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Lipid droplets restrict phagosome formation in antifungal immunity

Cellular & Molecular Immunology volume 22, pages 468–484 (2025)Cite this article

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Abstract

Lipid droplets (LDs) are intracellular organelles that can be induced and interact with phagosomes during the process of pathogen phagocytosis in macrophages. However, the function of LDs in phagocytosis remains elusive. Here, we unveil the role of LDs in modulating phagosome formation via a fungal infection model. Specifically, LD accumulation restricted the degree of phagosome formation and protected macrophages from death. Mechanistically, LD formation competitively consumed the intracellular endoplasmic reticulum membrane and altered RAC1 translocation and GTPase activity, which resulted in limited phagosome formation in macrophages during fungal engulfment. Mice with Hilpda-deficient macrophages were more susceptible to the lethal sequelae of systemic infection with C. albicans. Notably, administration of the ATGL inhibitor atglistatin improved host outcomes in disseminated fungal infections. Taken together, our study elucidates the mechanism by which LDs control phagosome formation to prevent immune cell death and offers a potential drug target for the treatment of C. albicans infections.

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Acknowledgements

We thank Dr. Changbin Chen (Institute Pasteur of Shanghai, CAS, Shanghai, China) for kindly providing the C. albicans strain SC5314. This work was supported by grants from the National Natural Science Foundation of China (82321002, 32230033 and 81930039 to CG) and the National Key Research and Development Program of China (2021YFC2300603 and 2023YFC2306102 to CG). This work was also supported by the Future Scholar Program of Shandong University (21510082364125).

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  1. These authors contributed equally: Wanwei Sun, Han Wu.

Authors and Affiliations

  1. Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, P. R. China

    Wanwei Sun, Han Wu, Guimin Zhao, Qing Shui, Lei Zhang, Xiaoxi Luan, Tian Chen, Feng Liu, Yi Zheng, Wei Zhao, Bingyu Liu & Chengjiang Gao

  2. Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, Shandong, 250012, P. R. China

    Wanwei Sun, Han Wu, Guimin Zhao, Qing Shui, Lei Zhang, Xiaoxi Luan, Feng Liu, Yi Zheng, Bingyu Liu & Chengjiang Gao

  3. Department of Pathogenic Biology, School of Biomedical Sciences, Shandong University, Jinan, Shandong, 250012, P. R. China

    Tian Chen & Wei Zhao

  4. Advanced Medical Research Institute, Shandong University, Jinan, Shandong, 250012, P. R. China

    Xiaopeng Qi

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Contributions

CG and WS conceived and designed the study. WS and HW performed the experiments with assistance from GZ, QS, LZ, XL, and TC; FL, YZ, WZ, XQ, and BL contributed to the discussion and provided reagents. CG and WS analyzed the data and wrote the paper, and TC helped to polish the English writing.

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Correspondence to Chengjiang Gao.

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The authors declare that they have no competing interests. CG is an editorial board member of Cellular & Molecular Immunology, but he has not been involved in the peer review or the decision-making of the article.

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Sun, W., Wu, H., Zhao, G. et al. Lipid droplets restrict phagosome formation in antifungal immunity. Cell Mol Immunol 22, 468–484 (2025). https://doi.org/10.1038/s41423-025-01282-x

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