Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P2X(7) receptors (P2X(7)Rs) are ATP-gated ion channels that trigger caspase-1 activation in the presence of TLR ligands. Inflammatory caspase-1 is responsible for the proteolytic activation of IL-1beta. However, the signaling events that couple P2X(7)Rs to caspase-1 activation remain undefined. In this study we demonstrate that ATP-induced cellular oxidation is critical for caspase-1 activation and subsequent IL-1beta processing. Purinergic receptor stimulation, including P2X(7)Rs, of endotoxin-primed human monocytes augments NADPH oxidase activity whereas concurrent purinergic receptor stimulation triggers protein denitroyslation, leading to the formation of peroxynitrite. IL-1beta cleavage is blocked under conditions where superoxide anion formation is blocked or monocytes are treated with antioxidants or a peroxynitrite scavenger. Nigericin, a K(+)/H(+) antiporter, also increases NADPH oxidase activity, leading to IL-1beta and caspase-1 processing that is blocked by a peroxynitrite scavenger or inhibition of NADPH oxidase. These data demonstrate that signaling via NADPH oxidase activity is fundamental for the processing of mature IL-1beta induced by P2X(7)R stimulation.
 ...
PMID:A key role for redox signaling in rapid P2X7 receptor-induced IL-1 beta processing in human monocytes. 1852 9

Aluminum hydroxide (alum) is the most widely used adjuvant in human vaccines, but the immune mechanisms that are activated by alum remain poorly understood. Alum has recently been shown to promote caspase-1 activation and IL-1beta secretion, but the cellular pathways involved remain elusive. Here we report that the release of IL-1beta triggered by alum is abrogated in macrophages deficient in the NLR family, pyrin domain containing 3 (Nlrp3) protein and the apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) but not the NLR family, CARD domain containing 4 (Nlrc4) protein. The requirement of the Nlrp3 inflammasome was specific for IL-1beta in that secretion of TNF-alpha was independent of Nlrp3 or Asc. Consistently, processing of pro-caspase-1 induced by alum was abolished in macrophages lacking Nlrp3 or Asc. Unlike caspase-1 processing and IL-1beta secretion triggered by LPS, alum-mediated activation of the inflammasome did not require exogenous ATP. Importantly, induction of IgG production against human serum albumin by alum was unimpaired in mice deficient in Nlrp3. These results indicate that alum induces IL-1beta via the Nlrp3 inflammasome but this activity is dispensable for alum-mediated adjuvant activity.
 ...
PMID:The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1beta secretion but dispensable for adjuvant activity. 1865 1

The aspartate-specific cysteine protease caspase-1 is activated by the inflammasomes and is responsible for the proteolytic maturation of the cytokines IL-1 beta and IL-18 during infection and inflammation. To discover new caspase-1 substrates, we made use of a proteome-wide gel-free differential peptide sorting methodology that allows unambiguous localization of the processing site in addition to identification of the substrate. Of the 1022 proteins that were identified, 20 were found to be specifically cleaved after Asp in the setup incubated with recombinant caspase-1. Interestingly, caspase-7 emerged as one of the identified caspase-1 substrates. Moreover half of the other identified cleavage events occurred at sites closely resembling the consensus caspase-7 recognition sequence DEVD, suggesting caspase-1-mediated activation of endogenous caspase-7 in this setup. Consistently recombinant caspase-1 cleaved caspase-7 at the canonical activation sites Asp(23) and Asp(198), and recombinant caspase-7 processed a subset of the identified substrates. In vivo, caspase-7 activation was observed in conditions known to induce activation of caspase-1, including Salmonella infection and microbial stimuli combined with ATP. Interestingly Salmonella- and lipopolysaccharide + ATP-induced activation of caspase-7 was abolished in macrophages deficient in caspase-1, the pattern recognition receptors Ipaf and Cryopyrin, and the inflammasome adaptor ASC, demonstrating an upstream role for the caspase-1 inflammasomes in caspase-7 activation in vivo. In contrast, caspase-1 and the inflammasomes were not required for caspase-3 activation. In conclusion, we identified 20 new substrates activated downstream of caspase-1 and validated caspase-1-mediated caspase-7 activation in vitro and in knock-out macrophages. These results demonstrate for the first time the existence of a nucleotide binding and oligomerization domain-like receptor/caspase-1/caspase-7 cascade and the existence of distinct activation mechanisms for caspase-3 and -7 in response to microbial stimuli and bacterial infection.
 ...
PMID:Targeted peptidecentric proteomics reveals caspase-7 as a substrate of the caspase-1 inflammasomes. 1866 12

