The NLRP1 inflammasome: new mechanistic insights and unresolved mysteries

Mitchell, Patrick S.; Sandstrom, Andrew; Vance, Russell E.

doi:10.1016/j.coi.2019.04.015

Cited by 137 publications

(124 citation statements)

References 70 publications

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“…In the process of activation, the FIIND undergoes self‐cleavage, an event that is required for activation. NLRP1 responds to the enzymatic activities of pathogen effectors such as the lethal toxin (leTox) from Bacillus anthracis and by non‐pathogen‐associated triggers such as the drug Val‐boro‐Pro, an anti‐cancer molecule that inhibits the cytosolic serine proteases Dpp8 and Dpp9 …”

Section: Nlrs Function As Sensors Of Pathogens and Cellular Perturbatmentioning

confidence: 99%

“…NLRP1 responds to the enzymatic activities of pathogen effectors such as the lethal toxin (leTox) from Bacillus anthracis 21 and by non-pathogen-associated triggers such as the drug Val-boro-Pro, an anti-cancer molecule that inhibits the cytosolic serine proteases Dpp8 and Dpp9. 22,23 Gain-of-function mutations within NLRP1 have been described in humans to cause uncontrolled inflammasome activation promoting a familial autoinflammatory skin disease associated with cancer. 24 Other mutations of NLRP1 have been linked to autoinflammation with arthritis and dyskeratosis (AIADK) also known as NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis).…”

Section: Nlr S Fun C Ti On a S S En Sor S Of Pathog En S And Cellulmentioning

confidence: 99%

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Inflammasomes contributing to inflammation in arthritis

Spel

Martinon

2020

Immunological Reviews

109

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Inflammasomes are intracellular multiprotein signaling platforms that initiate inflammatory responses in response to pathogens and cellular damage. Active inflammasomes induce the enzymatic activity of caspase‐1, resulting in the induction of inflammatory cell death, pyroptosis, and the maturation and secretion of inflammatory cytokines IL‐1β and IL‐18. Inflammasomes are activated in many inflammatory diseases, including autoinflammatory disorders and arthritis, and inflammasome‐specific therapies are under development for the treatment of inflammatory conditions. In this review, we outline the different inflammasome platforms and recent findings contributing to our knowledge about inflammasome biology in health and disease. In particular, we discuss the role of the inflammasome in the pathogenesis of arthritic diseases, including rheumatoid arthritis, gout, ankylosing spondylitis, and juvenile idiopathic arthritis, and the potential of newly developed therapies that specifically target the inflammasome or its products for the treatment of inflammatory diseases.

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Section: Nlrs Function As Sensors Of Pathogens and Cellular Perturbatmentioning

confidence: 99%

Section: Nlr S Fun C Ti On a S S En Sor S Of Pathog En S And Cellulmentioning

confidence: 99%

Inflammasomes contributing to inflammation in arthritis

Spel

Martinon

2020

Immunological Reviews

109

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“…NLRP1b is a sensor of pathogen effector proteins that induce degradation of its N‐terminus by the proteasome and release of an autoproteolytically‐generated, noncovalently associated C‐terminal CARD domain. The best‐studied activator of this inflammasome, the anthrax lethal factor protease (LF), cleaves the N‐terminus of NLRP1b to initiate destabilization of the protein through ubiquitylation by an N‐end rule E3 ubiquitin ligase 5–8 . Lethal toxin (LT), a major virulence factor of Bacillus anthracis , is an AB toxin comprised of two proteins, the receptor‐binding protective antigen (PA), which binds receptors and transports the second component, LF, to the host cell cytosol, where it cleaves its substrates.…”

Section: Introductionmentioning

confidence: 99%

Frontline Science: Anthrax lethal toxin-induced, NLRP1-mediated IL-1β release is a neutrophil and PAD4-dependent event

Greaney

Portley

O’Mard

et al. 2020

Journal of Leukocyte Biology

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Anthrax lethal toxin (LT) is a protease that activates the NLRP1b inflammasome sensor in certain rodent strains. Unlike better‐studied sensors, relatively little is known about the priming requirements for NLRP1b. In this study, we investigate the rapid and striking priming‐independent LT‐induced release of IL‐1β in mice within hours of toxin challenge. We find IL‐1β release to be a NLRP1b‐ and caspase‐1‐dependent, NLRP3 and caspase‐11‐independent event that requires both neutrophils and peptidyl arginine deiminiase‐4 (PAD4) activity. The simultaneous LT‐induced IL‐18 response is neutrophil‐independent. Bone marrow reconstitution experiments in mice show toxin‐induced IL‐1β originates from hematopoietic cells. LT treatment of neutrophils in vitro did not induce IL‐1β, neutrophil extracellular traps (NETs), or pyroptosis. Although platelets interact closely with neutrophils and are also a potential source of IL‐1β, they were unable to bind or endocytose LT and did not secrete IL‐1β in response to the toxin. LT‐treated mice had higher levels of cell‐free DNA and HMGB1 in circulation than PBS‐treated controls, and treatment of mice with recombinant DNase reduced the neutrophil‐ and NLRP1‐dependent IL‐1β release. DNA sensor AIM2 deficiency, however, did not impact IL‐1β release. These data, in combination with the findings on PAD4, suggest a possible role for in vivo NETs or cell‐free DNA in cytokine induction in response to LT challenge. Our findings suggest a complex interaction of events and/or mediators in LT‐treated mice with the neutrophil as a central player in induction of a profound and rapid inflammatory response to toxin.

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“…5a). This 'filament-seeding' phenomenon was not limited to the isolated CARDs, as Talabostat-activated full-length NLRP1 and CARD8 also formed filaments 9,15,19 and colocalized with ASC-CARD and CASP-1 CARD filaments, respectively ( Fig. S6).…”

Section: Structural Basis For the Distinct Downstream Card Preferencementioning

confidence: 95%

“…1A) 9,[12][13][14] . NLRP1 and CARD8 both harbor a poorly defined domain known as FIIND, whose auto-proteolytic activity is required for inflammasome activation 15,16 . The requirement of the adaptor protein ASC has also been a matter of debate for CARD-containing sensor proteins such as NLRP1 and NLRC4 17 .…”

Section: Introductionmentioning

confidence: 99%

Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

Gong

Robinson²,

et al. 2020

Preprint

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Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related NLR proteins, NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, the molecular mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIIND UPA -CARD) of NLRP1 and CARD8 self-oligomerize to trigger the assembly of distinct inflammasome complexes. Recombinant FIIND UPA -CARD of NLRP1 forms a two-layered filament, with an inner core composed of oligomerized CARD domains and the outer layer consisting of FIIND UPA rings.Biochemically, oligomerized NLRP1-CARD is sufficient to drive ASC speck formation in cultured human cells via filament formation-a process that is greatly enhanced by NLRP1-FIIND UPA , which forms ring-like oligomers in vitro. In addition, we report the cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments at 3.7 Å, which uncovers unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide unique structural insight into the mechanisms of activation for human NLRP1 and CARD8, uncovering an unexpected level of specificity in inflammasome signaling mediated by heterotypic CARD domain interactions.

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The NLRP1 inflammasome: new mechanistic insights and unresolved mysteries

Cited by 137 publications

References 70 publications

Inflammasomes contributing to inflammation in arthritis

Inflammasomes contributing to inflammation in arthritis

Frontline Science: Anthrax lethal toxin-induced, NLRP1-mediated IL-1β release is a neutrophil and PAD4-dependent event

Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

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