期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 42, 页码 36532-36549出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.237578
关键词
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资金
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Ghent University [IAP6/18, 3G010505, 01G06B6]
- R.S. McLaughlin Scholarship
- Ontario Graduate Scholarship
- Queen's University Research Award
- Robert J. Wilson Fellowship
- Ontario Graduate Scholarship in Science and Technology
- Queen's Graduate Award
- Franklin Bracken Scholarship
- Ontario HIV Treatment Network Studentship
- Canadian Institutes of Health
The signaling pathways of mammalian Toll-like receptors (TLRs) are well characterized, but the precise mechanism(s) by which TLRs are activated upon ligand binding remains poorly defined. Recently, we reported a novel membrane sialidase-controlling mechanism that depends on ligand binding to its TLR to induce mammalian neuraminidase-1 (Neu1) activity, to influence receptor desialylation, and subsequently to induce TLR receptor activation and the production of nitric oxide and pro-inflammatory cytokines in dendritic and macrophage cells. The alpha-2,3-sialyl residue of TLR was identified as the specific target for hydrolysis by Neu1. Here, we report a membrane signaling paradigm initiated by endotoxin lipopolysaccharide (LPS) binding to TLR4 to potentiate G protein-coupled receptor (GPCR) signaling via membrane G alpha(i) subunit proteins and matrix metalloproteinase-9 (MMP9) activation to induce Neu1. Central to this process is that a Neu1-MMP9 complex is bound to TLR4 on the cell surface of naive macrophage cells. Specific inhibition of MMP9 and GPCR G alpha(i)-signaling proteins blocks LPS-induced Neu1 activity and NF kappa B activation. Silencing MMP9 mRNA using lentivirus MMP9 shRNA transduction or siRNA transfection of macrophage cells and MMP9 knock-out primary macrophage cells significantly reduced Neu1 activity and NF kappa B activation associated with LPS-treated cells. These findings uncover a molecular organizational signaling platform of a novel Neu1 and MMP9 cross-talk in alliance with TLR4 on the cell surface that is essential for ligand activation of TLRs and subsequent cellular signaling.
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