Alternative titles; symbols
HGNC Approved Gene Symbol: CASP1
Cytogenetic location: 11q22.3 Genomic coordinates (GRCh38): 11:105,025,443-105,036,686 (from NCBI)
Caspase-1 is a cysteine protease that regulates inflammatory processes through its capacity to process and activate the interleukin-1-beta (IL1B; 147720), IL18 (600953), and IL33 (608678) precursor proteins. IL1B and IL18 are potent proinflammatory cytokines, and IL33 promotes responses mediated by type-2 helper T (Th2) cells (Keller et al., 2008).
Thornberry et al. (1992) purified ICE from the cytosol of the THP.1 human monocytic cell line and found that the active protease was made up of 2 peptides, which they called p20 and p10 based on their apparent molecular masses by SDS-PAGE. By PCR of a THP.1 cDNA library using primers based on tryptic peptide sequences of p20 and p10, followed by screening the same cDNA library, Thornberry et al. (1992) obtained 2 full-length ICE cDNAs that differed in the length of their 3-prime UTRs. The deduced 404-amino acid proprotein has a 119-amino acid propeptide that lacks characteristics of a hydrophobic signal sequence, followed by the p20 sequence, which ends in asp297, a 19-residue spacer, and the C-terminal p10 sequence, which ends in his404. The p20 sequence contains the catalytic cysteine, cys285. Neither the propeptide nor the spacer sequence were found in mature active ICE. Northern blot analysis revealed transcripts of 0.5, 1.6, and 2.3 kb in THP.1 cells, as well as in human neutrophils, T-lymphocytes, and the Raji B-lymphoblastoid cell line. The ICE proprotein had an apparent molecular mass of 45 kD following in vitro transcription and translation.
Cerretti et al. (1992) cloned ICE from a human peripheral blood neutrophil cDNA library. Northern blot analysis of human tissues and cells detected a major transcript of about 1.9 kb in peripheral blood monocytes, lymphocytes, and neutrophils, resting and activated T lymphocytes, placenta, and a B-lymphoblastoid cell line, but not in HepG2 or Raji cell lines. Minor transcripts of 2.5 and 0.5 were also observed in some samples.
Feng et al. (2004) noted that 5 alternatively spliced variants of CASP1 have been identified. The longest isoform is CASP1-alpha. Feng et al. (2004) cloned another CASP1 isoform, which they named CASP1-zeta, from an ovarian surface epithelial cell cDNA library. The CASP1-zeta transcript is identical to CASP1-alpha except for a 79-nucleotide deletion in the prodomain coding region. The deduced CASP1-zeta protein lacks 39 N-terminal amino acids compared with procaspase-1-alpha. This deleted region comprises the caspase-activating recruitment domain (CARD) required for interactions between caspases and other proteins. Secondary structure analysis of the CASP1-zeta CARD predicted the truncation of 2 alpha helices and part of the third compared with full-length procaspase-1-alpha. RT-PCR detected CASP1-zeta expression in many, but not all, adult human tissues.
Humke et al. (1998) identified a cDNA encoding a novel caspase that they designated ERICE (evolutionarily related ICE), or caspase-13 (CASP13). Koenig et al. (2001) presented evidence that the sequence reported by Humke et al. (1998) was not of human origin, but represented a bovine gene.
Thornberry et al. (1992) confirmed that ICE functions as cysteine protease, and they described the design of potent peptide aldehyde inhibitors. Selective inhibition of the enzyme in human blood monocytes blocked production of mature IL1B, indicating that it is a potential therapeutic target.
Cerretti et al. (1992) demonstrated that recombinant expression of CASP1 in COS-7 cells enabled the cells to process precursor IL-1-beta to the mature form. Sequence analysis indicated that the CASP1 enzyme itself may undergo proteolytic processing.
Yuan et al. (1993) demonstrated that the cell death gene ced-3 of Caenorhabditis elegans encodes a protein similar to mammalian IL1B convertase. Furthermore, Miura et al. (1993) showed that overexpression of the murine ICE gene or of the C. elegans ced-3 gene in a cultured cell line (Rat-1) caused the cells to undergo programmed cell death. Point mutations in a region homologous between the proteins produced by the C. elegans and mammalian genes eliminated the ability of the genes to cause cell death. The cell death caused by overexpression of the murine gene could be suppressed by overexpression of the crmA gene, a specific inhibitor of ICE, as well as by BCL2 (151430), a mammalian oncogene that can act to prevent programmed cell death. They interpreted the results to suggest that the ICE gene functions during mammalian development to cause programmed cell death.
