The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection

Hara, Hideki; Seregin, Sergey S.; Yang, Dahai; Fukase, Koichi; Chamaillard, Mathias; Alnemri, Emad S.; Inohara, Naohiro; Chen, Grace Y.; Núñez, Gabriel

doi:10.1016/j.cell.2018.09.047

Cited by 212 publications

(242 citation statements)

References 78 publications

(113 reference statements)

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“…Although earlier reports indicated that CASP11 has no role in protection against L. monocytogenes infection , casp11 −/− mice were recently demonstrated to have improved survival rates and lower bacterial loads in response to intravenously delivered L. monocytogenes as well as S. aureus 8325‐4 , indicating that the absence of CASP11 helps with the clearance of some Gram‐positive bacteria. To investigate the impact of CASP11 on bacterial pulmonary loads, we intratracheally infected WT and casp11 −/− mice with 2.5 × 10 8 CFU of MRSA and determined the bacterial burden at 96 h post‐infection.…”

Section: Resultsmentioning

confidence: 96%

Caspase‐11 counteracts mitochondrial ROS‐mediated clearance of Staphylococcus aureus in macrophages

et al. 2019

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Methicillin‐resistant Staphylococcus aureus (MRSA) is a growing health concern due to increasing resistance to antibiotics. As a facultative intracellular pathogen, MRSA is capable of persisting within professional phagocytes including macrophages. Here, we identify a role for CASP11 in facilitating MRSA survival within murine macrophages. We show that MRSA actively prevents the recruitment of mitochondria to the vicinity of the vacuoles they reside in to avoid intracellular demise. This process requires CASP11 since its deficiency allows increased association of MRSA‐containing vacuoles with mitochondria. The induction of mitochondrial superoxide by antimycin A (Ant A) improves MRSA eradication in casp11−/− cells, where mitochondria remain in the vicinity of the bacterium. In WT macrophages, Ant A does not affect MRSA persistence. When mitochondrial dissociation is prevented by the actin depolymerizing agent cytochalasin D, Ant A effectively reduces MRSA numbers. Moreover, the absence of CASP11 leads to reduced cleavage of CASP1, IL‐1β, and CASP7, as well as to reduced production of CXCL1/KC. Our study provides a new role for CASP11 in promoting the persistence of Gram‐positive bacteria.

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Section: Resultsmentioning

confidence: 96%

Caspase‐11 counteracts mitochondrial ROS‐mediated clearance of Staphylococcus aureus in macrophages

et al. 2019

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“…In a human embryonic kidney cell line, overexpressed NLRP6 has been shown to co‐precipitate with overexpressed caspase‐1 and ASC (Levy et al, ). Similarly, the pyrin domain of NLRP6 has been shown to interact with ASC in a purified protein system (Shen et al, ), whereas a recent study in myeloid cells argues that NLRP6 forms a heterogenous inflammasome with ASC, caspase‐1, and caspase‐11, which responds to lipoteichoic acid, a major constituent of the Gram‐positive bacterial cell wall (Hara et al, ; Figure ). Whether lipoteichoic acid stimulates NLRP6 in IECs remains to be determined.…”

Section: A General Overview Of Inflammasomesmentioning

confidence: 99%

Canonical and noncanonical inflammasomes in intestinal epithelial cells

Winsor

Krustev

Bruce

et al. 2019

Cellular Microbiology

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Inflammasomes are cytosolic, multimeric protein complexes capable of activating pro‐inflammatory cytokines such as IL‐1β and IL‐18, which play a key role in host defence. Inflammasome components are highly expressed in the intestinal epithelium. In recent years, studies have begun to demonstrate that epithelial‐intrinsic inflammasomes play a critical role in regulating epithelial homeostasis, both by defending the epithelium from pathogenic insult and through the regulation of the mucosal environment. However, the majority of research regarding inflammasome activation has focused on professional immune cells, such as macrophages. Here, we present an overview of the current understanding of inflammasome function in epithelial cells and at mucosal surfaces and, in particular, in the intestine.

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“…To validate the interactions determined by SAW, we used NMR spectroscopy to test the specific binding of PPE 1 , LTA, LPS, and Kdo 2 to Bet_v_1 (Table , Figure ). Substantial differences between theH‐N HSQC spectra of N‐labeled Bet_v_1 in the absence and presence of PPE 1 confirmed that the allergen specifically binds PPE 1 . The K d was consistent with a low to sub‐µmol/Laffinity, but intermediate exchange and a poor signal‐to‐noise ratio prevented direct measurement.…”

Section: Resultsmentioning

confidence: 86%

“…Other ligands of interest include deoxycholate (DOC), a secondary bile acid generated as a microbial metabolic byproduct that is structurally similar to brassinosteroids and serves as an established model ligand for Bet_v_1 . In addition, immunomodulatory microbial compounds (such as the TLR2 and NLRP6 agonist lipoteichoic acid, LTA, and the endotoxin lipopolysaccharide, LPS) have been proposed to interact with Bet_v_1 …”

Section: Introductionmentioning

confidence: 99%

Multiple roles of Bet v 1 ligands in allergen stabilization and modulation of endosomal protease activity

Soh

Aglas

Mueller

et al. 2019

Allergy

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Background: Over 100 million people worldwide suffer from birch pollen allergy. Bet v 1 has been identified as the major birch pollen allergen. However, the molecular mechanisms of birch allergic sensitization, including the roles of Bet v 1 and other components of the birch pollen extract, remain incompletely understood. Here, we examined how known birch pollen-derived molecules influence the endolysosomal processing of Bet v 1, thereby shaping its allergenicity. Methods: We analyzed the biochemical and immunological interaction of ligandswith Bet v 1. We then investigated the proteolytic processing of Bet v 1 by endosomal extracts in the presence and absence of ligands, followed by a detailed kinetic analysis of Bet v 1 processing by individual endolysosomal proteases as well as the T-cell epitope presentation in BMDCs. Results:We identified E 1 phytoprostanes as novel Bet v 1 ligands. Pollen-derived ligands enhanced the proteolytic resistance of Bet v 1, affecting degradation kinetics and preferential cleavage sites of the endolysosomal proteases cathepsin S and legumain. E 1 phytoprostanes exhibited a dual role by stabilizing Bet v 1 and inhibiting cathepsin protease activity. Conclusion:Bet v 1 can serve as a transporter of pollen-derived, bioactive compounds. When carried to the endolysosome, such compounds can modulate the proteolytic activity, including its processing by cysteine cathepsins. We unveil a paradigm shift from an allergen-centered view to a more systemic view that includes the host endolysosomal enzymes.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection

Cited by 212 publications

References 78 publications

Caspase‐11 counteracts mitochondrial ROS‐mediated clearance of Staphylococcus aureus in macrophages

Caspase‐11 counteracts mitochondrial ROS‐mediated clearance of Staphylococcus aureus in macrophages

Canonical and noncanonical inflammasomes in intestinal epithelial cells

Multiple roles of Bet v 1 ligands in allergen stabilization and modulation of endosomal protease activity

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