title: The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein.
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.
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Dianyuan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.|Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, Anhui Province, China.
authors.forename: Xintao
authors.initials: X
authors.lastname: Han
authors.affiliation: Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun, China.
authors.forename: Xuexing
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun, China.
authors.forename: Hualei
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Zaopeng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Di
authors.initials: D
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Han
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun, China.
authors.forename: Songtao
authors.initials: S
authors.lastname: Yang
authors.affiliation: Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun, China.
authors.forename: Xianzhu
authors.initials: X
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.|Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, Anhui Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.|College of Life Sciences, Peking University, Beijing, China.|Department of Biology Sciences and Biotechnology, Tsinghua University, Beijing, China.
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D029043:Ebolavirus / Q000276:immunology*; D006023:Glycoproteins; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505228:CLEC4G protein, human; D006023:Glycoproteins; D015850:Interleukin-6; D037181:Lectins, C-Type; D008024:Ligands; D008565:Membrane Proteins; D011994:Recombinant Proteins; C110546:TYROBP protein, human; D014409:Tumor Necrosis Factor-alpha