Functional degradation: a mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes

Sandstrom, Andrew; Mitchell, Patrick S.; Goers, Lisa; Mu, Edward W.; Lesser, Cammie F.; Vance, Russell E.

doi:10.1101/317834

Cited by 53 publications

(110 citation statements)

References 61 publications

(75 reference statements)

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“…In contrast, the mouse orthologues of NLRP1 have been better characterised, as it has been shown that Nlrp1b responds to the lethal toxin of Bacillis anthracis (Boyden & Dietrich, ; Moayeri et al, ; Terra et al, ). Recent work has shed light on to the mechanism of Nlrp1b activation by showing that proteolytic cleavage of Nlrp1b results in ubiquitination of the protein (Chui et al, ; Sandstrom et al, ). This ubiquitination targets the protein for proteasomal degradation, through the N‐end rule‐dependent pathway (Chui et al, ; Sandstrom et al, ).…”

Section: A General Overview Of Inflammasomesmentioning

confidence: 99%

“…Recent work has shed light on to the mechanism of Nlrp1b activation by showing that proteolytic cleavage of Nlrp1b results in ubiquitination of the protein (Chui et al, ; Sandstrom et al, ). This ubiquitination targets the protein for proteasomal degradation, through the N‐end rule‐dependent pathway (Chui et al, ; Sandstrom et al, ). As the C‐terminal end of NLRP1 is constitutively clipped and interacts noncovalently with the rest of the protein, the proteasomal degradation of Nlrp1b liberates a CARD‐containing C‐terminal NLRP1 fragment, which can subsequently assemble into an inflammasome (Chui et al, ; Sandstrom et al, ).…”

Section: A General Overview Of Inflammasomesmentioning

confidence: 99%

“…This ubiquitination targets the protein for proteasomal degradation, through the N‐end rule‐dependent pathway (Chui et al, ; Sandstrom et al, ). As the C‐terminal end of NLRP1 is constitutively clipped and interacts noncovalently with the rest of the protein, the proteasomal degradation of Nlrp1b liberates a CARD‐containing C‐terminal NLRP1 fragment, which can subsequently assemble into an inflammasome (Chui et al, ; Sandstrom et al, ). Thus, Nlrp1b appears to use a unique mechanism relying on proteasomal degradation to sense and respond to certain cellular proteases.…”

Section: A General Overview Of Inflammasomesmentioning

confidence: 99%

See 2 more Smart Citations

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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Section: A General Overview Of Inflammasomesmentioning

confidence: 99%

Section: A General Overview Of Inflammasomesmentioning

confidence: 99%

Section: A General Overview Of Inflammasomesmentioning

confidence: 99%

See 1 more Smart Citation

Canonical and noncanonical inflammasomes in intestinal epithelial cells

Winsor

Krustev

Bruce

et al. 2019

Cellular Microbiology

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“…While PYRIN is autoinhibited through interactions with 14‐3‐3 proteins, it can be activated upon the inactivation of cellular RhoA GTPases by various bacterial toxins (Xu et al, ; Masters et al, ). The mouse NLRP1B sensor is also basally autoinhibited through its N‐terminal regions, which can undergo proteasomal degradation, for example in response to anthrax lethal toxin, leading to the release of the CARD‐containing C‐terminal fragment that oligomerises to recruit caspase‐1 and activate the NLRP1 inflammasome (Chui et al, ; Sandstrom et al, ; Xu et al, ). Other than the inhibitors of the serine proteases DPP8/9 (Okondo et al, ; Zhong et al, ), physiological activators of human NLRP1 inflammasome remain to be discovered.…”

Section: Signals For Inflammasome Activationmentioning

confidence: 99%

“…IpaH7.8‐mediated GLMN depletion therefore results in increased inflammasome‐mediated death of macrophages (Suzuki, Suzuki, Mimuro, Mizushima, & Sasakawa, ). IpaH7.8 can also activate murine NLRP1B through ubiquitination and functional degradation of NLRP1B, whereby degradation of the amino‐terminal of NLRP1B releases a carboxyl terminal fragment able to activate caspase‐1 (Neiman‐Zenevich, Stuart, Abdel‐Nour, Girardin, & Mogridge, ; Sandstrom et al, ). Interestingly, IpaH7.8 does not activate human NLRP1 and, therefore, this pathway would not contribute to inflammasome activation during human Shigella infection.…”

