3.4.22.64: caspase-11
This is an abbreviated version!
For detailed information about caspase-11, go to the full flat file.
Word Map on EC 3.4.22.64
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3.4.22.64
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inflammasome
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pyroptosis
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lps
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lipopolysaccharide
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non-canonical
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gasdermin
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sepsis
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gsdmd
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interleukin-1
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lps-induced
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pyrin
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casp11
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apoptosis-associated
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nod-like
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caspase-5
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pore-forming
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speck-like
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guanylate-binding
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inflammasome-mediated
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wedelolactone
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rodentium
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pyroptosis-related
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inflammasome-dependent
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caspase-1/11
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caspase-1-mediated
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bmdms
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speck
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thailandensis
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medicine
- 3.4.22.64
- inflammasome
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pyroptosis
- lps
- lipopolysaccharide
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non-canonical
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gasdermin
- sepsis
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gsdmd
- interleukin-1
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lps-induced
- pyrin
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casp11
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apoptosis-associated
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nod-like
- caspase-5
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pore-forming
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speck-like
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guanylate-binding
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inflammasome-mediated
- wedelolactone
- rodentium
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pyroptosis-related
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inflammasome-dependent
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caspase-1/11
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caspase-1-mediated
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bmdms
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speck
- thailandensis
- medicine
Reaction
strict requirement for Asp at the P1 position and has a preferred cleavage sequence of (Ile/Leu/Val/Phe)-Gly-His-Asp-/- =
Synonyms
C14.012, CASP4, caspase 11, caspase-11, caspase-4, Ich-3, ICH-3 protease
ECTree
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General Information
General Information on EC 3.4.22.64 - caspase-11
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evolution
malfunction
metabolism
physiological function
additional information
evolution
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inflammatory caspases all share a similar prodomain at the N-terminus responsible for protein-protein interactions: the caspase activation and recruitment domain (CARD). The genes of the inflammatory caspases are all located adjacent to the Casp1 gene on the mammalian chromosome (chromosome 9 in mouse), forming an inflammatory gene cluster. The close proximity of these genes and the high degree of similarity in the caspase protein structures might explain that the multiple inflammatory caspases arose from amplification of the Casp1 gene locus in the early stages of mammalian evolution
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germline mutation of Casp11 in mouse strain 129 abolishes inflammasome activation by CTB. Strain 129 mice, like Casp11-/- mice, exhibits defects in IL-1beta production and harbours a mutation in the Casp11 locus that attenuates caspase-11 expression
malfunction
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all Casp1-/- mice also lack caspase-11, due to the generation of the Casp1-/- line in the 129 mouse strain background, which express a mis-spliced and truncated version of the Casp11 messenger RNA
malfunction
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all existing caspase-1 deficient mice also lack Caspase-11 due to the backcrossing of a mutant Casp11 allele from 129 into C57BL/6 mice
malfunction
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Casp11-/- knockout mouse strains are resistant to developing lethal sepsis
malfunction
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defects in the IFN-alpha/beta, but not IFN-gamma, pathways render macrophages severely impaired in processing of caspase-11 following infection with Salmonella typhimurium, EHEC or Citrobacter rodentium, while exogenous IFN-beta rescues caspase-11 processing in Trif-/- macrophages. The absence of the TRIF-IFNAR pathway abolishes both the expression and activation of caspase-11, and treatment of Trif-/- macrophages with IFN-beta or IFN-gamma restores both the precursor and cleaved forms of caspase-11
malfunction
