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AIM2 positively regulates B cell activation and function through the SNX9-PI3K-WASP axis

Cell Death & Differentiation (2025) Cite this article

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Abstract

AIM2, an inflammasome sensor, has been extensively investigated for its ability to induce pyroptosis in macrophages. However, its role in the adaptive immune system remains poorly studied, particularly in B cells. AIM2 knockout mice had decreased follicular (FO) and marginal zone (MZ) B cell subsets and impaired IgG3 switching. The activation of B cells enhanced the co-localization of AIM2 and BCR. Interestingly, AIM2 exerts dual regulatory effects on BCR signaling transduction by positively regulating the PI3K-AKT signaling axis and negatively regulating the BTK-NFκB signaling axis. Through immunoprecipitation-mass spectrometry (IP-MS) analysis, SNX9 was identified as a critical molecule that promotes downstream signaling by facilitating the association of PI3K with CD19 in an AIM2-dependent manner. Furthermore, AIM2 is involved in the endocytosis of BCR and CD19 and the subsequent antigen uptake and presentation processes via SNX9-WASP interaction. In AIM2 knockout mice, this dual regulation leads to reduced overall BCR signaling characterized by decreased calcium signaling and reduced antibody production following RBD immunization. Conversely, AIM2 is overexpressed in B cells of Kawasaki disease patients, contributing to the development of this autoimmune disease. In summary, our study has unveiled a novel positive regulatory role of AIM2 in B cell receptor activation, endocytosis, and humoral response, focusing on AIM2-associated signaling pathways in B cells.

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Fig. 1: AIM2 plays an important role in B lymphocytes and is overexpressed in B cells of Kawasaki disease.
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Fig. 2: AIM2 is required for splenic B cell maturation but is dispensable for BM development or B1 maturation.
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Fig. 3: AIM2 is involved in BCR signal transduction.
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Fig. 4: AIM2 amplifies PI3K and WASP signals by maintaining the scaffolding effect of SNX9.
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Fig. 5: AIM2 regulates OXPHOS in B cells through the PI3K-AKT-mTOR axis.
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Fig. 6: AIM2 is required for B cell cytoskeleton remodeling.
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Fig. 7: AIM2 is involved in the RBD-mediated immune response.
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Data availability

The mouse RNA-Seq data generated in this study have been deposited in the Genome Sequence Archive (GSA) database under accession code CRA017536.

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Funding

This study was 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, Hubei, China

    Yanmei Huang, Li Luo, Yuxin Bai, Weijiayi Wang, Panpan Jiang, Ju Liu, Jiang Chang, Xin Dai, Xi Luo, Fei Guan, Jiahui Lei, Lu Yang & Chaohong Liu

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

    Pengyue Gao

  3. GeneMind Biosciences Company Limited, Shenzhen, China

    Xin Zhang & Juan Lai

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

    Heather Miller

  5. State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Zhongshan Hospital, Fudan University, Shanghai Qi Zhi Institute, Shanghai, China

    Xingrong Du

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  1. Yanmei Huang
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Contributions

YH performed the flow cytometry assay, western blotting, immunofluorescence experiments, and Seahorse experiments, and drafted the initial manuscript. PG assisted in flow cytometry assay, immunization, western blotting, and confocal experiments. LL assisted in western blotting and confocal experiments. YB and WW assisted in the manuscript. PJ assisted in TEM and SEM. JL, JC, XD, LY, XL, and FG performed the flow cytometry assay. XZ, JL assisted in RNA-seq experiments and analysis. MH, XD revised the manuscript. JL reviewed and revised the manuscript. CL designed the research and reviewed the manuscript. All authors revised the manuscript and approved the final manuscript.

Corresponding author

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.

Ethics approval

All animal experiments were approved by the Animal Experiment System Protection and Ethics Committee of Tongji Medical College (Wuhan, China) and were conducted in strict accordance with relevant guidelines and regulations. All clinical trials were approved by the Wuhan Children’s Hospital Committee for Research Ethics (No. 2024R062) and informed consent was obtained from all human participants prior to the study. All experiments complied with the Declaration of Helsinki.

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Huang, Y., Gao, P., Luo, L. et al. AIM2 positively regulates B cell activation and function through the SNX9-PI3K-WASP axis. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01638-w

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