The inflammasome is a large multiprotein complex whose assembly leads to the activation of caspase-1, which promotes the maturation of proinflammatory cytokines interleukin-1beta (IL-1beta) and IL-18. Proteins encoded by the nucleotide-binding domain and leucine-rich repeat (NLR) containing gene family form the central components of inflammasomes and act as intracellular sensors to detect cytosolic microbial components and "danger" signals (such as ATP and toxins). The inflammasome not only plays a pivotal role in innate immune responses toward pathogens but also mediates the activity of aluminum adjuvants. Thus, the inflammasome and associated signaling pathways are attractive targets for new therapeutics and vaccines.
 ...
PMID:The caspase-1 inflammasome: a pilot of innate immune responses. 1877 46

Caspase-1 is an inflammatory caspase that controls the activation and secretion of the inflammatory cytokines, IL-1beta and IL-18. We observed that cellular levels of retinoic acid-inducible gene-I (RIG-I) were enhanced when the pan-caspase inhibitor Z-VAD-fmk or caspase-1-specific inhibitor Z-WEHD-fmk blocked caspase activity. Overexpression of caspase-1 reduced cellular levels of RIG-I and inhibited RIG-I-mediated signaling activity. Enzymatic activity of caspase-1 was necessary to control RIG-I, although it was not a substrate of proteolytic cleavage by caspase-1. Caspase-1 physically interacted with full length RIG-I, but not with mutant forms lacking either the amino- or carboxyl-terminal domains. RIG-I was present in the supernatant of cells transfected with active caspase-1 but not with caspase-4. Stimulating cells with LPS and ATP also induced secretion of endogenous RIG-I in macrophages. Our data suggest a novel mechanism that negatively regulates RIG-I-mediated signaling activity via caspase-1-dependent secretion of RIG-I protein.
 ...
PMID:Active caspase-1-mediated secretion of retinoic acid inducible gene-I. 1898 Nov 55

Macrophages are unique innate immune cells that play an integral role in the defense of the host by virtue of their ability to recognize, engulf, and kill pathogens while sending out danger signals via cytokines to recruit and activate inflammatory cells. It is becoming increasingly clear that purinergic signaling events are essential components of the macrophage response to pathogen challenges and disorders such as sepsis may be, at least in part, regulated by these important sensors. The activation of the P2X(7) receptor is a powerful event in the regulation of the caspase-1 inflammasome. We provide evidence that the inflammasome activation requires "priming" of macrophages prior to ATP activation of the P2X(7)R. Inhibition of the inflammasome activation by the tyrosine kinase inhibitor, AG126, suggests regulation by phosphorylation. Finally, the P2X(7)R may also be activated by other elements of the host response such as the antimicrobial peptide LL-37, which adds a new, physiologically relevant agonist to the P2X(7)R pathway. Therapeutic approaches to inflammation and sepsis will certainly be enhanced by an increased understanding of how purinergic receptors modulate the inflammasomes.
 ...
PMID:P2X(7) receptor and macrophage function. 1921 78

NLRP1 (NLR family, pyrin domain-containing 1) is a contributor to innate immunity involved in intracellular sensing of pathogens, as well as danger signals related to cell injury. NLRP1 is one of the core components of caspase-1-activating platforms termed "inflammasomes," which are involved in proteolytic processing of interleukin-1beta (IL-1beta) and in cell death. We previously discovered that anti-apoptotic proteins Bcl-2 and Bcl-X(L) bind to and inhibit NLRP1 in cells. Using an in vitro reconstituted system employing purified recombinant proteins, we studied the mechanism by which Bcl-2 and Bcl-X(L) inhibit NLRP1. Bcl-2 and Bcl-X(L) inhibited caspase-1 activation induced by NLRP1 in a concentration-dependent manner, with K(i) approximately 10 nM. Bcl-2 and Bcl-X(L) were also determined to inhibit ATP binding to NLRP1, which is required for oligomerization of NLRP1, and Bcl-X(L) was demonstrated to interfere with NLRP1 oligomerization. Deletion of the flexible loop regions of Bcl-2 and Bcl-X(L), which are located between the first and second alpha-helices of these anti-apoptotic proteins and which were previously shown to be required for binding NLRP1, abrogated ability to inhibit caspase-1 activation, ATP binding and oligomerization of NLRP1. Conversely, synthetic peptides corresponding to the loop region of Bcl-2 were sufficient to potently inhibit NLRP1. These findings thus demonstrate that the loop domain is necessary and sufficient to inhibit NLRP1, providing insights into the mechanism by which anti-apoptotic proteins Bcl-2 and Bcl-X(L) inhibit NLRP1.
 ...
PMID:Mechanism of Bcl-2 and Bcl-X(L) inhibition of NLRP1 inflammasome: loop domain-dependent suppression of ATP binding and oligomerization. 1922 83

