The Myeloid LSECtin Is a DAP12-Coupled Receptor That Is Crucial for Inflammatory Response Induced by Ebola Virus Glycoprotein

PLoS Pathogens

Xuexing Zheng¹  Xianzhu Xia²  Zaopeng Yang²  Li Tang²  Hualei Wang²  Dianyuan Zhao³  Songtao Yang³  Xiaowen Wang³  Jing Liu³  Xintao Han³  Wenting Yang³  Qingyang Dong³  Ke Han³  Fuchu He³  Di Liu³ 

[1] Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, Anhui Province, China;Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun, China;State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China

关键词: Cytokines;    Small interfering RNAs;    Enzyme-linked immunoassays;    Phosphorylation;    Immunoblotting;    Inflammation;    Ebola virus;    Tyrosine;   

DOI  :  10.1371/journal.ppat.1005487

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

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