Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.36 (caspase-1)
6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-1 is a primary mediator of immune responses to injury and infection, but the mechanism of its cellular release is unknown. IL-1 exists as two agonist forms (IL-1 alpha and IL-1 beta) present in the cytosol of activated monocytes/macrophages. IL-1 beta is synthesized as an inactive precursor that lacks a signal sequence, and its trafficking does not use the classical endoplasmic reticulum-Golgi route of secretion. Using primary cultured murine peritoneal macrophages, we demonstrate that P2X7 receptor activation causes release of IL-1 beta and IL-1 alpha via a common pathway, dependent upon the release of Ca(2+) from endoplasmic reticulum stores and caspase-1 activity. Increases in intracellular Ca(2+) alone do not promote IL-1 secretion because a concomitant efflux of K(+) through the plasmalemma is required. In addition, we demonstrate the existence of an alternative pathway for the secretion of IL-1 alpha, independent of P2X7 receptor activation, but dependent upon Ca(2+) influx. The identification of these mechanisms provides insight into the mechanism of IL-1 secretion, and may lead to the identification of targets for the therapeutic modulation of IL-1 action in inflammation.
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PMID:Ca2+ stores and Ca2+ entry differentially contribute to the release of IL-1 beta and IL-1 alpha from murine macrophages. 1262 57

The regulation of cell death has been investigated in a number of clinical disorders including renal ischemic and toxic acute renal failure. Caspases play a crucial role in the execution or final phase of cell death by cleaving and inactivating various structural and functional intracellular proteins that are essential for cell survival and proliferation. Evidence is now emerging to implicate the caspase pathway in a variety of renal diseases including the pathogenesis of acute renal failure. Among the 14 known members of the caspase family thus far identified several executioner caspases including caspases-3, -6, and -7 and the proinflammatory caspase including caspase-1 may participate in the final degradation of intracellular proteins. The activation of these caspases is regulated by the receptor- and mitochondrial-mediated cell signaling pathways as well as by the endoplasmic reticulum stress response. While the role of some caspases in renal injury is emerging, the roles of various proinflammatory and other executioner caspases remain to be determined. Although many pro- and anti-apoptotic molecules that act upstream of caspase activation have been identified, their regulation is yet to be determined in the pathogenesis of renal injury. A precise description of caspase-mediated cell death pathway and regulation of caspase activation is, therefore, critical to the understanding of the mechanism of renal injury and to the development of therapeutic targets that prevent renal diseases and preserve renal function.
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PMID:Role of caspases in renal tubular epithelial cell injury. 1368 May 31

Plants, animals, and several branches of unicellular eukaryotes use programmed cell death (PCD) for defense or developmental mechanisms. This argues for a common ancestral apoptotic system in eukaryotes. However, at the molecular level, very few regulatory proteins or protein domains have been identified as conserved across all eukaryotic PCD forms. A very important goal is to determine which molecular components may be used in the execution of PCD in plants, which have been conserved during evolution, and which are plant-specific. Using Arabidopsis thaliana, we have shown that UV radiation can induce apoptosis-like changes at the cellular level and that a UV experimental system is relevant to the study of PCD in plants. We report here that UV induction of PCD required light and that a protease cleaving the caspase substrate Asp-Glu-Val-Asp (DEVDase activity) was induced within 30 min and peaked at 1 h. This DEVDase appears to be related to animal caspases at the biochemical level, being insensitive to broad-range cysteine protease inhibitors. In addition, caspase-1 and caspase-3 inhibitors and the pan-caspase inhibitor p35 were able to suppress DNA fragmentation and cell death. These results suggest that a YVADase activity and an inducible DEVDase activity possibly mediate DNA fragmentation during plant PCD induced by UV overexposure. We also report that At-DAD1 and At-DAD2, the two A. thaliana homologs of Defender against Apoptotic Death-1, could suppress the onset of DNA fragmentation in A. thaliana, supporting an involvement of the endoplasmic reticulum in this form of the plant PCD pathway.
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PMID:Ultraviolet-C overexposure induces programmed cell death in Arabidopsis, which is mediated by caspase-like activities and which can be suppressed by caspase inhibitors, p35 and Defender against Apoptotic Death. 1457 11

