NrCAM activates the NF-κB signalling pathway by competitively binding to SUMO-1 and promotes Th17 cell differentiation in Graves' disease.

IF 4.1 4区 医学 Q2 IMMUNOLOGY Scandinavian Journal of Immunology Pub Date : 2024-11-01 Epub Date: 2024-08-19 DOI:10.1111/sji.13401
Fengjiao Huang, Lijuan Zhang, Yingying Zhou, Shuiying Zhao, Jiao Wang
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Abstract

This study aimed to explore the molecular mechanism of neuronal cell adhesion molecule (NrCAM) by regulating Th17 cell differentiation in the pathogenesis of Graves' disease (GD). Naïve CD4+ T cells were isolated from peripheral blood mononuclear cells of GD patients and healthy control (HC) subjects. During the differentiation of CD4+ T cells into Th17 cells, NrCAM level in GD group was improved. Interference with NrCAM in CD4+ T cells of GD patients decreased the percentage of Th17 cells. NrCAM overexpression in CD4+ T cells of HC subjects increased the percentage of Th17 cells and upregulated p-IκBα, p50, p65, c-Rel protein expressions, and NF-κB inhibitor BAY11-7082 partially reversed NrCAM effect. NrCAM overexpression promoted the degradation of IκBα, and overexpression of small ubiquitin-related modifier 1 (SUMO-1) inhibited IκBα degradation. NrCAM overexpression reduced IκBα binding to SUMO-1. During Th17 cell differentiation in HC group, NrCAM overexpression increased IL-21 levels and secretion, and IL-21 neutralizing antibody reversed this effect. IL-21 level was decreased after p65 interference in CD4+ T cells of HC subjects. p65 interacts with IL-21 promoter region. In conclusion, NrCAM binds to SUMO-1 and increases phosphorylation of IκBα, leading to activation of NF-κB pathway, which promotes Th17 cell differentiation.

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NrCAM 通过与 SUMO-1 竞争性结合激活 NF-κB 信号通路,并促进巴塞杜氏病 Th17 细胞的分化。
本研究旨在探讨神经元细胞粘附分子(NrCAM)调控Th17细胞分化在巴塞杜氏病(GD)发病机制中的分子机制。研究人员从巴塞杜氏病患者和健康对照组(HC)的外周血单核细胞中分离出了幼稚的CD4+ T细胞。在CD4+ T细胞向Th17细胞分化的过程中,GD组的NrCAM水平有所提高。干扰 GD 患者 CD4+ T 细胞中的 NrCAM 会降低 Th17 细胞的比例。在 HC 受试者的 CD4+ T 细胞中过表达 NrCAM 会增加 Th17 细胞的比例,并上调 p-IκBα、p50、p65 和 c-Rel 蛋白的表达,NF-κB 抑制剂 BAY11-7082 可部分逆转 NrCAM 的作用。NrCAM的过表达促进了IκBα的降解,而泛素相关小修饰物1(SUMO-1)的过表达抑制了IκBα的降解。NrCAM的过表达减少了IκBα与SUMO-1的结合。在HC组Th17细胞分化过程中,NrCAM过表达增加了IL-21的水平和分泌,IL-21中和抗体逆转了这一效应。p65与IL-21启动子区域相互作用。总之,NrCAM与SUMO-1结合并增加IκBα的磷酸化,导致NF-κB通路的激活,从而促进Th17细胞的分化。
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来源期刊
CiteScore
7.70
自引率
5.40%
发文量
109
审稿时长
1 months
期刊介绍: This peer-reviewed international journal publishes original articles and reviews on all aspects of basic, translational and clinical immunology. The journal aims to provide high quality service to authors, and high quality articles for readers. The journal accepts for publication material from investigators all over the world, which makes a significant contribution to basic, translational and clinical immunology.
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