Expression of USP25 associates with fibrosis, inflammation and metabolism changes in IgG4-related disease

Panpan Jiang, Yukai Jing, Siyu Zhao, Caini Lan, Lu Yang, Xin Dai, Li Luo, Shaozhe Cai, Yingzi Zhu, Heather Miller, Juan Lai, Xin Zhang, Xiaochao Zhao, Yonggui Wu, Jingzhi Yang, Wen Zhang, Fei Guan, Bo Zhong, Hisanori Umehara, Jiahui Lei, Lingli Dong () and Chaohong Liu ()
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Panpan Jiang: Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Yukai Jing: Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Siyu Zhao: School of Medicine, Yangtze University
Caini Lan: Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Lu Yang: Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Xin Dai: Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Li Luo: Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Shaozhe Cai: Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Yingzi Zhu: Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Heather Miller: R&D Clinical Reagents
Juan Lai: GeneMind Biosciences Company Limited
Xin Zhang: GeneMind Biosciences Company Limited
Xiaochao Zhao: GeneMind Biosciences Company Limited
Yonggui Wu: the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, PR China; Center for Scientific Research of Anhui Medical University
Jingzhi Yang: Qilu Hospital of Shandong University
Wen Zhang: National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases
Fei Guan: Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Bo Zhong: Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University
Hisanori Umehara: Nagahama City Hospital
Jiahui Lei: Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology
Lingli Dong: Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Chaohong Liu: Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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 Usp25 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.

Date: 2024
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DOI: 10.1038/s41467-024-45977-7

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