Recent studies have suggested that neuronal death in Alzheimer's disease or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Although caspase-12 has been implicated in ER stress-induced apoptosis and amyloid-beta (Abeta)-induced apoptosis in rodents, it is controversial whether similar mechanisms operate in humans. We found that human caspase-4, a member of caspase-1 subfamily that includes caspase-12, is localized to the ER membrane, and is cleaved when cells are treated with ER stress-inducing reagents, but not with other apoptotic reagents. Cleavage of caspase-4 is not affected by overexpression of Bcl-2, which prevents signal transduction on the mitochondria, suggesting that caspase-4 is primarily activated in ER stress-induced apoptosis. Furthermore, a reduction of caspase-4 expression by small interfering RNA decreases ER stress-induced apoptosis in some cell lines, but not other ER stress-independent apoptosis. Caspase-4 is also cleaved by administration of Abeta, and Abeta-induced apoptosis is reduced by small interfering RNAs to caspase-4. Thus, caspase-4 can function as an ER stress-specific caspase in humans, and may be involved in pathogenesis of Alzheimer's disease.
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PMID:Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. 1512 40

Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.
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PMID:Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. 1512 68

Extracellular adenosine significantly reduced cell viability in a dose (0.1-20mM)- and treatment time (24-72h)-dependent manner in GT3-TKB cells, a human gastric cancer cell line. Nuclei of cells were reactive to Hoechst 33342, a marker of apoptosis, and an anti-single-stranded DNA. Adenosine-induced GT3-TKB cell death was significantly inhibited by dipyridamole, an inhibitor of adenosine transporter, and 5'-amino-5'-deoxyadenosine, an inhibitor of adenosine kinase, but the effect was not affected by theophylline, a broad inhibitor of adenosine receptors, 8-cyclopentyltheophylline, an inhibitor of A(1) adenosine receptors or 3,7-dimethyl-1-propargylxanthine, an inhibitor of A(2a) adenosine receptors. Adenosine had no effect on mitochondrial membrane potentials. The effect of adenosine on GT3-TKB cell death was not inhibited by a pancaspase inhibitor or inhibitors of caspase-1,-3,-4,-8, and -9. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR), an activator of AMP-activated protein kinase (AMPK), significantly reduced GT3-TKB cell viability, but the AICAR action was not reinforced in the presence of adenosine. The results of the present study, thus, suggest that extracellular adenosine induces apoptosis in GT3-TKB cells by its uptake into cells and conversion to AMP followed by activation of AMPK, regardless of caspase activation linked to the mitochondria and the endoplasmic reticulum.
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PMID:Adenosine induces apoptosis in the human gastric cancer cells via an intrinsic pathway relevant to activation of AMP-activated protein kinase. 1513 Jul 76

Legionella pneumophila is an intracellular bacterium that causes an acute form of pneumonia called Legionnaires' disease. After infection of human macrophages, the Legionella-containing phagosome (LCP) avoids fusion with the lysosome allowing intracellular replication of the bacterium. In macrophages derived from most mouse strains, the LCP is delivered to the lysosome resulting in Legionella degradation and restricted bacterial growth. Mouse macrophages lacking the NLR protein Ipaf or its downstream effector caspase-1 are permissive to intracellular Legionella replication. However, the mechanism by which Ipaf restricts Legionella replication is not well understood. Here we demonstrate that the presence of flagellin and a competent type IV secretion system are critical for Legionella to activate caspase-1 in macrophages. Activation of caspase-1 in response to Legionella infection also required host Ipaf, but not TLR5. In the absence of Ipaf or caspase-1 activation, the LCP acquired endoplasmic reticulum-derived vesicles, avoided fusion with the lysosome, and allowed Legionella replication. Accordingly a Legionella mutant lacking flagellin did not activate caspase-1, avoided degradation, and replicated in wild-type macrophages. The regulation of phagosome maturation by Ipaf occurred within 2 h after infection and was independent of macrophage cell death. In vivo studies confirmed that flagellin and Ipaf play an important role in the control of Legionella clearance. These results reveal that Ipaf restricts Legionella replication through the regulation of phagosome maturation, providing a novel function for NLR proteins in host defense against an intracellular bacterium.
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PMID:Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf. 1698 19