Koedel et al. (2002) found that CASP1 levels were elevated in the cerebrospinal fluid of patients with acute bacterial meningitis, and the level of CASP1 correlated with the clinical outcome. Casp1 mRNA and protein were also upregulated in rodent brains during experimental pneumococcal meningitis. Deletion of the Casp1 gene in mice or pharmacologic blockade of Casp1 reduced the meningitis-induced increase in Il1b, diminished inflammatory host response to pneumococci, and reduced meningitis-induced intracranial complications, leading to improved clinical status.
Using gene targeting to generate mice deficient in Asc (606838) or Ipaf (CARD12; 606831), Mariathasan et al. (2004) found an absence of the p20 and p10 of Casp1 in homozygous mutant but not wildtype or heterozygote macrophages after stimulation with lipopolysaccharide (LPS). After priming by LPS and stimulation with Salmonella typhimurium, secretion of Il1b was significantly reduced in Asc -/- and Ipaf -/-, but not Ripk2 (603455)-deficient, macrophages. Immunoprecipitation analysis showed that Asc associates with Casp1, indicating that components of the inflammasome, a multiple adaptor complex in activated monocytes and macrophages, are released from cells secreting mature Il1b. Asc -/- and Ipaf -/- macrophages also failed to process Casp1 after priming with Tlr (e.g., TLR4, 603030) agonists in response to ATP, leading to impaired release of Il1b, Il1a (147760), and Il18 (600953). Challenge of Asc-deficient mice with a normally lethal dose of LPS resulted in only 30% mortality in 48 hours and full recovery in the remainder by day 7. There were also some survivors among the heterozygotes. Analysis of responses to LPS and Tnf (191160) showed no role for Asc in Erk (e.g., MAPK3, 601795) or Nfkb (see 164011) signaling. Infection of Asc- or Ipaf-deficient macrophages with wildtype but not SipB-toxin-deficient S. typhimurium does not result in cell death as is seen in wildtype macrophages. Mariathasan et al. (2004) concluded that ASC is essential for CASP1 activation within the inflammasome and that CARD12 is required for CASP1 activation in response to at least 1 intracellular pathogen.
Feng et al. (2004) found that overexpression of CASP1-zeta in embryonic kidney cells induced apoptosis comparable to that induced by CASP1-alpha. Mutation of cys246 in the active center of CASP1-zeta or of cys285 in the active center of CASP1-alpha completely abolished their apoptotic activities. Feng et al. (2004) concluded that the first 39 amino acids of the N-terminal amino CARD in procaspase-1 are not required for apoptotic activity.
Agostini et al. (2004) noted that NALP1 (606636), unlike other short NALP proteins, contains a C-terminal CARD domain that interacts with and activates CASP5 (602665). CASP1 and CASP5 are activated when they assemble with NALP1 and ASC to form the inflammasome, which is responsible for processing the inactive IL1B precursor (proIL1B) to release active IL1B cytokine. Using immunoprecipitation analysis, Agostini et al. (2004) found that CARD8 (609051), which contains C-terminal FIIND (function to find) and CARD domains, associated with constructs of NALP2 (609364) and NALP3 (NLRP3; 606416) lacking the N-terminal pyrin domain and/or the C-terminal leucine-rich repeat domain. They determined that the interaction was mediated by the FIIND domain of CARD8 and the centrally located NACHT domain of NALP2 and NALP3. The pyrin domain of NALP2 and NALP3, like that of NALP1, interacted with the pyrin domain of ASC, which recruits CASP1. Transfection experiments showed that an inflammasome could be assembled containing ASC, CARD8, CASP1, and a short NALP, resulting in activation of CASP1, but not CASP5, and strong processing of proIL1B.
Kanneganti et al. (2006) showed the effect of cryopyrin deficiency on inflammasome function and immune responses. Cryopyrin and ASC (606838) are essential for CASP1 activation and IL1B (147720) and IL18 production in response to bacterial RNA and the imidazoquinoline compounds R837 and R848. In contrast, secretion of TNFA and IL6 (147620), as well as activation of NF-kappa-B (see 164011) and mitogen-activated protein kinases were unaffected by cryopyrin deficiency. Furthermore, Kanneganti et al. (2006) showed that Toll-like receptors and cryopyrin control the secretion of IL1B and IL18 through different intracellular pathways. Kanneganti et al. (2006) concluded that these results reveal a critical role for cryopyrin in host defense through bacterial RNA-mediated activation of CASP1, and provide insights regarding the pathogenesis of autoinflammatory syndromes.
