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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
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
  • both CASP4 and CASP5 are functionally important for appropriate responses to intracellular Gram-negative bacteria
  • 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