High-affinity caspase-4 binding to LPS presented as high molecular mass aggregates or in outer membrane vesicles

Wacker, Mark A; Teghanemt, Athmane; Weiss, Jerrold; Barker, Jason

doi:10.1177/1753425917695446

Cited by 34 publications

(36 citation statements)

References 45 publications

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“…As judged by gel electrophoresis and size‐exclusion chromatography, binding of caspase‐4/5/11 to purified LPS yields high molecular weight caspase/LPS complexes, consistent with binding of caspase to the naturally aggregated form of LPS . Using catalytically inactive purified recombinant pro‐caspase‐4 to model the initial interactions with LPS, we have shown that recombinant pro‐caspase‐4 interacts with high affinity both to purified LPS aggregates and to OMVs but not to protoplasts of Gram‐positive bacteria or complexes of LPS monomers with CD14 . Taken together, these findings seem most compatible with preferential interactions of pro‐caspase‐4/5/11 with the multiple anionic groups (e.g., phosphates, acidic sugars) of LPS clustered in close proximity at an LPS‐rich interface …”

Section: What Is the Form Of Lps That Engages Cytosolic Pro‐caspase‐4supporting

confidence: 62%

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

Barker

Weiss

2019

Journal of Leukocyte Biology

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Proinflammatory immune responses to Gram-negative bacterial lipopolysaccharides (LPS) are crucial to innate host defenses but can also contribute to pathology. How host cells sensitively detect structural features of LPS was a mystery for years, especially given that a portion of the molecule essential for its potent proinflammatory properties-lipid A-is buried in the bacterial membrane. Studies of responses to extracellular and vacuolar LPS revealed a crucial role for accessory proteins that specifically bind LPS-rich membranes and extract LPS monomers to generate a complex of LPS, MD-2, and TLR4. These insights provided means to understand better both the remarkable host sensitivity to LPS and the means whereby specific LPS structural features are discerned. More recently, the noncanonical inflammasome, consisting of caspases-4/5 in humans and caspase-11 in mice, has been demonstrated to mediate responses to LPS that has reached the host cytosol. Precisely how LPS gains access to cytosolic caspases-and in what form-is not well characterized, and understanding this process will provide crucial insights into how the noncanonical inflammasome is regulated during infection. Herein, we briefly review what is known about LPS detection by cytosolic caspases-4/5/11, focusing on lessons derived from studies of the better-characterized TLR4 system that might direct future mechanistic questions. K E Y W O R D Scaspase, inflammasome, outer membrane vesicle

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Section: What Is the Form Of Lps That Engages Cytosolic Pro‐caspase‐4supporting

confidence: 62%

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

Barker

Weiss

2019

Journal of Leukocyte Biology

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“…The sensing of OMVs by the noncanonical inflammasome sensors in human cells, namely caspase‐4 and ‐5, have not been thoroughly examined previously. A recent study showed that aggregates of LPS, as well as OMVs from Neisseria meningitidis , bound to caspase‐4 . We have previously shown that caspase‐4 is required for sensing of free LPS from S. Typhimurium; however, both caspase‐4 and ‐5 are involved in the sensing of LPS present in live bacteria .…”

Section: Discussionmentioning

confidence: 97%

Membrane vesicles from Pseudomonas aeruginosa activate the noncanonical inflammasome through caspase‐5 in human monocytes

et al. 2018

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Outer membrane vesicles (OMVs) are constitutively produced by Gram-negative bacteria both in vivo and in vitro. These lipid-bound structures carry a range of immunogenic components derived from the parent cell, which are transported into host target cells and activate the innate immune system. Recent advances in the field have shed light on some of the multifaceted roles of OMVs in host-pathogen interactions. In this study, we investigated the ability of OMVs from two clinically important pathogens, Pseudomonas aeruginosa and Helicobacter pylori, to activate canonical and noncanonical inflammasomes. P. aeruginosa OMVs induced inflammasome activation in mouse macrophages, as evidenced by "speck" formation, as well as the cleavage and secretion of interleukin-1β and caspase-1. These responses were independent of AIM2 and NLRC4 canonical inflammasomes, but dependent on the noncanonical caspase-11 pathway. Moreover, P. aeruginosa OMVs alone were able to activate the inflammasome in a TLR-dependent manner, without requiring an exogenous priming signal. In contrast, H. pylori OMVs were not able to induce inflammasome activation in macrophages. Using CRISPR/Cas9 knockout THP-1 cells lacking the human caspase-11 homologs, caspase-4 and -5,we demonstrated that caspase-5 but not caspase-4 is required for inflammasome activation by P. aeruginosa OMVs in human monocytes. In contrast, free P. aeruginosa lipopolysaccharide (LPS) transfected into cells induced inflammasome responses via caspase-4. This suggests that caspase-4 and caspase-5 differentially recognize LPS depending on its physical form or route of delivery into the cell. These findings have relevance to Gram-negative infections in humans and the use of OMVs as novel vaccines.

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“…Our finding that LPS promotes the close association of GBPs with pathogen membranes could indeed also be explained by a model in which GBPs form part of an LPS‐sensing macromolecular complex that assembles on the bacterial outer membrane and that contains LPS, GBPs, and caspase‐11. Indeed, it has been suggested that OMVs present LPS to human caspase‐4 (Wacker et al , ), and caspase‐11 has been found to localize to OMVs or even cytosolic bacteria (Thurston et al , ; Vanaja et al , ), although these preliminary observations will need independent confirmation and additional controls. As part of such a complex, GBPs could, for example, disrupt the outer bacterial membrane and help LPS, namely its lipid A moiety, to get more accessible for recognition by caspase‐11.…”

Section: Discussionmentioning

confidence: 99%

LPS targets host guanylate‐binding proteins to the bacterial outer membrane for non‐canonical inflammasome activation

et al. 2018

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Pathogenic and commensal Gram-negative bacteria produce and release outer membrane vesicles (OMVs), which present several surface antigens and play an important role for bacterial pathogenesis. OMVs also modulate the host immune system, which makes them attractive as vaccine candidates. At the cellular level, OMVs are internalized by macrophages and deliver lipopolysaccharide (LPS) into the host cytosol, thus activating the caspase-11 non-canonical inflammasome. Here, we show that OMV-induced inflammasome activation requires TLR4-TRIF signaling, the production of type I interferons, and the action of guanylate-binding proteins (GBPs), both in macrophages and Mechanistically, we find that isoprenylated GBPs associate with the surface of OMVs or with transfected LPS, indicating that the key factor that determines GBP recruitment to the Gram-negative bacterial outer membranes is LPS itself. Our findings provide new insights into the mechanism by which GBPs target foreign surfaces and reveal a novel function for GBPs in controlling the intracellular detection of LPS derived from extracellular bacteria in the form of OMVs, thus extending their function as a hub between cell-autonomous immunity and innate immunity.

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High-affinity caspase-4 binding to LPS presented as high molecular mass aggregates or in outer membrane vesicles

Cited by 34 publications

References 45 publications

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

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

Membrane vesicles from Pseudomonas aeruginosa activate the noncanonical inflammasome through caspase‐5 in human monocytes

LPS targets host guanylate‐binding proteins to the bacterial outer membrane for non‐canonical inflammasome activation

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