Gurcel et al. (2006) used aerolysin to study cellular survival mechanisms in response to pore-forming toxins. They found that aerolysin induced a decrease in cytosolic potassium following channel formation in the plasma membrane. The drop in intracellular potassium activated both the IPAF and NALP3 inflammasomes, permitting processing of CASP1. Activated CASP1 then induced processing of SREBPs (see 184756) by S1P (MBTPS1; 603355) and S2P (MBTPS2; 300294), leading to upregulation of lipogenic genes. Gurcel et al. (2006) concluded that CASP1 links intracellular ion composition to lipid metabolic pathways, membrane biogenesis, and survival.
Using a yeast 2-hybrid screen with MAL (TIRAP; 606252) as bait, Miggin et al. (2007) identified CASP1 as a MAL-interacting protein. They found that CASP1 cleaved MAL and was required for TLR2 (603028)- and TLR4-mediated NFKB and p38 MAPK (MAPK14; 600289) activation, but not IL1 or TLR7 (300365) signaling. Induction of TNF was attenuated in CASP1-deficient cells. A CASP1-resistant MAL mutant was unable to signal and inhibited TLR2 and TLR4 signaling. Miggin et al. (2007) concluded that CASP1 regulates TLR2 and TLR4 signaling through MAL.
Keller et al. (2008) found that activation of caspase-1 by inflammation was directly linked to IL1-alpha secretion from activated mouse macrophages and ultraviolet light-irradiated human keratinocytes. Secretion of FGF2 (134920) was also dependent on caspase-1 expression and activity. Both pro-IL1-alpha and FGF2 bound caspase-1, suggesting a role of the protease as a carrier in an endoplasmic reticulum/Golgi-independent protein secretion pathway. Secretion of caspase-1 itself required enzymatic activity, and caspase-1 inhibition prevented secretion of its binding proteins. Using a proteomic approach, Keller et al. (2008) identified several leaderless proteins in human keratinocytes that were secreted in a caspase-1-dependent manner.
Keller et al. (2009) showed that administration of thalidomide, an antiinflammatory drug with strong teratogenic activity, prior to ultraviolet B (UVB) irradiation of keratinocytes inhibited the induction of CASP1 activation, leading to reduced secretion of IL1B and FGF2, but not proteins that use the classical protein secretion pathway and have conventional leader sequences. Cell viability was also enhanced by pretreatment with thalidomide or a CASP1 inhibitor, YVAD. Thalidomide blocked CASP1 activation in cultured cells, but not in vitro, most likely via a metabolite. Unlike macrophages, keratinocytes constitutively express pro-IL1A and -IL1B, leading to TNF production. Either thalidomide or IL1R antagonist (IL1RN; 147679) could prevent keratinocyte production of TNF, indicating that TNF is induced via a CASP1- or an IL1-dependent pathway. Keller et al. (2009) concluded that thalidomide acts through CASP1 and proposed that use of an agent such as recombinant IL1RN might be safer for the treatment of lupus erythematosus (SLE; 152700) and inflammatory complications of leprosy (see 609888).
To identify CASP1 functions in vivo, von Moltke et al. (2012) devised a strategy for cytosolic delivery of bacterial flagellin, a specific ligand for the NAIP5 (see 600355)/NLRC4 (606831) inflammasome. Von Moltke et al. (2012) showed that systemic inflammasome activation by flagellin leads to a loss of vascular fluid into the intestine and peritoneal cavity, resulting in rapid (less than 30 minutes) death in mice. This unexpected response depends on the inflammasome components NAIP5, NLRC4, and CASP1, but is independent of the production of IL1-beta or IL18 (600953). Instead, inflammasome activation results, within minutes, in an 'eicosanoid storm'--a pathologic release of signaling lipids, including prostaglandins and leukotrienes, that rapidly initiate inflammation and vascular fluid loss. Mice deficient in cyclooxygenase-1 (COX1, PTGS1; 176805), a critical enzyme in prostaglandin biosynthesis, are resistant to these rapid pathologic effects of systemic inflammasome activation by either flagellin or anthrax lethal toxin. Inflammasome-dependent biosynthesis of eicosanoids is mediated by the activation of cytosolic phospholipase A2 (see 172410) in resident peritoneal macrophages, which are specifically primed for the production of eicosanoids by high expression of eicosanoid biosynthetic enzymes. Von Moltke et al. (2012) concluded that their results identified eicosanoids as a previously unrecognized cell type-specific signaling output of the inflammasome with marked physiologic consequences in vivo.
