Abstract
Stable retinoic acid-related orphan nuclear receptor γt (RORγt) expression is pivotal for the development and function of Th17 cells. Here we demonstrate that expression of the transcription factor RORγt can be regulated through deubiquitination, which prevents proteasome-mediated degradation. We establish that USP17 stabilizes RORγt protein expression by reducing RORγt polyubiquitination at its Lys-360 residue. In contrast, knockdown of endogenous USP17 in Th17 cells resulted in decreased RORγt 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 RORγt expression in Th17 cells can be positively regulated by USP17, thereby modulating Th17 cell functions.
Highlights
receptor ␥t (ROR␥t) is the master transcription factor in Th17 cells
We screened the effects of deubiquitinating enzymes (DUBs) on ROR␥t-mediated transcriptional activities via the cotransfection of 18 DUBs with ROR␥t and luciferase constructs derived from the Il17a promoter into 293T cells
These results suggest that USP17 operates directly on ROR␥t to enhance ROR␥t-mediated Il17a promoter activation and that the enzymatic activity of USP17 is essential for positive regulation
Summary
ROR␥t is the master transcription factor in Th17 cells. Results: USP17 stabilizes ROR␥t via deubiquitination, and USP17 levels are up-regulated in systemic lupus erythematosus. We demonstrate that expression of the transcription factor ROR␥t can be regulated through deubiquitination, which prevents proteasome-mediated degradation. Our data reveal a molecular mechanism in which ROR␥t expression in Th17 cells can be positively regulated by USP17, thereby modulating Th17 cell functions. Retinoic acid-related orphan nuclear receptor ␥t (ROR␥t) has been identified as the master transcription factor required for the differentiation, maintenance, and proinflammatory functions of Th17 cells [7, 8]. Protein ubiquitination is process that attaches ubiquitin to lysine residues on target proteins and is mediated reciprocally by both E3 ubiquitin ligases and deubiquitinating enzymes This modification regulates a host of intracellular processes, including proteasome proteolysis, protein trafficking, and functional modulation [12, 13]. Novel positive regulator of ROR␥t that is crucial for Th17 cell functions
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