DOCK2 regulates antifungal immunity by regulating RAC GTPase activity.
Xiaojian MaXi TanBingbing YuWanwei SunHeping WangHuijun HuYanyun DuRuirui HeRu GaoQianwen PengZhihui CuiTing PanXiong FengJunhan WangChengqi XuBin ZhuWei LiuChenhui WangPublished in: Cellular & molecular immunology (2022)
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.
Keyphrases
- candida albicans
- reactive oxygen species
- tyrosine kinase
- drug resistant
- cell migration
- gene expression
- innate immune
- multidrug resistant
- dna damage
- cardiovascular events
- epidermal growth factor receptor
- signaling pathway
- cell death
- type diabetes
- dna methylation
- risk factors
- cardiovascular disease
- young adults
- genome wide
- binding protein
- cell wall
- coronary artery disease
- acinetobacter baumannii
- epithelial mesenchymal transition
- sensitive detection
- single molecule
- quantum dots