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inhibition of caspase-11 expression with either wedelolactone or siRNAs reduces the number of methamphetamine-induced apoptotic cells, silencing of caspase-11 protects PC-12 cells from methamphetamine-induced apoptosis. In addition, blocking caspase-11 expression inhibits methamphetamine-induced activation of caspase-3 and PARP in vitro and in vivo
malfunction
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inhibition of caspase-11 expression with either wedelolactone or siRNAs reduces the number of methamphetamine-induced apoptotic cells. In addition, blocking caspase-11 expression inhibits methamphetamine-induced activation of caspase-3 and PARP in vitro and in vivo
malfunction
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upon infection with Salmonella typhimurium, the level of pro-interleukin-1beta maturation in bone marrow derived macrophages is reduced in the absence of caspase-11
malfunction
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germline mutation of Casp11 in mouse strain 129 abolishes inflammasome activation by CTB. Strain 129 mice, like Casp11-/- mice, exhibits defects in IL-1beta production and harbours a mutation in the Casp11 locus that attenuates caspase-11 expression
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malfunction
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all existing caspase-1 deficient mice also lack Caspase-11 due to the backcrossing of a mutant Casp11 allele from 129 into C57BL/6 mice
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malfunction
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inhibition of caspase-11 expression with either wedelolactone or siRNAs reduces the number of methamphetamine-induced apoptotic cells, silencing of caspase-11 protects PC-12 cells from methamphetamine-induced apoptosis. In addition, blocking caspase-11 expression inhibits methamphetamine-induced activation of caspase-3 and PARP in vitro and in vivo
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apoptosis is triggered by the initiator caspases, caspase-2, -8, -9, and -10, which subsequently activate the executioner caspases, caspase-3, -6, and -7
metabolism
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apoptosis is triggered by the initiator caspases, caspase-2, -8, -9, and -10, which subsequently activate the executioner caspases, caspase-3, -6, and -7
metabolism
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Gram-negative bacteria and certain pore-forming toxins induce a caspase-11-dependent noncanonical inflammasome that contributes to NLRP3-dependent interleukin-1beta release and also triggers NLRP3- and caspase-1-independent cell death and interleukin-1alpha release
metabolism
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Gram-negative bacteria are specifically detected via a surveillance mechanism that involves activation of extracellular receptors such as Toll-like receptors followed by intracellular recognition and activation of pathways such as caspase-11. Extracellular LPS primarily stimulates TLR4, which can serve as a priming signal for expression of inflammasome components. Intracellular LPS can then trigger caspase-11-dependent inflammasome activation in the cytoplasm. Bacterial infection triggers caspase-11 activation and leads to two distinct signals: (i) caspase-1-dependent interleukin-1beta/interleukin-18 secretion and caspase-1-independent pyroptosis
metabolism
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while Salmonella typhimurium and Legionella pneumophila normally reside in the vacuole, specific mutants (sifA and sdhA, respectively) that aberrantly enter the cytosol trigger Caspase-11, enhancing clearance of S. typhimurium sifA in vivo. This response does not require NLRP3, NLRC4, or ASC inflammasome pathways. Burkholderia species that naturally invade the cytosol also trigger Caspase-11, protecting mice from lethal challenge with Burkholderia thailandensis and Burkholderia pseudomallei. Caspase-11 is critical for surviving exposure to ubiquitous environmental pathogens
metabolism
caspase-11 auto-cleavage at the intersubunit linker is essential for optimal catalytic activity and subsequent proteolytic cleavage of gasdermin D. Macrophages from caspase-11-processing dead KI mice (Casp11Prc D285A/D285A) exhibit defective caspase-11 auto-processing and phenocopy Casp11-/- and caspase-11 enzymatically dead KI (Casp11Enz C254A/C254A) macrophages in attenuating responses to cytoplasmic lipopolysaccharide or Gram-negative bacteria infection. Gasdermin D D276A/D276A KI macrophages also fail to cleave gasdermin D and are hyporesponsive to inflammasome stimuli
metabolism
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while Salmonella typhimurium and Legionella pneumophila normally reside in the vacuole, specific mutants (sifA and sdhA, respectively) that aberrantly enter the cytosol trigger Caspase-11, enhancing clearance of S. typhimurium sifA in vivo. This response does not require NLRP3, NLRC4, or ASC inflammasome pathways. Burkholderia species that naturally invade the cytosol also trigger Caspase-11, protecting mice from lethal challenge with Burkholderia thailandensis and Burkholderia pseudomallei. Caspase-11 is critical for surviving exposure to ubiquitous environmental pathogens
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caspase-11 mediates non-canonical inflammasome activation.Caspase-11 rather than caspase-1 is required for lipopolysaccharide-induced lethality. Interleukin-1beta secretion in response to other bacterial toxins, including adenylcyclase toxin, listeriolysin O toxin, or Clostridium difficile toxin B, is not affected by caspase-11 deficiency. Caspase-11 also is dispensable for NLRP3-dependent IL-1beta secretion in response to monosodium urate, calcium pyrophosphate, or the ionophore nigericin. In contrast, NLRP3- and ASC-dependent IL-1beta secretion from BMDMs infected with live Escherichia coli, Citrobacter rodentium and Vibriae cholerae, requires caspase-11, with or without lipopolysaccharide priming
physiological function
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activated caspase-11 triggers cell death, caspase-11 is essential for the induction of endotoxic shock in vivo
physiological function
