Taxonomic group: bacteria / Proteobacteria (Phylum: Proteobacteria)
Associated disease: infection due to Escherichia coli [ICD11: XN6P4 ]; infection due to Shigella flexneri [ICD11: XN7Y2 ]
 
NCBI PubMed ID: 33329561
Publication DOI: 10.3389/fimmu.2020.585146
Journal NLM ID: 101560960
Publisher: Lausanne: Frontiers Research Foundation
Correspondence: alla.zamyatinaboku.ac.at
Institutions: Institute of Organic Chemistry, Department of Chemistry, University of Natural Resources and Life Sciences, Vienna, Austria, Research Group Innate Immunity, Research Center Borstel-Leibniz Lung Center, Airway Research Center North (ARCN), German Center for Lung Disease (DZL), Borstel, Germany

The innate immune response to lipopolysaccharide is essential for host defense against Gram-negative bacteria. In response to bacterial infection, the TLR4/MD-2 complex that is expressed on the surface of macrophages, monocytes, dendritic, and epithelial cells senses picomolar concentrations of endotoxic LPS and triggers the production of various pro-inflammatory mediators. In addition, LPS from extracellular bacteria which is either endocytosed or transfected into the cytosol of host cells or cytosolic LPS produced by intracellular bacteria is recognized by cytosolic proteases caspase-4/11 and hosts guanylate binding proteins that are involved in the assembly and activation of the NLRP3 inflammasome. All these events result in the initiation of pro-inflammatory signaling cascades directed at bacterial eradication. However, TLR4-mediated signaling and caspase-4/11-induced pyroptosis are largely involved in the pathogenesis of chronic and acute inflammation. Both extra- and intracellular LPS receptors-TLR4/MD-2 complex and caspase-4/11, respectively-are able to directly bind the lipid A motif of LPS. Whereas the structural basis of lipid A recognition by the TLR4 complex is profoundly studied and well understood, the atomic mechanism of LPS/lipid A interaction with caspase-4/11 is largely unknown. Here we describe the LPS-induced TLR4 and caspase-4/11 mediated signaling pathways and their cross-talk and scrutinize specific structural features of the lipid A motif of diverse LPS variants that have been reported to activate caspase-4/11 or to induce caspase-4/11 mediated activation of NLRP3 inflammasome (either upon transfection of LPS in vitro or upon infection of cell cultures with intracellular bacteria or by LPS as a component of the outer membrane vesicles). Generally, inflammatory caspases show rather similar structural requirements as the TLR4/MD-2 complex, so that a 'basic' hexaacylated bisphosphorylated lipid A architecture is sufficient for activation. However, caspase-4/11 can sense and respond to much broader variety of lipid A variants compared to the very 'narrow' specificity of TLR4/MD-2 complex as far as the number and the length of lipid chains attached at the diglucosamine backbone of lipid A is concerned. Besides, modification of the lipid A phosphate groups with positively charged appendages such as phosphoethanolamine or aminoarabinose could be essential for the interaction of lipid A/LPS with inflammatory caspases and related proteins.

lipid A, chemical structure, molecular recognition, inflammation, innate immunity, aminoarabinose, LR4/MD-2, structural basis

Structure type: oligomer
Location inside paper: Fig.3, acylation pattern: 4 + 2
Trivial name: lipid IVA
Compound class: LOS, lipid A, glycolipid
Contained glycoepitopes: IEDB_135394,IEDB_135515,IEDB_141807,IEDB_151531,IEDB_176772,IEDB_534864
 
Comments, role: review; h- and mTLR4 agonist, activates caspase-4, activates caspase-11
 
NCBI Taxonomy refs (TaxIDs): 83333, 623, 67825
Reference(s) to other database(s): GlycomeDB:7396
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