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The E3 deubiquitinase USP17 is a positive regulator of retinoic acid-related orphan nuclear receptor ?t (ROR?t) in Th17 cells.

ABSTRACT: Stable retinoic acid-related orphan nuclear receptor ?t (ROR?t) expression is pivotal for the development and function of Th17 cells. Here we demonstrate that expression of the transcription factor ROR?t can be regulated through deubiquitination, which prevents proteasome-mediated degradation. We establish that USP17 stabilizes ROR?t protein expression by reducing ROR?t polyubiquitination at its Lys-360 residue. In contrast, knockdown of endogenous USP17 in Th17 cells resulted in decreased ROR?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?t expression in Th17 cells can be positively regulated by USP17, thereby modulating Th17 cell functions.

SUBMITTER: Han L

PROVIDER: S-EPMC4162160 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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The E3 deubiquitinase USP17 is a positive regulator of retinoic acid-related orphan nuclear receptor γt (RORγt) in Th17 cells.

Han Lei L Yang Jing J Wang Xiuwen X Wu Qingsi Q Yin Shuying S Li Zhiyuan Z Zhang Jing J Xing Yue Y Chen Zuojia Z Tsun Andy A Li Dan D Piccioni Miranda M Zhang Yu Y Guo Qiang Q Jiang Lindi L Bao Liming L Lv Ling L Li Bin B

The Journal of biological chemistry 20140728 37

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 ...[more]

PMID: 25070893

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Project description:BackgroundAllergic asthma is a heterogeneous chronic inflammatory disease of the airways with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific TH2 and TH17 cells, respectively. Therefore successful treatment of allergic asthma will require suppression of both TH2 and TH17 cells.ObjectiveWe sought to investigate the role of the TH17 cell pathway in regulating TH2 cell responses in allergic asthma.MethodsAllergic asthma was induced by intranasal challenge with proteinase allergens in C57BL/6, Il17a-/-Il17f-/-, and retinoic acid receptor-related orphan receptor γt (RORγt)gfp/gfp mice. A pharmacologic RORγt inhibitor was used to evaluate its preventive and therapeutic effects in allergic asthma. Characteristics of allergic airway inflammation were analyzed by using flow cytometry, histology, quantitative real-time PCR, and ELISA. Mixed bone marrow chimeric mice, fate mapping analysis, short hairpin RNA transduction, and in vitro T-cell differentiation were used for mechanistic studies.ResultsMice deficient in IL-17A and IL-17F, as well as RORγt, exhibited a significant reduction not only in TH17 cell responses but also in TH2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an RORγt inhibitor had significantly diminished TH17 and TH2 cell responses, leading to reduced neutrophil and eosinophil numbers in the airway. RORγt-deficient T cells were intrinsically defective in differentiating into TH2 cells and expressed increased levels of B-cell lymphoma 6 (Bcl6). Bcl6 knockdown resulted in a remarkable restoration of TH2 cell differentiation in RORγt-deficient T cells. Blockade of RORγt also significantly hampered the differentiation of human TH2 and TH17 cells from naive CD4+ T cells.ConclusionRORγt in T cells is required for optimal TH2 cell differentiation by suppressing Bcl6 expression; this finding suggests that targeting RORγt might be a promising approach for the treatment of allergic asthma by concomitantly suppressing TH17 and TH2 cell responses in the airway.

Dataset Information

The E3 deubiquitinase USP17 is a positive regulator of retinoic acid-related orphan nuclear receptor ?t (ROR?t) in Th17 cells.

Publications

The E3 deubiquitinase USP17 is a positive regulator of retinoic acid-related orphan nuclear receptor γt (RORγt) in Th17 cells.

Similar Datasets

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