Functional and Evolutionary Analyses Identify Proteolysis as a General Mechanism for NLRP1 Inflammasome Activation

Chavarría-Smith, Joseph; Mitchell, Patrick S.; Ho, Alvin M.; Daugherty, Matthew D.; Vance, Russell E.

doi:10.1371/journal.ppat.1006052

Cited by 120 publications

(128 citation statements)

References 57 publications

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“…This toxin is a protease and N‐terminally processes Nlrp1b, leading to its activation in mice. Although human NLRP1 is neither cleaved nor activated by lethal toxin, experimental cleavage of its N‐terminal sequence is sufficient to activate NLRP1 . This suggests that human NLRP1 may detect pathogen infection by an as yet unknown protease.…”

Section: Nlr Inflammasomesmentioning

confidence: 99%

Role of inflammasomes in the pathogenesis of periodontal disease and therapeutics

Marchesan

Girnary

Moss

et al. 2019

Periodontology 2000

113

106

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Inflammasomes are a group of multimolecular intracellular complexes assembled around several innate immune proteins. Recognition of a diverse range of microbial, stress and damage signals by inflammasomes results in direct activation of caspase‐1, which subsequently induces the only known form of secretion of active interleukin‐1β and interleukin‐18. Although the importance of interleukin‐1β in the periodontium is not questioned, the impact of inflammasomes in periodontal disease and its potential for therapeutics in periodontology is still in its very early stages. Increasing evidence in preclinical models and human data strongly implicate the involvement of inflammasomes in a number of inflammatory, autoinflammatory and autoimmune disorders. Here we review: (a) the currently known inflammasome functions, (b) clinical/preclinical data supporting inflammasome involvement in the context of periodontal and comorbid diseases and (c) potential therapies targeting inflammasomes. To clarify further the inflammasome involvement in periodontitis, we present analyses of data from a large clinical study (n = 5809) that measured the gingival crevicular fluid‐interleukin‐1β and grouped the participants based on current periodontal disease classifications. We review data on 4910 European‐Americans that correlate 16 polymorphisms in the interleukin‐1B region with high gingival crevicular fluid‐interleukin‐1β levels. We show that inflammasome components are increased in diseased periodontal tissues and that the caspase‐1 inhibitor, VX‐765, inhibits ~50% of alveolar bone loss in experimental periodontitis. The literature review further supports that although patients clinically present with the same phenotype, the disease that develops probably has different underlying biological pathways. The current data indicate that inflammasomes have a role in periodontal disease pathogenesis. Understanding the contribution of different inflammasomes to disease development and distinct patient susceptibility will probably translate into improved, personalized therapies.

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Section: Nlr Inflammasomesmentioning

confidence: 99%

Role of inflammasomes in the pathogenesis of periodontal disease and therapeutics

Marchesan

Girnary

Moss

et al. 2019

Periodontology 2000

113

106

View full text Add to dashboard Cite

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“…). Mouse Nlrp1a is also activated by N‐terminal proteolytic cleavage . Likewise, human NLRP1 undergoes proteolysis within a specific N‐terminal linker region between the PYD and NBD .…”

Section: Nlrp1 Inflammasomementioning

confidence: 99%

“…The protective antigen translocates the lethal factor across the cell membrane, where the lethal factor directly cleaves Nlrp1b at the N-terminal domain. [23][24][25][26] The FIIND of Nlrp1b may also undergo autoproteolytic cleavage. [32][33][34] Cleavage of Nlrp1b induces assembly of the inflammasome.…”

Section: Canonical Nlrpinflammasomementioning

confidence: 99%

Molecular mechanisms of inflammasome signaling

Mathur

Hayward

Man

2017

Journal of Leukocyte Biology

153

123

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The inflammasome is a macromolecular protein complex that mediates proteolytic cleavage of pro-IL-1β and -IL-18 and induces cell death in the form of pyroptosis. Certain nucleotide-binding oligomerization domain-like receptors (NLRs), absent in melanoma 2 (AIM2)-like receptors (ALRs), or tripartite motif (TRIM) family receptors trigger the assembly of an inflammasome in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Recent studies have revealed a multitude of host components and signals that are essential for controlling canonical and noncanonical inflammasome activation and pyroptosis. These include pore-forming gasdermin proteins, the never in mitosis A-related kinase 7 (NEK7), IFN-inducible proteins (IFIs), reactive oxygen species (ROS), autophagy, potassium efflux, mitochondrial perturbations, and microbial metabolites. Here, we provide a comprehensive overview of the molecular and signaling mechanisms that provide stringent regulation over the activation and effector functions of the inflammasome.

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“…Further, most studies characterizing the non-canonical inflammasome have employed mouse models, which do not fully recapitulate inflammasome activation in humans. In mice, cytoplasmic LPS sensing occurs by caspase-11, which differs from its human homologue, caspase-4, in several ways [20][21][22][23][24][25]. First, caspase-11 is highly inducible following engagement of the TLRs/TRIF pathways and/or IFN signaling [9,10,26,27].…”

Section: Introductionmentioning

confidence: 99%

A genome‐wide screen identifies IRF2 as a key regulator of caspase‐4 in human cells

et al. 2019

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Caspase‐4, the cytosolic LPS sensor, and gasdermin D, its downstream effector, constitute the non‐canonical inflammasome, which drives inflammatory responses during Gram‐negative bacterial infections. It remains unclear whether other proteins regulate cytosolic LPS sensing, particularly in human cells. Here, we conduct a genome‐wide CRISPR/Cas9 screen in a human monocyte cell line to identify genes controlling cytosolic LPS‐mediated pyroptosis. We find that the transcription factor, IRF2, is required for pyroptosis following cytosolic LPS delivery and functions by directly regulating caspase‐4 levels in human monocytes and iPSC‐derived monocytes. CASP4, GSDMD, and IRF2 are the only genes identified with high significance in this screen highlighting the simplicity of the non‐canonical inflammasome. Upon IFN‐γ priming, IRF1 induction compensates IRF2 deficiency, leading to robust caspase‐4 expression. Deficiency in IRF2 results in dampened inflammasome responses upon infection with Gram‐negative bacteria. This study emphasizes the central role of IRF family members as specific regulators of the non‐canonical inflammasome.

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Functional and Evolutionary Analyses Identify Proteolysis as a General Mechanism for NLRP1 Inflammasome Activation

Cited by 120 publications

References 57 publications

Role of inflammasomes in the pathogenesis of periodontal disease and therapeutics

Role of inflammasomes in the pathogenesis of periodontal disease and therapeutics

Molecular mechanisms of inflammasome signaling

A genome‐wide screen identifies IRF2 as a key regulator of caspase‐4 in human cells

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