2. Academic Validation
  3. DOCK2 regulates antifungal immunity by regulating RAC GTPase activity

DOCK2 regulates antifungal immunity by regulating RAC GTPase activity

  • Cell Mol Immunol. 2022 May;19(5):602-618. doi: 10.1038/s41423-021-00835-0.
Xiaojian Ma  # 1,  Xi Tan  # 1,  Bingbing Yu  # 2,  Wanwei Sun  # 1,  Heping Wang 1,  Huijun Hu 1,  Yanyun Du 1,  Ruirui He 1 3 4,  Ru Gao 1,  Qianwen Peng 1,  Zhihui Cui 1,  Ting Pan 1,  Xiong Feng 1,  Junhan Wang 5,  Chengqi Xu 6,  Bin Zhu 7,  Wei Liu 8,  Chenhui Wang 9 10 11
Affiliations

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.
  • 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.
  • 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.
  • 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.
  • 5 University-Affiliated Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China.
  • 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.
  • 7 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. [email protected].
  • 8 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. [email protected].
  • 9 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. [email protected].
  • 10 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. [email protected].
  • 11 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. [email protected].
  • # Contributed equally.
PMID: 35079145 DOI: 10.1038/s41423-021-00835-0
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.

Keywords

Anti-fungal immunity; DOCK2; IVT-mRNA; RAC.

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