Heneka et al. (2013) demonstrated strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer disease (104300), suggesting a role for the inflammasome in this neurodegenerative disease.
Arbore et al. (2016) found that the NLRP3 inflammasome assembled in human CD4 (186940)-positive T cells and initiated CASP1-dependent IL1B secretion, thereby promoting IFNG (147570) production and T-helper-1 (Th1) differentiation in an autocrine fashion. NLRP3 assembly required intracellular C5 (120900) activation and stimulation of C5AR1 (113995), and this process was negatively regulated by C5AR2 (609949). Aberrant NLRP3 activity in T cells affected inflammatory responses in patients with cryopyrin-associated periodic syndrome (FCAS1; 120100) and in mouse models of inflammation and infection. Arbore et al. (2016) concluded that NLRP3 inflammasome activity is involved in normal adaptive Th1 responses, as well as in innate immunity.
Naik et al. (2017) reported a prolonged memory to acute inflammation that enables mouse epithelial stem cells (EpSCs) to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fueling this memory is Aim2 (604578), which encodes an activator of the inflammasome. The absence of Aim2 or its downstream effectors, caspase-1 and interleukin-1-beta (147720), erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.
Wilson et al. (1994) determined the high-resolution structure of human interleukin-1-beta convertase in complex with an inhibitor. The structure confirmed the relationship between the human enzyme and cell-death proteins in other organisms. The active site spanned both the 10- and 20-kD subunits, which associate to form a tetramer, suggesting a mechanism for ICE autoactivation.
Cerretti et al. (1994) demonstrated that the IL1BC gene consists of 10 exons spanning at least 10.6 kb. They found a single transcription start site approximately 33 bp upstream of the initiator met codon. Casano et al. (1994) found that in the mouse the Il1bc gene is present in single copy and is 8,616 bp in size. It is organized into 10 exons. Two initiation sites, 37 and 32 nucleotides upstream of the initiator methionine, were identified by primer extension analysis.
Cerretti et al. (1992) mapped the CASP1 gene to 11q23, a site frequently involved in rearrangement in human cancers, including a number of leukemias and lymphomas, by Southern DNA blot analysis of rodent-human hybrids and by in situ hybridization to normal human metaphase chromosomes. Using a genomic IL1BC clone, Cerretti et al. (1994) confirmed the localization of the gene to 11q22.2-q22.3 by fluorescence in situ hybridization. Nett et al. (1992) mapped the murine homolog to the proximal region of mouse chromosome 9.
Kuida et al. (1995) showed that adherent monocytes from Ice -/- mice were unable to export Il1b, Il1a (147760), tumor necrosis factor (TNF; 191160), or Il6 (147620) after stimulation with lipopolysaccharide. Thymocytes from Ice -/- mice were normally sensitive to apoptosis induced by dexamethasone or ionizing radiation, but resisted apoptosis induced by Fas (TNFRSF6; 134637) antibody.
Li et al. (1995) and Li et al. (1997) generated Ice-deficient mice through gene targeting technology. Ice-deficient mice developed normally, appeared healthy, and were fertile. Peritoneal macrophages from Ice-deficient mice underwent apoptosis normally upon ATP treatment. Thymocytes from young Ice-deficient mice also underwent apoptosis when triggered by dexamethasone, gamma irradiation, or aging. The most striking result from the study was that the Ice-deficient mice were highly resistant to the lethal effects of endotoxin. With high-dose lipopolysaccharide that killed all wildtype mice within 30 hours, all Ice-deficient mice survived the first 48 hours and 70% of them survived after 7 days. These studies suggested to Li et al. (1997) the therapeutic potential of ICE inhibitors in inflammatory diseases such as septic shock and inflammatory bowel diseases.
