期刊
CELLULAR SIGNALLING
卷 22, 期 2, 页码 314-324出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2009.09.038
关键词
Cell signaling; Receptor activation; Sialic acid; TOLL-like receptor; Trypanosome trans-sialidase; Cellular sialidase; Glycosylation
类别
资金
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Harry Botterell Foundation for Neuroscience Research, ARC
- Garfield Kelly Cardiovascular Research and Development Fund
- Queen's University Research Award
- Robert J. Wilson Fellowship
- Canadian Institutes of Health (CIHR)
- 'Interuniversitaire Attractiepolen' [IAP6/18]
- 'Fonds voor Wetenschappelijk Onderzoek-Vlaanderen' [3G010505]
- 'Geconcerteercle Onderzoeksacties' of the Ghent University [01G06136]
The ectodomain of TOLL-like receptors (TLR) is highly glycosylated with several N-linked gylcosylation sites located in the inner concave surface. The precise role of these sugar N-glycans in TLR receptor activation is unknown. Recently, we have shown that Neu1 sialidase and not Neu 2,-3 and -4 forms a complex with TLR-2,-3 and -4 receptors on the cell-surface membrane of naive and activated macrophage cells (Glycoconj J DOI 10.1007/s10719-009-9239-8). Activation of Neu1 is induced by TLR ligands binding to their respective receptors. Here, we show that endotoxin lipopolysaccharide (LPS)-induced MyD88/TLR4 complex formation and subsequent NF kappa B activation is dependent on the removal of alpha-2,3-sialyl residue linked to beta-galactoside of TLR4 by the Neu1 activity associated with LPS-stimulated live primary macrophage cells, macrophage and dendritic cell lines but not with primary Neu1-deficient macrophage cells. Exogenous alpha-2,3 sialyl specific neuraminidase (Streptoccocus pneumoniae) and wild-type T cruzi trans-sialidase (TS) but not the catalytically inactive mutant TS Delta Asp98-Glu mediate TLR4 dimerization to facilitate MyD88/TLR4 complex formation and NF kappa B activation similar to those responses seen with LPS. These same TLR ligand-induced NF kappa B responses are not observed in TLR deficient HEK293 cells, but are re-established in HEK293 cells stably transfected with TLR4/MD2, and are significantly inhibited by alpha-2,3-siallyl specific Maacida amurensis (MAL-2) lectin, alpha-2,3-sialyl specific galectin-1 and neuraminidase inhibitor Tamiflu but not by alpha-2,6-sialyl specific Sambucus nigra lectin (SNA). Taken together, the findings suggest that Neu1 desialylation of alpha-2,3-sialyl residues of TLR receptors enables in removing a steric hinderance to receptor association for TLR activation and cellular signaling. (C) 2009 Elsevier Inc. All rights reserved.
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