We recently reported that P2X7 receptor (P2X7R)-induced activation of caspase-1 inflammasomes is accompanied by release of MHC class II (MHC-II) protein into extracellular compartments during brief stimulation of murine macrophages with ATP. Here we demonstrate that MHC-II containing membranes released from macrophages or dendritic cells (DCs) in response to P2X7R stimulation comprise two pools of vesicles with distinct biogenesis: one pool comprises 100- to 600-nm microvesicles derived from direct budding of the plasma membrane, while the second pool is composed of 50- to 80-nm exosomes released from multivesicular bodies. ATP-stimulated release of MHC-II in these membrane fractions is observed within 15 min and results in the export of approximately 15% of the total MHC-II pool within 90 min. ATP did not stimulate MHC-II release in macrophages from P2X7R knockout mice. The inflammasome regulatory proteins, ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain) and NLRP3 (NLR family, pyrin domain containing 3), which are essential for caspase-1 activation, were also required for the P2X7R-regulated release of the exosome but not the microvesicle MHC-II pool. Treatment of bone marrow-derived macrophages with YVAD-cmk, a peptide inhibitor of caspase-1, also abrogated P2X7R-dependent MHC-II secretion. Surprisingly, however, MHC-II release in response to ATP was intact in caspase-1(-/-) macrophages. The inhibitory actions of YVAD-cmk were mimicked by the pan-caspase inhibitor zVAD-fmk and the serine protease inhibitor TPCK, but not the caspase-3 inhibitor DEVD-cho. These data suggest that the ASC/NLRP3 inflammasome complexes assembled in response to P2X7R activation involve protease effector(s) in addition to caspase-1, and that these proteases may play important roles in regulating the membrane trafficking pathways that control biogenesis and release of MHC-II-containing exosomes.
 ...
PMID:P2X7 receptor-stimulated secretion of MHC class II-containing exosomes requires the ASC/NLRP3 inflammasome but is independent of caspase-1. 1934 85

The inflammasome is a multiprotein complex involved in innate immunity. Activation of the inflammasome causes the processing and release of the cytokines interleukins 1beta and 18. In primary macrophages, potassium ion flux and the membrane channel pannexin 1 have been suggested to play roles in inflammasome activation. However, the molecular mechanism(s) governing inflammasome signaling remains poorly defined, and it is undetermined whether these mechanisms apply to the central nervous system. Here we show that high extracellular potassium opens pannexin channels leading to caspase-1 activation in primary neurons and astrocytes. The effect of K(+) on pannexin 1 channels was independent of membrane potential, suggesting that stimulation of inflammasome signaling was mediated by an allosteric effect. The activation of the inflammasome by K(+) was inhibited by the pannexin 1 channel blocker probenecid, supporting a role of pannexin 1 in inflammasome activation. Co-immunoprecipitation of neuronal lysates indicates that pannexin 1 associates with components of the multiprotein inflammasome complex, including the P2X7 receptor and caspase-1. Moreover antibody neutralization of the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) blocked ATP-induced cell death in oocytes co-expressing P2X7 receptor and pannexin 1. Thus, in contrast to macrophages and monocytes in which low intracellular K(+) has been suggested to trigger inflammasome activation, in neural cells, high extracellular K(+) activates caspase-1 probably through pannexin 1.
 ...
PMID:The pannexin 1 channel activates the inflammasome in neurons and astrocytes. 1941 75

Despite being used for more than 80 years, the mechanisms of induction of immune responses by aluminum adjuvants, generically referred to as 'alum', remain largely unknown. However, substantial amounts of recently gathered data demonstrate that aluminum salts induce an innate immune reaction at the site of vaccination. Thus, aluminum salts activate dendritic cells, monocytes and macrophages with enhanced expression of adhesion molecules CD54 and CD58 and co-stimulatory molecules CD40 and CD86, which are crucial in T cell activation; induce chemokines CCL2, CCL3, CCL4 and CXCL8, which mediate recruitment of inflammatory cells at the site of vaccination; and stimulate cytokines crucial in the innate immune response. Aluminum adjuvants activate the nucleotide-binding domain and leucine-rich-repeat-containing gene family pyrin-domain-containing 3 (known as NLRP3 or NALP3) inflammasome to activate caspase-1 and to induce proinflammatory cytokines interleukin (IL)-1beta and IL-18 by innate cells. Aluminum adjuvants activate NLRP3 by multiple mechanisms such as by causing damage and rupture of the phagolysosomes, generating reactive oxygen species, inducing K(+) efflux and via release from injured tissues of molecules that constitute danger-associated molecular patterns (DAMPs) such as uric acid and ATP. These novel cellular and molecular mechanisms of aluminum salts are likely to influence how we design effective and safe adjuvants in the future.
 ...
PMID:Novel cellular and molecular mechanisms of induction of immune responses by aluminum adjuvants. 1943 72


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>