Orphan Nuclear Receptor γt (RORγt) in Th17 Cells

Stable retinoic acid-related orphan nuclear receptor gamma t (ROR gamma t) expression is pivotal for the development and function of Th17 cells. Here we demonstrate that expression of the transcription factor ROR gamma t can be regulated through deubiquitination, which prevents proteasome-mediated degradation. We establish that USP17 stabilizes ROR gamma t protein expression by reducing ROR gamma t polyubiquitination at its Lys-360 residue. In contrast, knockdown of endogenous USP17 in Th17 cells resulted in decreased ROR gamma t protein levels and down-regulation of Th17-related genes. Furthermore, USP17 expression was up-regulated in CD4(+) T cells from systemic lupus erythematosus patients. Our data reveal a molecular mechanism in which ROR gamma t expression in Th17 cells can be positively regulated by USP17, thereby modulating Th17 cell functions.