ASC is essential for LPS‐induced activation of procaspase‐1 independently of TLR‐associated signal adaptor molecules

Yamamoto, Masayuki; Yaginuma, Katsuyuki; Tsutsui, Hiroko; Sagara, Junji; Guan, Xin; Seki, Ekihiro; Yasuda, Koubun; Yamamoto, Masahiro; Akira, Shizuo; Nakanishi, Kenji; Noda, Tetsuo; Taniguchi, Shun’ichiro

doi:10.1111/j.1365-2443.2004.00789.x

Cited by 171 publications

(159 citation statements)

References 49 publications

(94 reference statements)

Supporting

Mentioning

145

Contrasting

Unclassified

Order By: Relevance

“…As a result, procaspase-1 is activated by the induced proximity mechanism, and is then capable of processing pro-IL-1b into the mature IL-1b cytokine, which mounts the inflammatory response. Supporting this model crude LPS, which contains PGN could induce procaspase-1 activation independent of the TLR adaptors MyD88 and Trif, 39 suggesting that activation of caspase-1 could be mediated by direct interaction of LPS or PGN with cryopyrin or other related NLR family members in the cytoplasm.…”

Section: Discussionmentioning

confidence: 74%

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

et al. 2005

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 74%

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

et al. 2005

View full text Add to dashboard Cite

show abstract

“…ASC contains an N-terminal PYD and a C-terminal CARD and is an essential component for inflammasome formation. 62 The CARD domain within ASC binds and recruits caspase-1 to the inflammasome 33,63 ( Figure 2). The inflammasome may also recruit other caspases such as caspase-5 via the C-terminal CARD of NALP1 or a second caspase-1 via the C-terminal CARD of CARDINAL, another possible component of the inflammasome.…”

Section: Activation Of Inflammatory Caspases: Inflammasomes and Othermentioning

confidence: 99%

Inflammatory caspases and inflammasomes: master switches of inflammation

2006

View full text Add to dashboard Cite

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...

show abstract

“…C57BL/6 background caspase-1-deficient mice, NALP3-deficient (Nlrp3 À/À ) mice [22], NLRC4-deficient (Nlrc4 À/À ) mice [25] and ASC (Asc À/À or Pycard À/À )-deficient mice [26] were housed in pathogen-free facility. BMM were prepared from the femurs and tibias of the above-mentioned mice and cultured for 5-6 days in 10% FBS-RPMI 1640 supplemented with 30% L-cell supernatant.…”

Section: Bacterial Strainsmentioning

confidence: 99%

Cytotoxins of the human pathogen Aeromonas hydrophila trigger, via the NLRP3 inflammasome, caspase‐1 activation in macrophages

et al. 2010

View full text Add to dashboard Cite

Aeromonas hydrophila is a Gram-negative pathogen that causes serious infectious disease in humans. A. hydrophila induces apoptosis in infected macrophages, but the host proinflammatory responses triggered by macrophage death are largely unknown. Here, we demonstrate that the infection of mouse macrophages with A. hydrophila triggers the activation of caspase-1 and release of IL-1b. Caspase-1 activation was abrogated in macrophages deficient in Nod-like receptor family, pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), but not NLR family, CARD domain containing 4 (NLRC4). The activation of the NLRP3 inflammasome was mediated by three cytotoxins (aerolysin, hemolysin and multifunctional repeat-in-toxin) produced by A. hydrophila. Our results indicated that the NLRP3 inflammasome senses A. hydrophila infection through the action of bacterial cytotoxins.Key words: Aeromonas . Caspase-1 . Nod-like receptor Supporting Information available online IntroductionThe genus Aeromonas is responsible for a significant number of animal and human infections. Aeromonas are opportunistic human pathogens that can cause intestinal and extraintestinal, wound, soft tissue, skin, and blood infections and septicemia. The most common human disease associated with Aeromonas infection is gastroenteritis with diarrhea symptoms. Among the 21 species that have been differentiated based on DNA-DNA hybridization, A. caviae, A. veronii biotype sobria and A. hydrophila are most commonly associated with human infections and account for more than 85% of all clinical isolates [1,2].Recently, it has been reported that infection with A. hydrophila induces apoptosis in macrophages [3,4]. Although the cytotoxicity by the bacteria is believed to enable the bacteria to evade eradication and clearance by the macrophages, the host proinflammatory responses triggered by the death of the macrophages remain unknown.Induction of apoptosis is considered a virulence mechanism of pathogenic bacteria that can cause tissue damage and Here, we investigated the cell death of macrophages infected with A. hydrophila and demonstrate that the bacteria cause pyroptosis with caspase-1 activation via the NLRP3 inflammasome. Aerolysin, hemolysin (HlyA) and multifunctional repeat-intoxin (RtxA) produced by A. hydrophila are required to elicit the NLRP3 inflammasome and necrotic cell death. We identify the essential bacterial and host factors for eliciting caspase-1 activation and proinflammatory responses. SHORT COMMUNICATION Results and discussionInfection with A. hydrophila induces caspase-1 activation, IL-1b release and pyroptosis It has been reported that aerolysin produced by A. salmonicida induces caspase-1 activation in CHO cells [20,21]. However, whether whole bacterial infection by A. hydrophila leads to caspase-1 activation in macrophages has not been elucidated. We examined caspase-1 activation in infected primary mouse BMderived macrophages (BMM) and observed that BMM infected with WT strai...

show abstract

ASC is essential for LPS‐induced activation of procaspase‐1 independently of TLR‐associated signal adaptor molecules

Abstract: Toll-like receptors (TLRs

Cited by 171 publications

References 49 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

Cytotoxins of the human pathogen Aeromonas hydrophila trigger, via the NLRP3 inflammasome, caspase‐1 activation in macrophages

Contact Info

Product

Resources

About