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FLASH GENE

Symbol

CASP8

contributors: mct/np - updated : 03-07-2019

HGNC name	caspase 8, apoptosis-related cysteine peptidase
HGNC id	1509

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a N terminal (Fas-associating protein with DEATH domain) FADD-MORT like death effector domain
	a conserved QACXG pentapeptide active site motif
	a prodomain (inactive proenzyme)
	a large protease subunit (inactive proenzyme)
	a small protease subunit (inactive proenzyme)
	2 death effector (DED) domains

mono polymer

heteromer , dimer

HOMOLOGY

interspecies	homolog to rattus Casp8 (67.80 pc)
	homolog to murine Casp8 (69.57 pc)

Homologene

FAMILY	cysteine-aspartic acid protease (caspase) family
	CASP3 subfamily
	peptidase C14 family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria,interspace
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,cytosolic
	intracellular,cytoplasm,cytoskeleton
	intracellular,nucleus,nucleoplasm
text	stored in the mitochondrial intermembrane space and released into cytosol after appropriate apoptotic stimuli

basic FUNCTION	promoting CD95/APO1/Fas apoptosis via the cleavage of BID, required for lymphocyte activation
	involved in the programmed cell death induced by Fas and various apoptotic stimuli
	cleaving and activating CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10
	may participate in the GZMB apoptotic pathways
	cleaving ADPRT
	hydrolyzing the small-molecule substrate, Ac-Asp-Glu-Val-Asp-AMC
	having an essential role in lymphocyte activation, immune cell homeostasis, and protective immunity
	involved in the recruitment of the IKK alpha, beta complex, its activation, and the nuclear translocation of NF kappa B
	with FADD modulate autophagic signaling in a manner vital to T cell clonal expansion
	modulator of PIK3R1 Rab-GAP activity and endosomal trafficking
	is necessary for the efficient activation of downstream events associated with epidermal growth factor (EGF) signaling
	CASP1, CASP8, and calpain are dispensable for IL33 release by macrophages
	with FADD, have also been implicated in necroptosis
	involved in the extrinsic death receptor pathway
	RIPK1 and caspase-8 were recruited to the DDX58 complex after viral infection and served antagonistic regulatory roles
	an essential executioner of the death receptor (DR) apoptotic pathway
	catalyzes an essential intermediate step in the ubiquitination and proteasome-mediated degradation of IRF3
	catalyzes cleavage of IR-3 during dsRNA-dependent signaling
	CASP8-mediated cleavage and degradation of activated IRF3 is involved in the down-regulation of dsRNA-inducible genes
	critical function of caspase-8 in regulating intestinal homeostasis and in protecting intestinal epithelial cells (IECs from TNF-induced necroptotic cell death)
	is a key initiator of apoptotic cell death where it functions as the apical protease in death receptor-mediated apoptosis triggered via the death-inducing signalling complex (DISC)
	CASP8 plays an essential cell-intrinsic role in innate inflammatory cytokine production during Yersinia infection
	importance of CASP8 in the development and homeostasis
	in addition to their role in amyloid processing, CASP8 and its downstream effector CASP3 are involved in synaptic plasticity, learning, memory and control of microglia pro-inflammatory activation and associated neurotoxicity
	inhibits programmed necrosis by processing CYLD
	in the presence of CASP1, CASP8 acts as a positive modulator of the NLRP3-dependent CASP1 signaling cascades that drive both IL1B production and pyroptotic death
	TNFSF10 and CASP8 expression levels were positively correlated with apoptosis in osteosarcoma
	importance of TNFRSF10B and CASP8 as critical signal conduits for apoptosis activation upon ER stress
	CASP8 collaborates with CASP11 to drive tissue damage and execution of endotoxic shock
	cell-death- and inflammation-independent function of RIPK1 and CASP8, promoting faithful chromosome alignment in mitosis and thereby ensuring genome stability

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	FAS/FADD/caspase-8 complex is known as the death-inducing signaling complex (DISC)
	CASP8/CFLAR heterodimer implicated in control of inflammatory cytokines during microbial infection

