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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	11q22.3      Physical location : 104.813.593 - 104.839.325
Synonym name	apoptotic cysteine protease Mih1/TX
	caspase 4, apoptosis-related cysteine protease
	ICH-2 protease
	caspase-4
	protease ICH-2
	protease TX
	caspase 11
Synonym symbol(s)	TX, ICH-2, Mih1/TX, ICEREL-II, ICE(rel)II, ICE(rel)-II, CASP-4
EC.number	3.4.22.57, 3.4.22.36

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

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_033306 9 splicing 1352 NP_150649 - 321 - 1999 9931493 transcript variant gamma NM_001225 9 splicing 1319 NP_001216 - 377 - 1999 9931493 transcript variant alpha

EXPRESSION

Type

widely

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       lowly Digestive intestine large intestine colon   lowly   intestine small intestine     highly   liver       moderately Endocrine pancreas       lowly Lymphoid/Immune spleen       highly   thymus       lowly Nervous brain         Homo sapiens Reproductive female system ovary     highly   female system placenta     highly   male system testis     lowly   male system prostate     lowly Urinary kidney       lowly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective bone     highly

cells

System Cell Pubmed Species Stage Rna symbol Nervous glia 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
	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
	System Type Disorder Pubmed immunology autoimmune   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