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FLASH GENE
Symbol CASP4 contributors: shn/npt/pgu - updated : 06-04-2020
HGNC name caspase 4, apoptosis-related cysteine peptidase
HGNC id 1505
DNA
TYPE functioning gene
STRUCTURE 25.73 kb     9 Exon(s)
10 Kb 5' upstream gene genomic sequence study
text structure colocalizes with a cluster of functionally related genes CASP1, 5 and 12 and CASP1 pseudo genes ICE-BERG, COP and INCA
MAPPING cloned Y linked N status provisional
Map cen - D11S4951 - D11S1886 - CASP4 - D11S1781 - D11S2017 - qter
Physical map
LOC390248 11 similar to matrix metalloproteinase 1 precursor MMP10 11q22.2-q22.3 matrix metalloproteinase 10 (stromelysin 2) MMP1 11q22.2-q22.3 matrix metalloproteinase 1 (interstitial collagenase) LOC120321 11q22.2 similar to casein kinase 1, alpha 1 MMP3 11q22.2-q22.3 matrix metalloproteinase 3 (stromelysin 1, progelatinase) MMP12 11q22.3 matrix metalloproteinase 12 (macrophage elastase) MMP13 11q22.2-q22.3 matrix metalloproteinase 13 (collagenase 3) MGC2714 11q22.2 hypothetical protein MGC2714 DNCH2 11q21-q22.1 dynein, cytoplasmic, heavy polypeptide 2 SCDGF-B CASP12P1 11q22.3 caspase 12 pseudogene 1 CASP4 11q22.2-q22.3 caspase 4, apoptosis-related cysteine protease CASP5 11q22.2-q22.3 caspase 5, apoptosis-related cysteine protease CASP1 11q22.2-q22.3 caspase 1, apoptosis-related cysteine protease (interleukin 1, beta, convertase) COP  clathrin-ordered protein ICEBERG 11q21-q22 ICEBERG caspase-1 inhibitor OR2AL1P 11q23.3 olfactory receptor, family 2, subfamily AL, member 1 pseudogene GRIA4 11q22.3 glutamate receptor, ionotrophic, AMPA 4 KIAA1826 11q22 KIAA1826 protein KBTBD3 11q22.3 kelch repeat and BTB (POZ) domain containing 3 AASDHPPT 11q22 aminoadipate-semialdehyde dehydrogenase-phosphopantetheinyl transferase GUCY1A2 11q21-q22 guanylate cyclase 1, soluble, alpha 2 LOC341230 11q23.1 similar to argininosuccinate synthetase
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
9 splicing 1352 - 321 - 1999 9931493
  • transcript variant gamma
  • 9 splicing 1319 - 377 - 1999 9931493
  • transcript variant alpha
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   lowly
    Digestiveintestinelarge intestinecolon lowly
     intestinesmall intestine  highly
     liver   moderately
    Endocrinepancreas   lowly
    Lymphoid/Immunespleen   highly
     thymus   lowly
    Nervousbrain     Homo sapiens
    Reproductivefemale systemovary  highly
     female systemplacenta  highly
     male systemtestis  lowly
     male systemprostate  lowly
    Urinarykidney   lowly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone  highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousglia Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal (Fas-associating protein with DEATH domain) FADD-like death effector domain
  • a conserved QACXG pentapeptide active site motif
  • mono polymer heteromer , dimer
    isoforms Precursor precursor producing two subunits,large and small,that dimerize
    HOMOLOGY
    interspecies homolog to mammalian interleukin 1 beta convertase (IL1BC)
    ortholog to Casp4, Mus musculus
    ortholog to Casp4, Rattus norvegicus
    ortholog to CASP4, Pan troglodytes
    Homologene
    FAMILY
  • cysteine-aspartic acid protease (caspase) family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,mitochondria,interspace
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic
    text
  • stored in the mitochondrial intermembrane space and released into cytosol after appropriate apoptotic stimuli
  • ocalized to the ER membrane
  • basic FUNCTION
  • involved in Fas-mediated apoptosis
  • cysteine containing aspartate-specific protease, potentially involved in procytokine activation
  • promoting apoptosis
  • a key mediator of apoptosis and inflammation in human retinal pigment epithelial cells
  • plays a role in induction of apoptosis by endoplasmic reticulum (ER) stress
  • contributes to TNFSF10-induced apoptosis and is associated with induction of ER stress by TNFSF10 in melanoma cells
  • required for non-canonical inflammasome-triggered macrophage cell death, indicating that SCAF11 (CASP4) orchestrates both caspase-1-dependent and -independent outputs
