1. The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein
- Author
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Xuexing Zheng, Jing Liu, Tang Li, Fuchu He, Xintao Han, Songtao Yang, Zaopeng Yang, Qingyang Dong, Dianyuan Zhao, Hualei Wang, Wenting Yang, Ke Han, Di Liu, Xiaowen Wang, and Xianzhu Xia
- Subjects
0301 basic medicine ,RNA viruses ,Viral Diseases ,Physiology ,medicine.medical_treatment ,Syk ,Ligands ,medicine.disease_cause ,Pathology and Laboratory Medicine ,Biochemistry ,Mice ,0302 clinical medicine ,Immune Physiology ,Medicine and Health Sciences ,Small interfering RNAs ,Post-Translational Modification ,Phosphorylation ,Enzyme-Linked Immunoassays ,lcsh:QH301-705.5 ,Immune Response ,Mice, Inbred BALB C ,Innate Immune System ,biology ,hemic and immune systems ,Ebolavirus ,Recombinant Proteins ,Cell biology ,Nucleic acids ,Cytokine ,Infectious Diseases ,Medical Microbiology ,Filoviruses ,Viral Pathogens ,Viruses ,Cytokines ,Tumor necrosis factor alpha ,medicine.symptom ,Signal transduction ,Pathogens ,Ebola Virus ,Signal Transduction ,Research Article ,Neglected Tropical Diseases ,lcsh:Immunologic diseases. Allergy ,Immunology ,Immunoblotting ,Molecular Probe Techniques ,Inflammation ,Research and Analysis Methods ,Ebola Hemorrhagic Fever ,Microbiology ,03 medical and health sciences ,Signs and Symptoms ,Virology ,medicine ,Genetics ,Animals ,Humans ,Gene silencing ,Lectins, C-Type ,Interleukin 6 ,Non-coding RNA ,Immunoassays ,Molecular Biology Techniques ,Molecular Biology ,Microbial Pathogens ,Adaptor Proteins, Signal Transducing ,Glycoproteins ,Viral Hemorrhagic Fevers ,Ebola virus ,Biology and life sciences ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Hemorrhagic Fever Viruses ,Macrophages ,Organisms ,Correction ,Membrane Proteins ,Proteins ,Dendritic Cells ,Hemorrhagic Fever, Ebola ,Molecular Development ,Tropical Diseases ,Gene regulation ,030104 developmental biology ,lcsh:Biology (General) ,Immune System ,biology.protein ,Immunologic Techniques ,RNA ,Parasitology ,Gene expression ,lcsh:RC581-607 ,030215 immunology ,Developmental Biology - Abstract
Fatal Ebola virus infection is characterized by a systemic inflammatory response similar to septic shock. Ebola glycoprotein (GP) is involved in this process through activating dendritic cells (DCs) and macrophages. However, the mechanism is unclear. Here, we showed that LSECtin (also known as CLEC4G) plays an important role in GP-mediated inflammatory responses in human DCs. Anti-LSECtin mAb engagement induced TNF-α and IL-6 production in DCs, whereas silencing of LSECtin abrogated this effect. Intriguingly, as a pathogen-derived ligand, Ebola GP could trigger TNF-α and IL-6 release by DCs through LSECtin. Mechanistic investigations revealed that LSECtin initiated signaling via association with a 12-kDa DNAX-activating protein (DAP12) and induced Syk activation. Mutation of key tyrosines in the DAP12 immunoreceptor tyrosine-based activation motif abrogated LSECtin-mediated signaling. Furthermore, Syk inhibitors significantly reduced the GP-triggered cytokine production in DCs. Therefore, our results demonstrate that LSECtin is required for the GP-induced inflammatory response, providing new insights into the EBOV-mediated inflammatory response., Author Summary Ebola virus (EBOV), a highly virulent pathogen, causes a severe hemorrhagic fever syndrome. The fatal infection is characterized by a systemic inflammatory response similar to septic shock. Ebola glycoprotein (GP) is thought to contribute to disease pathogenesis, as high amounts of shed GP from virus-infected cells are detected in patients, and activate macrophages and dendritic cells (DCs) to produce proinflammatory cytokines. Here, we show that LSECtin plays an important role in GP-mediated inflammatory responses in human DCs. LSECtin is a DAP12-coupled receptor able to initiate specific signaling events in human DCs. LSECtin interacts with Ebola GP and results in DAP12 phosphorylation. LSECtin knockdown impairs the production of proinflammatory cytokines induced by Ebola GP. Thus, this study suggests that LSECtin may contribute to Ebola GP-mediated pathogenicity.
- Published
- 2016