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DOCK2 regulates antifungal immunity by regulating RAC GTPase activity

Cellular & Molecular Immunology volume 19, pages 602–618 (2022)Cite this article

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Abstract

Fungal infections cause ~1.5 million deaths each year worldwide, and the mortality rate of disseminated candidiasis currently exceeds that of breast cancer and malaria. The major reasons for the high mortality of candidiasis are the limited number of antifungal drugs and the emergence of drug-resistant species. Therefore, a better understanding of antifungal host defense mechanisms is crucial for the development of effective preventive and therapeutic strategies. Here, we report that DOCK2 (dedicator of cytokinesis 2) promotes indispensable antifungal innate immune signaling and proinflammatory gene expression in macrophages. DOCK2-deficient macrophages exhibit decreased RAC GTPase (Rac family small GTPase) activation and ROS (reactive oxygen species) production, which in turn attenuates the killing of intracellular fungi and the activation of downstream signaling pathways. Mechanistically, after fungal stimulation, activated SYK (spleen-associated tyrosine kinase) phosphorylates DOCK2 at tyrosine 985 and 1405, which promotes the recruitment and activation of RAC GTPases and then increases ROS production and downstream signaling activation. Importantly, nanoparticle-mediated delivery of in vitro transcribed (IVT) Rac1 mRNA promotes the activity of Rac1 and helps to eliminate fungal infection in vivo. Taken together, this study not only identifies a critical role of DOCK2 in antifungal immunity via regulation of RAC GTPase activity but also provides proof of concept for the treatment of invasive fungal infections by using IVT mRNA.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Shuyan Liang and Zhixin Qiu from Wuhan Biobank Co., Ltd., for their kind help with flow cytometric analysis. This investigation was supported by a grant from the National Key Research and Development Program of China (2020YFA0710700 to CHW); the National Natural Science Foundation of China (Grant No. 82101859 to WWS); the Original Exploration Program of National Natural Science Foundation of China (82150102, to CHW); the Key Research and Development Program of Sichuan Province (22ZDYF3738, to CHW); the Fundamental Research Funds for the Central Universities, HUST (2021GCRC031 to CHW); the National Natural Science Foundation of China (31870165 to BZ) and the Shenzhen Science and Technology Innovation Fund (JCYJ20210324115811032 to BZ).

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  1. These authors contributed equally: Xiaojian Ma, Xi Tan, Bingbing Yu, Wanwei Sun.

Authors and Affiliations

  1. Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China

    Xiaojian Ma, Xi Tan, Wanwei Sun, Heping Wang, Huijun Hu, Yanyun Du, Ruirui He, Ru Gao, Qianwen Peng, Zhihui Cui, Ting Pan, Xiong Feng, Wei Liu & Chenhui Wang

  2. Key Laboratory of Molecular Biophysics, the Ministry of Education, College of Life Science and Technology and Shenzhen College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Bingbing Yu & Bin Zhu

  3. The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, China

    Ruirui He & Chenhui Wang

  4. Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China

    Ruirui He & Chenhui Wang

  5. University-Affiliated Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China

    Junhan Wang

  6. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, 430074, PR China

    Chengqi Xu

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  1. Xiaojian Ma
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Contributions

XJM performed the experiments with assistance from WWS, HPW, HJH, YYD, RG, RRH, QWP, ZHC, TP, and XF; JHW and CQX helped to obtain human PBMC samples. BBY and BZ helped to synthesize the mRac-1 single-stranded mRNA; XT and WL helped to produce and characterize the mRac-1-Flag@LNPs; XJM and CHW analyzed the data; and WWS and CHW wrote the manuscript. CHW supervised the project with BZ and WL.

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Correspondence to Bin Zhu, Wei Liu or Chenhui Wang.

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Ma, X., Tan, X., Yu, B. et al. DOCK2 regulates antifungal immunity by regulating RAC GTPase activity. Cell Mol Immunol 19, 602–618 (2022). https://doi.org/10.1038/s41423-021-00835-0

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