Deubiquitination of aryl hydrocarbon receptor by USP21 negatively regulates T helper 17 cell differentiation.

IF 3.6 3区医学 Q3 CELL BIOLOGY Journal of Leukocyte Biology Pub Date : 2024-12-31 DOI:10.1093/jleuko/qiae148

Lingbiao Wang, Hao Cheng, Xiaoxia Wang, Fangming Zhu, Na Tian, Zhan Xu, Hanlin Yin, Minrui Liang, Xue Yang, Xinnan Liu, Hongying Shan, Rong Fu, Boran Cao, Dan Li, Lianbo Xiao, Liangjing Lu, Sheng-Ming Dai, Qingwen Wang, Ling Lv, Hejian Zou, Bin Li

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Abstract

Aryl hydrocarbon receptor (AhR) is a key transcription factor that modulates the differentiation of T helper 17 (Th17) cells. How AhR is regulated at the post-translational level in Th17 cells remains largely unclear. Here, we identify USP21 as a newly defined deubiquitinase of AhR. We demonstrate that USP21 interacts with and stabilizes AhR by removing the K48-linked polyubiquitin chains from AhR. Interestingly, USP21 inhibits the transcriptional activity of AhR in a deubiquitinating-dependent manner. USP21 deubiquitinates AhR at the K432 residue, and the maintenance of ubiquitination on this site is required for the intact transcriptional activity of AhR. Moreover, the deficiency of USP21 promotes the differentiation of Th17 cells both in vitro and in vivo. Consistently, adoptive transfer of USP21-deficient naïve CD4+ T cells elicits more severe colitis in Rag1-/- recipients. Therefore, our study reveals a novel mechanism in which USP21 deubiquitinates AhR and negatively regulates the differentiation of Th17 cells.

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USP21对芳基烃受体（AhR）的去泛素化对Th17细胞的分化具有负向调节作用。

芳基烃受体（AhR）是调节 T 辅助细胞 17（Th17）分化的关键转录因子。AhR如何在Th17细胞中进行翻译后调控，目前仍不清楚。在这里，我们发现 USP21 是一种新定义的 AhR 去泛素化酶。我们证明了 USP21 能与 AhR 相互作用，并通过去除 AhR 上与 K48 链接的多泛素链来稳定 AhR。有趣的是，USP21以去泛素依赖的方式抑制了AhR的转录活性。USP21 在 K432 残基上对 AhR 进行去泛素化，而该位点上泛素化的维持是 AhR 完整转录活性所必需的。此外，缺乏 USP21 会促进 Th17 细胞在体外和体内的分化。同样，在 Rag1-/- 受体中，缺乏 USP21 的幼稚 CD4+ T 细胞的采纳性转移会引起更严重的结肠炎。因此，我们的研究揭示了 USP21 去泛素化 AhR 并负向调节 Th17 细胞分化的新机制。

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来源期刊

Journal of Leukocyte Biology 医学-免疫学

CiteScore

11.50

自引率

0.00%

发文量

358

审稿时长

2 months

期刊介绍： JLB is a peer-reviewed, academic journal published by the Society for Leukocyte Biology for its members and the community of immunobiologists. The journal publishes papers devoted to the exploration of the cellular and molecular biology of granulocytes, mononuclear phagocytes, lymphocytes, NK cells, and other cells involved in host physiology and defense/resistance against disease. Since all cells in the body can directly or indirectly contribute to the maintenance of the integrity of the organism and restoration of homeostasis through repair, JLB also considers articles involving epithelial, endothelial, fibroblastic, neural, and other somatic cell types participating in host defense. Studies covering pathophysiology, cell development, differentiation and trafficking; fundamental, translational and clinical immunology, inflammation, extracellular mediators and effector molecules; receptors, signal transduction and genes are considered relevant. Research articles and reviews that provide a novel understanding in any of these fields are given priority as well as technical advances related to leukocyte research methods.