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Neu1 sialidase and matrix metalloproteinase-9 cross-talk is essential for toll-like receptor activation and cellular signaling

(2011) JOURNAL OF BIOLOGICAL CHEMISTRY. 286(42). p.36532-36549
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
Abstract
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.
Keywords
MATRIX METALLOPROTEINASES, LYSOSOMAL SIALIDASE, GENE-EXPRESSION, EXOGENOUS ANTIGENS, PLASMA-MEMBRANE, GROWTH-FACTOR RECEPTOR, MEMBRANE-ASSOCIATED SIALIDASE, DENDRITIC CELLS, T-LYMPHOCYTES, CLASS-I

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Citation

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Chicago
Abdulkhalek, Samar, Schammim Ray Amith, Susan L Franchuk, Preethi Jayanth, Merry Guo, Trisha Finlay, Alanna Gilmour, et al. 2011. “Neu1 Sialidase and Matrix Metalloproteinase-9 Cross-talk Is Essential for Toll-like Receptor Activation and Cellular Signaling.” Journal of Biological Chemistry 286 (42): 36532–36549.
APA
Abdulkhalek, S., Amith, S. R., Franchuk, S. L., Jayanth, P., Guo, M., Finlay, T., Gilmour, A., et al. (2011). Neu1 sialidase and matrix metalloproteinase-9 cross-talk is essential for toll-like receptor activation and cellular signaling. JOURNAL OF BIOLOGICAL CHEMISTRY, 286(42), 36532–36549.
Vancouver
1.
Abdulkhalek S, Amith SR, Franchuk SL, Jayanth P, Guo M, Finlay T, et al. Neu1 sialidase and matrix metalloproteinase-9 cross-talk is essential for toll-like receptor activation and cellular signaling. JOURNAL OF BIOLOGICAL CHEMISTRY. 2011;286(42):36532–49.
MLA
Abdulkhalek, Samar, Schammim Ray Amith, Susan L Franchuk, et al. “Neu1 Sialidase and Matrix Metalloproteinase-9 Cross-talk Is Essential for Toll-like Receptor Activation and Cellular Signaling.” JOURNAL OF BIOLOGICAL CHEMISTRY 286.42 (2011): 36532–36549. Print.
@article{1955057,
  abstract     = {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.},
  author       = {Abdulkhalek, Samar and Amith, Schammim Ray and Franchuk, Susan L and Jayanth, Preethi and Guo, Merry and Finlay, Trisha and Gilmour, Alanna and Guzzo, Christina and Gee, Katrina and Beyaert, Rudi and Szewczuk, Myron R},
  issn         = {0021-9258},
  journal      = {JOURNAL OF BIOLOGICAL CHEMISTRY},
  keyword      = {MATRIX METALLOPROTEINASES,LYSOSOMAL SIALIDASE,GENE-EXPRESSION,EXOGENOUS ANTIGENS,PLASMA-MEMBRANE,GROWTH-FACTOR RECEPTOR,MEMBRANE-ASSOCIATED SIALIDASE,DENDRITIC CELLS,T-LYMPHOCYTES,CLASS-I},
  language     = {eng},
  number       = {42},
  pages        = {36532--36549},
  title        = {Neu1 sialidase and matrix metalloproteinase-9 cross-talk is essential for toll-like receptor activation and cellular signaling},
  url          = {http://dx.doi.org/10.1074/jbc.M111.237578},
  volume       = {286},
  year         = {2011},
}

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