  • a unique pro-inflammatory role for SCAF11 in the innate immune response to clinically significant bacterial infections
  • CASP4 is a critical regulator of noncanonical inflammasome activation that initiates defense against bacterial pathogens in primary human macrophages
  • CASP4 mediates non-canonical activation of the NLRP3 inflammasome in human myeloid cells
  • is an important part of the innate immune response
  • CASP4 modulates microglial cells in a manner that increases proinflammatory processes
  • CASP4 gene product contributes to Alzheimer-related synaptic and behavioural deficits
  • CASP4 is upstream of CASP1 in the pathway that regulates pyroptosis and IL1B synthesis in macrophages during DENV-2 infection
  • CASP4 modulates the actin cytoskeleton to promote the maturation of phagosomes harboring intracellular pathogens such as Legionella pneumophila but not those enclosing nonpathogenic bacteria
  • novel role of CASP4 in regulating autophagy in response to B. cenocepacia infection
  • inflammatory caspases, including human CASP4, play key roles in innate immune responses to promote fusion of phagosomes harboring pathogenic bacteria with lysosomes
  • inflammatory caspases can regulate cell migration through actin remodeling , suggesting a role of CASP4 in cancer cell behavior
  • CELLULAR PROCESS cell life, differentiation
    cell life, proliferation/growth
    cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS inflammation
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
  • direct interaction of APBB1 and TSHZ3 with the promoter region of CASP4
  • RNA
    small molecule
    protein
  • cleaving and activating CASP1
  • NALP1
  • Caspase-14, CASP14 (Hu et al, 1998)
  • TNF receptor-associated factor 6, TRAF6
  • involved in induction of apoptosis by TNF-related apoptosis-inducing ligand (TNFSF10) in human melanoma cells
  • CASP4 directly activates CASP9 by the processing of procaspase-9 at Asp-315 in ER stress-induced neuronal apoptosis
  • important role of CASP4 in inflammation and innate immunity through activation of CASP1
  • TLR3 stimulation in keratinocytes induces a CASP4 dependent release of pro-IL1B, but further processing to active IL1B is limited
  • regulation of CASP1 activity by CASP4 could represent a unique mechanism in humans, and may partially explain the higher sensitivity to endotoxins
  • CASP4 and caspase-5 mediate IL1A and IL1B release from human monocytes after lipopolysaccharide (LPS) stimulation
  • IFNA1 may possess anti-cervical cancer capacity by activating cell apoptosis via the intrinsic mitochondrial pathway and CASP4-related ER stress-induced pathway
  • CASP4, CASP5, and SCAF11 directly bind endotoxin (LOS/LPS) and can be activated in the absence of any co-factors
  • CTSG is directly engaged in CASP4 activation by a bacterial ligand, which is responsible for cell death and IL1A secretion in human gingival fibroblasts (HGFs)
  • CASP4 physically interacts with CASP1 and is believed to be a proinflammatory caspase that can induce the inflammatory form of programmed cell death (pyroptosis) and the release of mature interleukin IL1B
  • GBP1 facilitated CASP4 recruitment to Salmonella leading to its enhanced activation and pyroptosis
  • IRF2, is required for pyroptosis following cytosolic LPS delivery and functions by directly regulating CASP4 levels in human monocytes
  • IRF2 was found to be a transcriptional activator of CASP4, and in its absence, induction of IRF1 could substitute to maintain CASP4 expression
  • cell & other
    REGULATION
    activated by activation of CASP4 (and presumably CASP5 and SCAF11) are mediated by interactions with activating endotoxin-rich membrane interfaces rather than by endotoxin monomers
    inhibited by inhibitor 9, PI9
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    immunologyautoimmune 
    represents a novel target for the treatment of (auto)inflammatory diseases
    ANIMAL & CELL MODELS
  • knock-down of CASP4 by siRNA reduces NF-kappaB activation and nuclear translocation
  • Casp11(-/-) mice, exhibited defects in IL-1&
  • 946; production and harboured a mutation in the Casp11 locus that attenuated caspase-11 expression
  • loss of caspase-11 rather than caspase-1 protected mice from a lethal dose of lipopolysaccharide