Ona et al. (1999) studied the effect of inhibition of caspase-1 on the progression of Huntington disease (143100) in the mouse model developed by Mangiarini et al. (1996), which they called R6/2 mice. Ona et al. (1999) crossed R6/2 mice with a well-characterized transgenic mouse strain expressing a dominant-negative mutant of caspase-1 in the brain (NSE M17Z). R6/2-NSE M17Z mice showed extended survival and delayed appearance of neuronal inclusions, neurotransmitter receptor alterations, and onset of symptoms, indicating that caspase-1 is important in the pathogenesis of Huntington disease. Ona et al. (1999) also demonstrated that intracerebroventricular administration of a caspase inhibitor delayed disease progression and mortality. The authors suggested that caspase-1 inhibitors may be applicable to human Huntington disease.
Transgenic mice expressing N-terminal mutant huntingtin show intranuclear huntingtin accumulation and develop progressive neurologic symptoms. Inhibiting caspase-1 can prolong the survival of these HD mice. Li et al. (2000) reported that intranuclear huntingtin induces the activation of caspase-3 (600636) and the release of cytochrome c from mitochondria in cultured cells. As a result, cells expressing intranuclear huntingtin underwent apoptosis. Intranuclear huntingtin increased the expression of caspase-1, which may in turn activate caspase-3 and trigger apoptosis. The authors proposed that the increased level of caspase-1 induced by intranuclear huntingtin may contribute to HD-associated cell death.
Lara-Tejero et al. (2006) showed that mice lacking Casp1 were more susceptible to oral S. typhimurium infection than wildtype controls. Susceptibility was independent of a functional Nramp1 (SLC11A1; 600266) allele.
Systemic inflammatory response syndrome (SIRS), an important cause of mortality in intensive care units, is diagnosed on the basis of 2 or more of the following conditions: fever or hypothermia, tachycardia, and leukopenia or leukocytosis. SIRS is differentiated from sepsis by the absence of a documented source of infection. An important role for the IL1B network in LPS-induced SIRS has been suggested by rodent gene deletion models. Mastronardi et al. (2007) hypothesized that CASP1 regulates the brain transcriptome in response to LPS-induced SIRS. Using microarray and RT-PCR analyses, they found that mice lacking Casp1 showed differentially increased expression of chemokines, GTPases, the metalloproteinase Adamts1 (605174), Il1ra (IL1R1; 147810), Cox2 (PTGS2; 600262), and inducible Nos (NOS2A; 163730) during SIRS. Mastronardi et al. (2007) proposed that neurologic and psychiatric disorders involving inflammation may benefit from targeting of CASP1.
Keller et al. (2009) found that mice lacking Casp1 had reduced UVB-induced skin inflammation and neutrophil accumulation compared with wildtype mice. Wildtype mice could be protected by thalidomide treatment, indicating that thalidomide and Casp1 act in the same pathway.
Thomas et al. (2009) found that mice lacking Casp1 or Nlrp3 exhibited significantly increased morbidity in response to influenza virus infection. Enhanced morbidity correlated with reduced neutrophil and monocyte recruitment and reduced production of cytokines, notably Il1 and Il18, and chemokines, including Mip2 (CXCL2; 139110) and Kc (CXCL1; 155730). However, adaptive response and virus control were not impaired in mutant mice. Early epithelial necrosis was more severe in infected mutant mice, with extensive collagen deposition leading to later respiratory compromise, suggesting a function for the cryopyrin inflammasome in healing responses. Thomas et al. (2009) concluded that NLRP3 and CASP1 are central to both innate immunity and to moderating lung pathology in influenza pneumonia.
Miao et al. (2010) detected Nlrc4-dependent Il1b secretion and Casp1 processing in mouse bone marrow macrophages infected with an S. typhimurium mutant that persistently expressed flagellin, but not in macrophages infected with wildtype S. typhimurium. Unlike mice infected with wildtype S. typhimurium, mice infected with the mutant did not succumb to infection. Clearance of mutant S. typhimurium was independent of Il1b and Il18 and dependent on Casp1 and Nlrc4. Clearance of bacteria through Nlrc4 was associated with pyroptosis, a proinflammatory form of programmed cell death in which macrophages lose membrane integrity and release cytosolic contents, including bacterial pathogens that are then exposed to uptake and killing by neutrophils and reactive oxygen species. Mice lacking Ncf1 (608512), which encodes a subunit of the oxidase complex, were vulnerable to flagellin-deficient mutant S. typhimurium. Miao et al. (2010) concluded that, in wildtype mice, pyroptosis is beneficial to the host, but in the absence of downstream killing by neutrophils, repeated rounds of pyroptosis can cause substantial damage to tissues.