INTERACTION

DNA

RNA

small molecule

protein	HIP1/ESRRBL1 heterodimer complex
	CASP8AP2 protein
	with FADD impact autophagic signaling (both FADD and CASP8 acting in concert to limit general macroautophagy in a number of cell types)
	CFLAR
	PEA15
	ABCF1, AKAP1, CPE, DOPEY1 and GOPC may be targeted specifically by the initiator CASP8 and CASP10 during the early stages of apoptosis
	interaction between CASP8 and PIK3R1 promotes RAB5A GTP loading, alters endosomal trafficking, and results in the accumulation of RAB5A-positive endosomes at the edge of the cell
	CYLD is a substrate for CASP8, and caspase 8 cleaves CYLD to generate a survival signal
	role for TRAF2-dependent CASP8 ubiquitination as a gatekeeper for extrinsic apoptosis activation in mammalian cells
	TRAF2-mediated ubiquitin shutoff timer that inactivates CASP8 to exert crucial control over cell-extrinsic apoptosis
	SMAD7 can directly interact with the CASP8 promoter and act as a transcriptional coactivator
	CASP8 control of death receptor and TLR necrotic death signaling depends on basal catalytic activity that suppresses the RIPK3 kinase pathway
	evidence for a mechanism to control CASP8-dependent cell death by the atypical cadherin FAT1
	RIPK1 blocks early postnatal lethality mediated by CASP8 and RIPK3
	TNFAIP8L2 can regulate TLR4 inflammatory effect and inhibit further amplification of cascade reaction via CASP8
	TNF-induced apoptosis leads to CASP8-dependent PAWR-cleavage followed by nuclear accumulation of the C-terminal PAWR (132-340) fragment, which then induces apoptosis
	indirectly RIPK1 regulates likely CASP8 activation, in part via interaction with the ER stress sensor inositol-requiring protein 1 (ERN1)
	RIPK3 is an unexpected positive regulator of CASP8 activity that promotes IL1B maturation in bone marrow-derived dendritic cells (BMDCs)
	EPHA7 interacts with CASP8 to induce apoptotic cell signaling
	CASP8 functions uniquely in macrophages by controlling the response to TLR activation and macrophage polarization in an RIPK-dependent manner
	MAP3K7 regulates necroptotic signaling as well as CASP8-mediated apoptotic signaling through both NFKB1-dependent and -independent mechanisms
	essential role for the adaptor protein TRADD in CASP8 activation and necrosome formation triggered by MAP3K7 inhibition
	CASP10 negatively regulates CASP8-mediated cell death
	CASP8 is required upstream of both CFLAR and CASP10 and death-inducing signaling complex (DISC) formation critically depends on the scaffold function of CASP8
	SCAF11 enhanced the activation of CASP8 and extrinsic cell death machinery within the lower small intestine
	CFLAR is a central regulator of CASP8-mediated apoptosis and necroptosis
	PLK1 is recruited into mitotic ripoptosomes, where PLK1's activity is controlled via RIPK1-dependent recruitment and CASP8-mediated cleavage
	N4BP1 is a suppressor of cytokine production that is cleaved and inactivated by CASP8

cell & other

REGULATION

activated by	HIP1/ESRRBL1 heterodimer complex
	by TNF in mitochondria pathway for apoptosis
	proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits

Other

regulating FAS/TNFR1 induced apoptosis

ASSOCIATED DISORDERS

corresponding disease(s)

CASP8D

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral       loss of function in neuroblastoma tumoral somatic mutation       mutation 1225_1226delTG might lead to the loss of cell death function and contribute to the pathogenesis of hepatocellular carcinomas tumoral somatic mutation     loss of function inactivated by somatic mutations in advanced gastric carcinomas constitutional       loss of function prevented CYLD degradation, resulting in necrotic death

Susceptibility

contribute to an inherited predisposition to SmCC (small cell carcinoma) of the lung to breast cancer to Alzheimer disease

Variant & Polymorphism SNP	polymorphisms D302H significantly associated with a highly decreased familial breast cancer risk
	for CASP8 variants, p.K148R and p.I298V, the association remained significant with Alzheimer disease

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

caspase-8-deficient mice exhibit inflammatory skin disorders due to unregulated activation and accumulation of active IRF3