Cutting Edge: CIAS1/Cryopyrin/PYPAF1/NALP3/ CATERPILLER 1.1 Is an Inducible Inflammatory Mediator with NF-κB Suppressive Properties

O’Connor, William; Harton, Jonathan A.; Zhu, Xiaojuan; Linhoff, Michael W.; Ting, Jenny P.Y.

doi:10.4049/jimmunol.171.12.6329

Cited by 172 publications

(135 citation statements)

References 25 publications

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“…[29][30][31][32][33] Since these studies were performed in transfected cells overexpressing ASC, the results of these studies may not reflect the normal physiological function of ASC. This is especially true in light of the results of the ASC knockout mice, which demonstrated that ASC does not appear to play a role in NF-kB activation in response to LPS or TNF-a.…”

Section: Resultsmentioning

confidence: 99%

“…Cryopyrin is primarily expressed in peripheral blood leukocytes. 28,29 Recent reports suggest that cryopyrin is involved in the regulation of NF-kB activation, [29][30][31][32][33] and this in turn regulates the expression of genes involved in the immune response and inflammation. 34 Cryopyrin also regulates IL-1b generation by assembling an inflammasome complex with ASC and caspase-1.…”

Section: Introductionmentioning

confidence: 99%

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Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization

et al. 2005

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Mutations in cryopyrin and pyrin proteins are responsible for several autoinflammatory disorders in humans, suggesting that these proteins play important roles in regulating inflammation. Using a HEK293 cell-based reconstitution system that stably expresses ASC and procaspase-1 we demonstrated that neither cryopyrin nor pyrin or their corresponding disease-associated mutants could significantly activate NF-jB in this system. However, both cryopyrin and two disease-associated cryopyrin mutants induced ASC oligomerization and ASC-dependent caspase-1 activation, with the disease-associated mutants being more potent than the wild-type (WT) cryopyrin, because of increased selfoligomerization. Contrary to the proposed anti-inflammatory activity of WT pyrin, our results demonstrated that pyrin, like cryopyrin, can also assemble an inflammasome complex with ASC and procaspase-1 leading to ASC oligomerization, caspase-1 activation and interleukin-1b processing. Thus, we propose that pyrin could function as a proinflammatory molecule.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization

et al. 2005

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“…Alternative splicing of the LRR region is evident for virtually all NALPs as detected by EST analysis and the cloning of various NALPs. 66,67 Moreover, it is interesting to note that exon-exon junctions disrupt the b-strand that is predicted in binding targets. Therefore, alternative splicing not only reorganize the numbers of bstrand but generate completely new b-strands allowing maximal variability in the ligand recognition region.…”

Section: Repertoire and Genomic Organization Of The Nalp Lrrsmentioning

confidence: 99%

Inflammatory caspases and inflammasomes: master switches of inflammation

2006

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Fifteen years have passed since the cloning and characterization of the interleukin-1b-converting enzyme (ICE/caspase-1), the first identified member of a family of proteases currently known as caspases. Caspase-1 is the prototypical member of a subclass of caspases involved in cytokine maturation termed inflammatory caspases that also include caspase-4 caspase -5, caspase -11 and caspase -12. Efforts to elucidate the molecular mechanisms involved in the activation of these proteases have uncovered an important role for the NLR family members, NALPs, NAIP and IPAF. These proteins promote the assembly of multiprotein complexes termed inflammasomes, which are required for activation of inflammatory caspases. This article will review some evolutionary aspects, biochemical evidences and genetic studies, underlining the role of inflammasomes and inflammatory caspases in innate immunity against pathogens, autoinflammatory syndromes and in the biology of reproduction. Inflammatory CaspasesThe history of caspases began with the identification of an aspartate-specific protease activity involved in the conversion of the 31 kDa proIL-1b precursor to its active 17 kDa biologically active form, 1,2 and the identification of caspase-1 as the protease responsible for proIL-1b maturation. 3,4 The subsequent discovery of ced-3, that shares similarities with caspase-1 and which is involved in programmed cell death (PCD) in Caenorhabditis elegans, suggested that caspases might play fundamental roles in apoptosis. 5 As reviewed in the papers accompanying this issue of Cell Death and Differentiation, the role of apoptotic caspases in C. elegans and in vertebrates is crucial and deal with many facets of cell biology, development and diseases. In this review, we will focus on a subset of caspases present only in vertebrates and known as inflammatory caspases.Inflammatory caspases (also known as group I caspases) are encoded by three main genes in humans caspase-1, caspase-4 and caspase-5 and three main genes in mouse, caspase-1, caspase-11 and caspase-12. 6,7 In mammals, these caspases are characterized by the presence of a CARD domain at the N-terminus (Figure 1a). Human, chimp and mouse inflammatory caspases share significant similarity and are organized in a single locus (Figure 1c). Phylogenetic analysis of the conserved CARD domain suggests that the inflammatory caspases can be separated in evolutionaryrelated clusters (Figure 1b). The caspase-1 cluster contains caspase-1 and four other genes encoding decoy caspases: cop, inca1, inca2 and iceberg. These decoy caspase-1-like genes are absent in the mouse genome, suggesting that they have arisen recently by duplication of caspase-1. Although human and mouse caspase-1 are likely orthologues, sequence analysis suggests that human caspase-4 and caspase-5 have originated from a duplication of caspase-11. 7 However, the human caspase-12 gene, which in the chimp genome contains an SHG box important for it enzymatic activity, 8 evolved towards an enzymatically inactive form at some stage...

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“…However, others have reported that Monarch-1 dampens NF-kB signals triggered by TLRs or TNF stimulation. 122,123 In the past few years, the group of Tschopp has pioneered research on the role of Nalps in shaping and regulating caspase-1-triggering complexes, the so-called 'inflammosomes.' 124 The Nalp1 inflammosome induces the activation of both caspase-1 and -5, through formation of a complex containing, in addition to these two caspases, the proteins Nalp1 and ASC.…”

Section: Nalpsmentioning

confidence: 99%

TIR, CARD and PYRIN: three domains for an antimicrobial triad

2006

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Innate immunity to microorganisms in mammals has gained a substantial interest during the last decade. The discovery of the Toll-like receptor (TLR) family has allowed the identification of a class of membrane-spanning receptors dedicated to microbial sensing. TLRs transduce downstream signaling via their intracellular Toll-interleukin-1 receptor (TIR) domain. More recently, the role of intracellular microbial sensors has been uncovered. These molecules include the Nod-like receptors Nod1, Nod2, Ipaf and Nalps, together with the helicase domain-containing antiviral proteins RIG-I and Mda-5. The intracellular microbial sensors lack the TIR domain, but instead transduce downstream signals via two domains also implicated in homophilic protein-protein interactions, the caspase activation and recruitment domain (CARD) and PYRIN domains. In light with these recent findings, we propose that TIR, CARD and PYRIN domains represent the three arms of innate immune detection of microorganisms in mammals.

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Cutting Edge: CIAS1/Cryopyrin/PYPAF1/NALP3/ CATERPILLER 1.1 Is an Inducible Inflammatory Mediator with NF-κB Suppressive Properties

Cited by 172 publications

References 25 publications

Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization

Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization

Inflammatory caspases and inflammasomes: master switches of inflammation

TIR, CARD and PYRIN: three domains for an antimicrobial triad

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