Mammalian cells export most proteins by the endoplasmic reticulum/Golgi-dependent pathway. However, some proteins are secreted via unconventional, poorly understood mechanisms. The latter include the proinflammatory cytokines interleukin(IL)-1beta, IL-18, and IL-33, which require activation by caspase-1 for biological activity. Caspase-1 itself is activated by innate immune complexes, the inflammasomes. Here we show that secretion of the leaderless proteins proIL-1alpha, caspase-1, and fibroblast growth factor (FGF)-2 depends on caspase-1 activity. Although proIL-1alpha and FGF-2 are not substrates of the protease, we demonstrated their physical interaction. Secretome analysis using iTRAQ proteomics revealed caspase-1-mediated secretion of other leaderless proteins with known or unknown extracellular functions. Strikingly, many of these proteins are involved in inflammation, cytoprotection, or tissue repair. These results provide evidence for an important role of caspase-1 in unconventional protein secretion. By this mechanism, stress-induced activation of caspase-1 directly links inflammation to cytoprotection, cell survival, and regenerative processes.
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PMID:Active caspase-1 is a regulator of unconventional protein secretion. 1832 68

Caspase-12 is a dominant-negative regulator of caspase-1 (IL-1beta-converting enzyme) and an attenuator of cytokine responsiveness to septic infections. This molecular role for caspase-12 appears to be akin to the role of cFLIP in regulating caspase-8 in the extrinsic cell death pathway; however, unlike cFLIP/Usurpin, we demonstrate here that caspase-12 is catalytically competent. To examine these catalytic properties, rat caspase-12 was cloned, and the recombinant enzyme was used to examine the cleavage of macromolecular and synthetic fluorogenic substrates. Although caspase-12 could mediate autoproteolytic maturation of its own proenzyme, in both cis and trans, it was not able to cleave any other polypeptide substrate, including other caspase proenzymes, apoptotic substrates, cytokine precursors, or proteins in the endoplasmic reticulum that normally undergo caspase-mediated proteolysis. The dearth of potential substrates for caspase-12 also was confirmed by whole-cell diagonal-gel analysis. Autolytic cleavage within the caspase-12 proenzyme was mapped to a single site at the large-small subunit junction, ATAD(319), and this motif was recognized by caspase-12 when incorporated into synthetic fluorogenic substrates. The specific activity of caspase-12 with these substates was several orders of magnitude lower than caspases-1 and -3, highlighting its relative catalytic paucity. In intact cells, caspase-12 autoproteolysis occurred in the inhibitory complex containing caspase-1. We propose that the proteolytic activity of caspase-12 is confined to its own proenzyme and that autocleavage within the caspase-1 complex may be a means for temporal limitation of the inhibitory effects of caspase-12 on proinflammatory cytokine maturation.
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PMID:Confinement of caspase-12 proteolytic activity to autoprocessing. 1833 41

A-kinase-anchoring protein 149 (AKAP149) is a member of a structurally diverse, though functionally similar anchoring protein family and is localized to the outer membrane of mitochondria and in the endoplasmic reticulum-nuclear envelope network. AKAP149 plays an important role in controlling the subcellular localization and temporal specificity of protein phosphorylation and mRNA metabolism by tethering kinases and phosphatases, such as protein kinase A and type I protein phosphatase, through its N-terminal protein-binding motifs and mRNAs via its C-terminal RNA-binding motifs. It is well recognized that caspases play a central role in transducing and amplifying the intracellular death signal and that apoptosis is executed as a consequence of caspase-mediated cleavage of multiple cellular substrates. The identification of novel death substrates and elucidation of the consequences of their proteolytic cleavages by caspases are therefore crucial for our understanding of cell death and other biological processes. Herein, we demonstrated that AKAP149 is a direct substrate of active caspase-3, -8 -and -10 in vitro and in vivo. 35S-labeled full-length AKAP149 was completely cleaved in vitro by active caspase-3, -8 and -10 into two fragments of approximately 105 and 45 kDa, while caspase-2 cleaved it partially and caspase-1 did not cleave it at all. AKAP149 was also cleaved by caspases during Fas- and staurosporine-induced apoptosis in Jurkat T and HeLa cells, which were blocked by specific inhibitors of caspase-3 and -8. The specific cleavage site for these caspases was mapped in vitro and in vivo to Asp582 at AKAP149, which is located between the protein kinase A regulatory subunit anchoring and KH RNA-binding domains. In addition, HeLa cells transiently overexpressing AKAP149 D582E mutant were resistant to staurosporine-induced HeLa cell apoptosis. Taken together, these data suggest that AKAP149 activity may be deregulated by caspase-dependent proteolysis during apoptotic cell death and may provide useful information for elucidating the apoptosis signaling pathways in detail.
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PMID:Specific proteolysis of the A-kinase-anchoring protein 149 at the Asp582 residue by caspases during apoptosis. 1849 68


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