Using C57BL/6 Casp11 (CASP4; 602664) -/- mice, Kayagaki et al. (2011) found that Casp11 was critical for Casp1 activation and Il1b production in bacteria-infected macrophages. The defect in Il1b production was recapitulated in strain-129 mice, which harbored a Casp11 mutation that attenuated Casp11 expression. Kayagaki et al. (2011) noted that strain-129 mice were used by Kuida et al. (1995) and Li et al. (1995) to generate Casp1 -/- mice, and consequently these mice lacked both Casp1 and Casp11. Casp11 -/- macrophages were able to produce normal levels of Il1b in response to ATP and monosodium urate. Strain-129 macrophages lacking Casp1 but expressing C57BL/6 Casp11 were unable to secrete Il1b normally in response to any stimulus, confirming that Casp1 is essential for Il1b production. However, Casp11, rather than Casp1, was required for noncanonical inflammasome-triggered macrophage cell death. Loss of Casp11, rather than Casp1, protected mice from a lethal dose of LPS. Kayagaki et al. (2011) concluded that there is a unique proinflammatory role for Casp11 in innate immune response to clinically significant bacterial infections.
Broz et al. (2012) demonstrated that noncanonical caspase-11 activation contributes to macrophage death during S. typhimurium infection. TLR4 (603030)-dependent and TIR domain-containing adaptor-inducing interferon-beta (TRIF)-dependent interferon-beta (147640) production is crucial for caspase-11 activation in macrophages, but is only partially required for procaspase-11 expression, consistent with the existence of an interferon-inducible activator of caspase-11. Furthermore, Casp1-null mice were significantly more susceptible to infection with S. typhimurium than mice lacking both proinflammatory caspases (Casp1-null/Casp11-null). This phenotype was accompanied by higher bacterial counts, the formation of extracellular bacterial microcolonies in the infected tissue, and a defect in neutrophil-mediated clearance. Broz et al. (2012) concluded that caspase-11-dependent cell death is detrimental to the host in the absence of caspase-1-mediated innate immunity, resulting in extracellular replication of a facultative intracellular bacterial pathogen.
Heneka et al. (2013) found that Nlrp3-null (606416) or Casp1-null mice carrying mutations associated with familial Alzheimer disease (104300) were largely protected from loss of spatial memory and other sequelae associated with Alzheimer disease, and demonstrated reduced brain caspase-1 and interleukin-1-beta (IL1B; 147720) activation as well as enhanced amyloid-beta (see APP, 104760) clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-beta in the APP/PS1 (104311) model of Alzheimer disease. Heneka et al. (2013) concluded that their results showed an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer disease.
Wlodarska et al. (2014) found that mice deficient in Nlrp6 (609650), as well as mice deficient in Asc or Casp1, which are key components of the Nlrp6 inflammasome signaling pathway, were unable to clear Citrobacter rodentium, the attaching/effacing pathogen, from colon. Mice lacking Asc, Casp1, or Nlrp6 lacked a thick continuous overlaying inner mucus layer and exhibited marked goblet cell hyperplasia. Bacteria were also more invasive in mutant mice, penetrating deep into crypts, and were more frequently associated with goblet cells. The goblet cell defect in Nlrp6 inflammasome-deficient mice was independent of Il1 and Il18 mechanisms. Immunoblot analysis, immunofluorescence analysis, and electron microscopy demonstrated that the Nlrp6 inflammasome was critical for autophagy in intestinal epithelial cells. Wlodarska et al. (2014) concluded that the NLRP6 inflammasome is critical for mucus granule exocytosis, initiation of autophagy, and maintaining goblet cell function.
Members of the ICE/CED-3 protease family play key biologic roles in inflammation and mammalian apoptosis. Alnemri et al. (1996) indicated that 10 homologs of human origin had been published. They proposed a nomenclature for the human members of this protease family. They recommended use of the trivial name 'caspase' as a root for serial names for all family members. The selection of caspase was based on 2 catalytic properties of these enzymes. The 'c' was intended to reflect a cysteine protease mechanism, and 'aspase' referred to their ability to cleave after aspartic acid, the most distinctive catalytic feature of this protease family. To designate individual family members, caspase was to be followed by an arabic number, assigned on the date of publication. Assignments for the 10 previously described proteases were given. The root symbol for the corresponding gene was to be CASP, and this gene was symbolized CASP1.
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