Neu1 desialylation of sialyl α-2,3-linked β-galactosyl residues of TOLL-like receptor 4 is essential for receptor activation and cellular signaling
Neu1 desialylation of sialyl α-2,3-linked β-galactosyl residues of TOLL-like receptor 4 is essential for receptor activation and cellular signaling
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DOI：
10.1016/j.cellsig.2009.09.038
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发表时间：
2010-02-01
影响因子：
4.8
通讯作者：
Szewczuk, Myron R.
中科院分区：
文献类型：
--
作者：
Amith, Schammim Ray;Jayanth, Preethi;Szewczuk, Myron R.
TOLL样受体（TLR）的胞外域是高度糖基化的，具有位于内凹表面的几个N-连接的糖基化位点。这些糖N-聚糖在TLR受体活化中的确切作用尚不清楚。最近，我们已经表明Neu 1唾液酸酶而不是Neu 2、-3和-4与初始和活化的巨噬细胞的细胞表面膜上的TLR-2、-3和-4受体形成复合物（Glycoconj J DOI 10.1007/s10719-009-9239-8）。Neu 1的激活由TLR配体与其各自受体结合诱导。在这里，我们表明，内毒素脂多糖（LPS）诱导的MyD 88/TLR 4复合物的形成和随后的NF κ B活化依赖于α-2，3-唾液酸残基的去除连接到TLR 4的β-半乳糖苷的Neu 1活性与LPS刺激的活的原代巨噬细胞，巨噬细胞和树突状细胞系，但不与原代Neu 1缺陷的巨噬细胞。外源性α-2，3唾液酸特异性神经氨酸酶（肺炎链球菌）和野生型克氏锥虫转唾液酸酶（TS）而非催化失活突变体TS Δ Asp 98-Glu介导TLR 4二聚化以促进MyD 88/TLR 4复合物形成和NF κ B活化，类似于用LPS观察到的那些反应。在TLR缺陷的HEK 293细胞中没有观察到这些相同的TLR配体诱导的NF κ B应答，但在用TLR 4/MD 2稳定转染的HEK 293细胞中重新建立，并且被α-2，3-唾液酸特异性Maacida amurensis（MAL-2）凝集素、α-2，3-唾液酸特异性半乳糖凝集素-1和神经氨酸酶抑制剂Tamiflu显著抑制，但不被α-2，3-唾液酸特异性半乳糖凝集素-1和神经氨酸酶抑制剂Tamiflu抑制，6-唾液酸特异性接骨木凝集素（SNA）。总之，这些发现表明TLR受体的α-2，3-唾液酸残基的Neu 1去唾液酸化能够消除TLR活化和细胞信号传导的受体缔合的空间阻碍。(C)2009 Elsevier Inc. All rights reserved.
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.