Detecting lipopolysaccharide in the cytosol of mammalian cells: Lessons from MD-2/TLR4

Barker, Jason; Weiss, Jerrold

doi:10.1002/jlb.3mir1118-434r

Cited by 20 publications

(12 citation statements)

References 70 publications

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“…Such interpretation would be in line with a recent study showing that caspase-4 recognizes LPS-rich membrane interfaces. According to this study, caspase-4 could bind directly to LPS-rich OMVs formed by N. meningitidis as well as to the high molecular mass aggregates of purified metabolically radiolabeled LPS (172)(173)(174). Indeed, it has been demonstrated that purified caspase-4 (C258A) and CARD domain from E. coli could bind huge LPS micelles and disaggregate them to small complexes in vitro (175).…”

Section: Zamyatina and Heinementioning

confidence: 83%

Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways

2020

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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.

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Section: Zamyatina and Heinementioning

confidence: 83%

Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways

2020

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“…Activation of LPS-sensing cytosolic caspases by LPS also appears to depend upon the acylation state of LPS (36)(37)(38). An effect of AOAH-dependent LPS deacylation on regulating the activation of this cytosolic recognition/response system has not been reported.…”

Section: From Stimulus To Inhibitor: the Importance Of Lps Acylationmentioning

confidence: 99%

Biochemical transformation of bacterial lipopolysaccharides by acyloxyacyl hydrolase reduces host injury and promotes recovery

Munford

Weiss

2020

Journal of Biological Chemistry

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Animals can sense the presence of microbes in their tissues and mobilize their own defenses by recognizing and responding to conserved microbial structures (often called Microbe-Associated Molecular Patterns or “MAMPs”). Successful host defenses may kill the invaders, yet the host animal may fail to restore homeostasis if the stimulatory microbial structures are not silenced. Although mice have many mechanisms for limiting their responses to lipopolysaccharide (LPS), a major Gram-negative bacterial MAMP, a highly conserved host lipase is required to extinguish LPS sensing in tissues and restore homeostasis. We review recent progress in understanding how this enzyme, acyloxyacyl hydrolase (AOAH), transforms LPS from stimulus to inhibitor, reduces tissue injury and death from infection, prevents prolonged post-infection immunosuppression, and keeps stimulatory LPS from entering the bloodstream. We also discuss how AOAH may increase sensitivity to pulmonary allergens. Better appreciation of how host enzymes modify LPS and other MAMPs may help prevent tissue injury and hasten recovery from infection.

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“…It has recently been established that TLR4 is also involved in so-called canonical activation of the NRLP3 inflammasome. The LPS-induced activation of this inflammasome via the canonical and also via a non-canonical, hence not involving TLR4, pathways has been intensively studied and discussed in excellent reviews [105][106][107][108]. In brief, the NLRP3 inflammasome is a multimeric complex of NRLP3, ASC, NEK7 and pro-caspase-1, which ultimately serves to promote autoproteolysis and activation of caspase-1.…”

Section: Signaling Pathways Triggered By Tlr4mentioning

confidence: 99%

TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling

Ciesielska

Matyjek

Kwiatkowska

2020

Cell. Mol. Life Sci.

729

466

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Toll-like receptor (TLR) 4 belongs to the TLR family of receptors inducing pro-inflammatory responses to invading pathogens. TLR4 is activated by lipopolysaccharide (LPS, endotoxin) of Gram-negative bacteria and sequentially triggers two signaling cascades: the first one involving TIRAP and MyD88 adaptor proteins is induced in the plasma membrane, whereas the second engaging adaptor proteins TRAM and TRIF begins in early endosomes after endocytosis of the receptor. The LPS-induced internalization of TLR4 and hence also the activation of the TRIF-dependent pathway is governed by a GPI-anchored protein, CD14. The endocytosis of TLR4 terminates the MyD88-dependent signaling, while the following endosome maturation and lysosomal degradation of TLR4 determine the duration and magnitude of the TRIF-dependent one. Alternatively, TLR4 may return to the plasma membrane, which process is still poorly understood. Therefore, the course of the LPS-induced pro-inflammatory responses depends strictly on the rates of TLR4 endocytosis and trafficking through the endo-lysosomal compartment. Notably, prolonged activation of TLR4 is linked with several hereditary human diseases, neurodegeneration and also with autoimmune diseases and cancer. Recent studies have provided ample data on the role of diverse proteins regulating the functions of early, late, and recycling endosomes in the TLR4-induced inflammation caused by LPS or phagocytosis of E. coli. In this review, we focus on the mechanisms of the internalization and intracellular trafficking of TLR4 and CD14, and also of LPS, in immune cells and discuss how dysregulation of the endo-lysosomal compartment contributes to the development of diverse human diseases.

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Detecting lipopolysaccharide in the cytosol of mammalian cells: Lessons from MD-2/TLR4

Cited by 20 publications

References 70 publications

Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways

Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways

Biochemical transformation of bacterial lipopolysaccharides by acyloxyacyl hydrolase reduces host injury and promotes recovery

TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling

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