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caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1beta secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide and Gram-negative bacteria. Caspase-11 modulates the cationic channel composition of the cell and thus regulates the unconventional secretion pathway in a manner independent of caspase-1. Caspase-11 controls the TRPC1-dependent decrease in cytosolic Ca2+ following lipopolysaccharide treatment
physiological function
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caspase-11 is an inflammatory caspase that can also promote interleukin-1beta secretion dependent upon NLRP3, ASC, and Caspase-1. Inflammatory caspase-11 triggers pyroptosis, a form of programmed cell death. The enzyme can be detrimental in inflammatory disease,but has no protective role during infection. Caspase-11 is required for innate immunity to cytosolic, but not vacuolar, bacteria
physiological function
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caspase-11 is required for cofilin phosphorylation. Caspase-11-dependent cell death and interleukin-1beta secretion can only be detected in vitro in the absence of a NAIP/NLRC4 stimulus, e.g. flagellin. Caspase-11 is required for the release of the alarmins, interleukin-1alpha and HMGB1. The role of caspase-11 in pro-interleukin-18 and pro-interleukin-1beta maturation is dependent on NLRP3/ASC/CASP1 inflammasomes. Pro-inflammatory caspases play important roles in innate immunity. Caspase-11 contributes to host defenses against pathogen invasion. Caspase-11 functions and mechanisms of activation, overview
physiological function
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caspase-11 plays a role in the inflammasome in the cytoplasm. Activation of inflammatory caspases, e.g. caspase-11, leads to the processing and maturation of inflammatory cytokines, such as interleukin-1beta and interleukin-18, as well as a specific form of cell death termed pyroptosis. Caspase-11 can induce cell death and form hetero-complexes with caspase-1. Caspase-11 by itself inefficiently cleaves pro-interleukin-1beta, suggesting early on that caspase-11 might rely on caspase-1 for cytokine maturation. The caspase-11 non-canonical inflammasome plays a significant role in Gram-negative bacterial infections, including Escherichia coli, Citrobacter rodentium, Shigella flexneri, Salmonella typhimurium, Legionella pneumophila, and Burkholderia thailandensis, caspase-11 can restrict the replication of intracellular pathogenic bacteria (Salmonella typhimurium and Burkholderia species)
physiological function
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caspase-11 plays an essential role in methamphetamine-induced dopaminergic neuron apoptosis, the caspase-11/caspase-3 signal pathway is involved in methamphetamine-induced neurotoxicity
physiological function
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caspase-11 plays an essential role in methamphetamine-induced dopaminergic neuron apoptosis, the caspase-11/caspase-3 signal pathway is involved in methamphetamine-induced neurotoxicity
physiological function
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caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila. NLRP3 and ASC are both required for caspase-1 activation through the caspase-11-dependent pathway induced by Legionella pneumophila, caspase-11 is required for NAIP/NLRC4-independent pyroptosis Induced by Legionella pneumophila
physiological function
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caspase-11-dependent cell death and interleukin-1beta secretion can only be detected in vitro in the absence of a NAIP/NLRC4 stimulus, e.g. flagellin. Caspase-11 is required for the release of the alarmins, interleukin-1alpha and HMGB1. The role of caspase-11 in pro-interleukin-18 and pro-interleukin-1beta maturation is dependent on NLRP3/ASC/CASP1 inflammasomes. Pro-inflammatory caspases play important roles in innate immunity, analysis of mechanisms by which caspase-11 contributes to host defense. Caspase-11 functions and mechanisms of activation, implications for human disease, overview
physiological function
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mechanisms and implications of caspase-11-mediated noncanonical inflammasome activation, importance of this pathway in regulating host defense against intracellular bacterial pathogens. The pathway engages caspase-11 to trigger both caspase-1-dependent and -independent production of the inflammatory cytokines IL-1beta, IL-18, and IL-1alpha, as well as to promote pyroptosis, a form of genetically programmed cell death that is associated with the release of such cytokines. Caspase-11 is regulated in response to extracellular stimuli, such as lipopolysaccharide and interferons
physiological function
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mechanisms and implications of caspase-11-mediated noncanonical inflammasome activation, importance of this pathway in regulating host defense against intracellular bacterial pathogens. The pathway engages caspase-11 to trigger both caspase-1-dependent and -independent production of the inflammatory cytokines IL-1beta, IL-18, and IL-1alpha, as well as to promote pyroptosis, a form of genetically programmed cell death that is associated with the release of such cytokines. Caspase-11 is regulated in response to extracellular stimuli, such as lipopolysaccharide and interferons. Regulation of caspase-11 expression, models of activation, and caspase-11 effector functions, overview. Role of caspase-11 in pyroptosis, caspase-11 directly controls the activation of the effector caspases 3 and 7 of the apoptotic pathway independent of caspase-1
physiological function
Casp11-/- mice are highly susceptible to the azoxymethane dextran sulfate sodium model of colitis-associated cancer, compared to their wild-type littermates. Deficient IL-18 production occurs at initial inflammation stages of disease, and IL-1beta production is more significantly impaired in Casp11-/- colons during established colitis-associated cancer. Casp11-/- colons display defective STAT1 activation during disease progression, and IL-1beta signalling induces caspase-11 expression and STAT1 activation in primary murine macrophages and intestinal epithelial cells
