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WASH regulates B cell signaling, metabolism and function through STAT1

Cell Death & Differentiation (2025)Cite this article

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Abstract

Actin and actin polymerization factors regulate the immune system in a complex manner. The function in the cytoplasm has been well-established, where they are important components of the cytoskeleton, controlling cell migration, function, and vesicular transport. However, it remains poorly understood how they enter the nucleus to regulate immunological functions in B cells. Here, our study, through constructing a mouse model with specific WASH deletion in B cells, has shown that a deficiency of WASH leads to a decrease in BCR signaling and B cell metabolism, abnormal B cell differentiation, and a reduction of humoral response. Mechanistically, WASH interacts with pSTAT1 to promote the phosphorylation of STAT1, facilitating its translocation into the nucleus and regulating biological functions. Our study has unveiled the potential molecular mechanisms by which WASH influences B cell signaling, metabolism, and function through STAT1. These findings will offer potential avenues for therapeutic strategies targeting autoimmune diseases.

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Fig. 1: WASH is critical for the development of BM B cells and the differentiation of peripheral B cells.
Fig. 2: WASH positively regulates BCR signaling and early B cell activation.
Fig. 3: WASH regulates B cell spreading and migration via controlling actin.
Fig. 4: WASH regulates the mitochondria mediated cellular metabolism via regulating the RAC-actin-DRP1 axis.
Fig. 5: WASH affects BCR signaling and B cell metabolism by mediating the activation of STAT1.
Fig. 6: WASH controls the humoral immune response.

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Data availability

The RNA-seq and ATAC-seq datasets presented can be found in the online repository of China National GeneBank DataBase (CNGBdb) with accession numbers CNP0004631 and CNP0004928, respectively (https://db.cngb.org/cnsa/). The scRNA-seq data were obtained from the GEO database (https://www.ncbi.nlm.nih.gov/geo/) under accession codes GSE224198, GSE239459, and GSE254176, as well as from the GSA database (http://bigd.big.ac.cn/gsa-human) under accession code HRA001555.

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Acknowledgements

This study is in part supported by the National Key Research and Development Program of China (2023YFC2507900, 2023YFC2706300), the National Natural Science Foundation of China (82371784, 32311530061), R&D Program of Guangzhou Laboratory (SRPG22-006), Hubei Provincial Innovation Group Project 2025AFA204, the China Postdoctoral Science Foundation (2025M771424), the Postdoctor Project of Hubei Province (25110029004), State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases (2024ZZ10014) and the Open Project of Key Laboratory of Vascular Aging (HUST), Ministry of Education (VAME-2025-3).

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Authors and Affiliations

  1. Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China

    Panpan Jiang, Yukai Jing, Xin Dai, Li Luo, Qian Liu, Xiaoyu Li, Shuhan Chen, Zhangfan Wu, Junyang Zhou, Ruyuan Wang, Fei Guan, Lu Yang, Jiahui Lei & Chaohong Liu

  2. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Caini Lan

  3. Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China

    Siyu Zhao, Na Li & Qiuyue Chen

  4. GeneMind Biosciences Company Limited, Shenzhen, China

    Xin Zhang & Juan Lai

  5. Cytek Biosciences, R&D Clinical Reagents, Fremont, CA, USA

    Heather Miller

  6. Britton Chance Center and MoE Key Laboratory for Biomedical Photonics, School of Engineering Sciences, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, China

    Weibing Kuang

  7. Shanghai Key Laboratory of Metabolic Remodeling and Health Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China

    Xingrong Du

  8. Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Pengyan Xia & Zusen Fan

  9. Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou, China

    Zhen-Li Huang

  10. Division of Histology and Embryology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Jun He

  11. Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technolog, Wuhan, China

    Zheng Liu

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  1. Panpan Jiang
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  2. Caini Lan
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  3. Siyu Zhao
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Contributions

PJ drafted the paper and did the data analysis. CNL assisted with the paper. SZ performed flow cytometry experiments. XZ and JL conducted RNA-seq and ATAC-seq analysis. YJ and LL completed the TIRFm and confocal experiments. XD and JZ completed the Co-IP experiments. NL, QC, and QL performed the western blot experiments. XL, SC, ZW, FG, LY, and RW performed the ChIP-PCR experiments. ZH and WK performed STORM experiments. JH performed FRET experiments. ZF, PX, HM, ZL, XD, and JHL checked the manuscript. CHL devised the research and designed the study.

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Correspondence to Chaohong Liu.

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Competing interests

Xin Zhang and Juan Lai were hired from GeneMind Biosciences Company Limited, Shenzhen, China. Heather Miller was from Cytek Biosciences, R&D Clinical Reagents, Fremont, CA, United States. The rest of the authors have no competing interests.

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Jiang, P., Lan, C., Zhao, S. et al. WASH regulates B cell signaling, metabolism and function through STAT1. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01647-9

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