Section: Shigella – Inflammasome Interactions Are Cell‐type Specificmentioning

confidence: 99%

Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

Sanchez‐Garrido

Slater

Clements

et al. 2020

Cellular Microbiology

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Enteric pathogen–host interactions occur at multiple interfaces, including the intestinal epithelium and deeper organs of the immune system. Microbial ligands and activities are detected by host sensors that elicit a range of immune responses. Membrane‐bound toll‐like receptors and cytosolic inflammasome pathways are key signal transducers that trigger the production of pro‐inflammatory molecules, such as cytokines and chemokines, and regulate cell death in response to infection. In recent years, the inflammasomes have emerged as a key frontier in the tussle between bacterial pathogens and the host. Inflammasomes are complexes that activate caspase‐1 and are regulated by related caspases, such as caspase‐11, ‐4, ‐5 and ‐8. Importantly, enteric bacterial pathogens can actively engage or evade inflammasome signalling systems. Extracellular, vacuolar and cytosolic bacteria have developed divergent strategies to subvert inflammasomes. While some pathogens take advantage of inflammasome activation (e.g. Listeria monocytogenes, Helicobacter pylori), others (e.g. E. coli, Salmonella, Shigella, Yersinia sp.) deploy a range of virulence factors, mainly type 3 secretion system effectors, that subvert or inhibit inflammasomes. In this review we focus on inflammasome pathways and their immune functions, and discuss how enteric bacterial pathogens interact with them. These studies have not only shed light on inflammasome‐mediated immunity, but also the exciting area of mammalian cytosolic immune surveillance.

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Inflammasome Assays In Vitro and in Mouse Models

Guo

2020

CP in Immunology

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This article presents assays that allow induction and measurement of activation of different inflammasomes in mouse macrophages, human peripheral blood mononuclear cell (PBMC) cultures, and mouse peritonitis and endotoxic shock models. Basic Protocol 1 describes how to prime the inflammasome in mouse macrophages with different Toll-like receptor agonists and TNF-α; how to induce NLRP1, NLRP3, NLRC4, and AIM2 inflammasome activation by their corresponding stimuli; and how to measure inflammasome activationmediated maturation of interleukin (IL)-1β and IL-18 and pyroptosis. Since the well-established agonists for NLRP1 are inconsistent between mice and humans, Basic Protocol 2 describes how to activate the NLRP1 inflammasome in human PBMCs. Basic Protocol 3 describes how to purify, crosslink, and detect the apoptosis-associated speck-like protein containing a CARD (ASC) pyroptosome. Formation of the ASC pyroptosome is a signature of inflammasome activation. A limitation of ASC pyroptosome detection is the requirement of a relatively large cell number. Alternate Protocol 1 is provided to stain ASC pyroptosomes using an anti-ASC antibody and to measure ASC specks by fluorescence microscopy in a single cell. Intraperitoneal injection of lipopolysaccharides (LPS) and inflammasome agonists will induce peritonitis, which is seen as an elevation of IL-1β and other proinflammatory cytokines and an infiltration of neutrophils and inflammatory monocytes. Basic Protocol 4 describes how to induce NLRP3 inflammasome activation and peritonitis by priming mice with LPS and subsequently challenging them with monosodium urate (MSU). The method for measuring cytokines in serum and through peritoneal lavage is also described. Finally, Alternate Protocol 2 describes how to induce noncanonical NLRP3 inflammasome activation by high-dose LPS challenge in a sepsis model.

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Functional degradation: a mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes

Cited by 53 publications

References 61 publications

Canonical and noncanonical inflammasomes in intestinal epithelial cells

Canonical and noncanonical inflammasomes in intestinal epithelial cells

Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

Inflammasome Assays In Vitro and in Mouse Models

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