physiological function
caspase-1 and caspase-11 display differential roles in response to infection with the fungal pathogen Aspergillus fumigatus. Casp11-/- mice are more susceptible to infection with Aspergillus fumigatus conidia compared with wild-type mice. Casp11-/- mice succumb to infection with a delayed kinetic compared with Casp1Null mice or Casp1-/- Casp11-/- mice. Caspase-11 has no role in the activation of the inflammasome in bone marrow-derived dendritic cells in response to A. fumigatus, but contributes to the host defense against A. fumigatus infection in vivo
physiological function
caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1beta maturation. Macrophages from gasdermin-/- mice exhibit defective pyroptosis and interleukin-1beta secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. Gasdermin-/- mice are protected from a lethal dose of lipopolysaccharide
physiological function
caspase-11 deficiency shows the same effect as the combined absence of both caspase-1 and caspase-11 on oviduct pathology. Caspase-11-deficient mice show reduced dilation in both the oviducts and uterus. In the caspase-11-deficient mice, increased chlamydial burdens are observed in the upper genital tract, which correlate with increased CD4 T cell recruitment. There are significantly fewer neutrophils in the oviducts of caspase-11-deficient mice
physiological function
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gasdermin D fragment p30 that is liberated by caspase-11 forms pores in cellular membrane. p30 is only detected in the membrane-containing fraction of immortalized macrophages after caspase-11 activation by lipopolysaccharides
physiological function
in response to corneal infection with Aspergillus fumigatus, caspase-11-/- mice exhibit the same susceptibility phenotype as IL-1beta-/-, ASC-/-, NLRP3-7-, and caspase-1-/- mice, with impaired neutrophil recruitment to infected corneas and increased hyphal growth. Caspase-11 is required for caspase-1 activation and IL-1eta processing during infection. In vitro, caspase-11 is regulated by the common type I IFN receptor (IFNAR) through JAK-STAT signaling and caspase-11 is required for speck formation and caspase-1 activity
physiological function
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caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila. NLRP3 and ASC are both required for caspase-1 activation through the caspase-11-dependent pathway induced by Legionella pneumophila, caspase-11 is required for NAIP/NLRC4-independent pyroptosis Induced by Legionella pneumophila
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physiological function
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caspase-11 mediates non-canonical inflammasome activation.Caspase-11 rather than caspase-1 is required for lipopolysaccharide-induced lethality. Interleukin-1beta secretion in response to other bacterial toxins, including adenylcyclase toxin, listeriolysin O toxin, or Clostridium difficile toxin B, is not affected by caspase-11 deficiency. Caspase-11 also is dispensable for NLRP3-dependent IL-1beta secretion in response to monosodium urate, calcium pyrophosphate, or the ionophore nigericin. In contrast, NLRP3- and ASC-dependent IL-1beta secretion from BMDMs infected with live Escherichia coli, Citrobacter rodentium and Vibriae cholerae, requires caspase-11, with or without lipopolysaccharide priming
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physiological function
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caspase-11 is an inflammatory caspase that can also promote interleukin-1beta secretion dependent upon NLRP3, ASC, and Caspase-1. Inflammatory caspase-11 triggers pyroptosis, a form of programmed cell death. The enzyme can be detrimental in inflammatory disease,but has no protective role during infection. Caspase-11 is required for innate immunity to cytosolic, but not vacuolar, bacteria
-
physiological function
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caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1beta secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide and Gram-negative bacteria. Caspase-11 modulates the cationic channel composition of the cell and thus regulates the unconventional secretion pathway in a manner independent of caspase-1. Caspase-11 controls the TRPC1-dependent decrease in cytosolic Ca2+ following lipopolysaccharide treatment
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physiological function
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caspase-11 plays an essential role in methamphetamine-induced dopaminergic neuron apoptosis, the caspase-11/caspase-3 signal pathway is involved in methamphetamine-induced neurotoxicity
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caspase-1, -2, -4, -9, and -11 have particularly long pro-domains that contain either death effector domains (DED) or caspase recruitment domains (CARD), which are thought to confer specificity of activation since they mediate interactions with other DED- and CARD-containing adaptor proteins. Association with these adaptor proteins likely nucleates caspases, increasing their local concentration. This nucleation can favor activation through dimerization
additional information
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caspase-11 cooperatively interacts with actin-interacting protein to activate cofilin-dependent actin depolymerization leading to increased splenocyte migration, caspase-11-mediated actin depolymerization appears to be independent of its enzymatic activity. Caspase-1, -2, -4, -9, and -11 have particularly long pro-domains that contain either death effector domains (DED) or caspase recruitment domains (CARD), which are thought to confer specificity of activation since they mediate interactions with other DED- and CARD-containing adaptor proteins. Association with these adaptor proteins likely nucleates caspases, increasing their local concentration. This nucleation can favor activation through dimerization