Ganglioside GD1a Is an Essential Coreceptor for Toll-like Receptor 2 Signaling in Response to the B subunit of Type IIb Enterotoxin

Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2007; 282(10):7532-42. DOI: 10.1074/jbc.M611722200
Source: PubMed


Innate recognition and signaling by Toll-like receptors (TLRs) is facilitated by functionally associated coreceptors, although the cooperativity mechanisms involved are poorly understood. As a model we investigated TLR2 interactions with the GD1a ganglioside binding subunit of type IIb Escherichia coli enterotoxin (LT-IIb-B(5)). Both LT-IIb-B(5) and a GD1a binding-defective mutant (LT-IIb-B(5)(T13I)) could modestly bind to TLR2, but only the wild-type molecule displayed a dramatic increase in TLR2 binding activity in the presence of GD1a (although not in the presence of irrelevant gangliosides). Moreover, fluorescence resonance energy transfer experiments indicated that LT-IIb-B(5) induces lipid raft recruitment of TLR2 and TLR1 and their clustering with GD1a, in contrast to the GD1a binding-defective mutant, which moreover fails to activate TLR2 signaling. LT-IIb-B(5)-induced cell activation was critically dependent upon the Toll/IL-1 receptor domain-containing adaptor protein, which was induced to colocalize with TLR2 and GD1a, as shown by confocal imaging. Therefore, GD1a provides TLR2 coreceptor function by enabling the ligand to recruit, bind, and activate TLR2. These findings establish a model of TLR2 coreceptor function and, moreover, suggest novel mechanisms of adjuvanticity by non-toxic derivatives of type II enterotoxins dependent upon GD1a/TLR2 cooperative activity.

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    • "TLR2/1 and TLR2/6 complexes have been linked to proinflammatory and anti-inflammatory responses, respectively [7], [8]. TLR2 recognition of agonists is also influenced by co-receptors and accessory molecules, such as CD14 [9], CD36 [10], MD-2 [11], lipopolysaccharide-binding protein (LBP) [12], CD11b-CD18 integrin [13], and ganglioside GD1a [14]. "
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    PLoS ONE 06/2014; 9(6):e98512. DOI:10.1371/journal.pone.0098512 · 3.23 Impact Factor
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    • " immune system . Lipopolysaccharide - induced macrophage ganglioside expression and surface accessibility are dramatically altered with the modification of TLR4 - dependent downstream events ( Yohe et al . 1991 ; Macala and Yohe 1995 ) . TLR2 acts in concert with ganglioside coreceptors to mediate LT - IIb signaling ( Hajishengallis et al . 2005 ; Liang et al . 2007 ) . A TLR2 inter - active motif is found in both LT - IIb and LT - IIc ( Nawar et al . 2010 ) . Our results suggest that ganglioside co - reception for LT - IIc might be facilitated by long - chain fatty acyl ceramides . We further theorize that long - chain fatty acyl ceramide alters the orientation and surface accessibility of carbohy"
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    Glycobiology 08/2012; 23(1). DOI:10.1093/glycob/cws123 · 3.15 Impact Factor
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    • "It binds the β subunit of type IIb heat-labile enterotoxin of Escherichia coli, enabling this ligand to induce TLR2/TLR1 signaling within lipid rafts. GD1a does not appear to interact with triacyl molecules (Liang et al., 2007b). Since bacterial porins, which have been shown to be TLR2 ligands (Massari et al., 2002; Liu et al., 2008), are also oligomeric pore forming proteins that bind to the same dimer, there is a possibility that GD1a may also affect or enhance their signaling, but there is no experimental evidence supporting this hypothesis (Massari et al., 2006). "
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    Frontiers in Immunology 04/2012; 3:79. DOI:10.3389/fimmu.2012.00079
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