炎症
泛素
下调和上调
纤维化
RAC1
外周血单个核细胞
生物
癌症研究
细胞生物学
免疫学
信号转导
医学
病理
遗传学
体外
基因
作者
Panpan Jiang,Yukai Jing,Sheng‐Yin Zhao,ChuanYu Lan,Yang Lü,Xin Dai,Lijun Luo,Shaozhe Cai,Yaowu Zhu,Heather Miller,Juan Liu,X. Zhang,Xiangmo Zhao,Yuangang Wu,Jinmeng Yang,Xuan Zhang,Fei Guan,Bo Zhong,Hisanori Umehara,Jiahui Lei,Lingli Dong,Chaohong Liu
标识
DOI:10.1038/s41467-024-45977-7
摘要
Abstract IgG4-related disease (IgG4-RD) has complex clinical manifestations ranging from fibrosis and inflammation to deregulated metabolism. The molecular mechanisms underpinning these phenotypes are unclear. In this study, by using IgG4-RD patient peripheral blood mononuclear cells (PBMCs), IgG4-RD cell lines and Usp 25 knockout mice, we show that ubiquitin-specific protease 25 (USP25) engages in multiple pathways to regulate fibrotic and inflammatory pathways that are characteristic to IgG4-RD. Reduced USP25 expression in IgG4-RD leads to increased SMAD3 activation, which contributes to fibrosis and induces inflammation through the IL-1β inflammatory axis. Mechanistically, USP25 prevents ubiquitination of RAC1, thus, downregulation of USP25 leads to ubiquitination and degradation of RAC1. Decreased RAC1 levels result in reduced aldolase A release from the actin cytoskeleton, which then lowers glycolysis. The expression of LYN, a component of the B cell receptor signalosome is also reduced in USP25-deficient B cells, which might result in B cell activation deficiency. Altogether, our results indicate a potential anti-inflammatory and anti-fibrotic role for USP25 and make USP25 a promising diagnostic marker and potential therapeutic target in IgG4-RD.
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