CASP8 (caspase 8)

Gene

• Entrez ID: 841
• Gene name: Caspase 8
• Gene symbol: CASP8
• Synonyms: ALPS2B, CAP4, Casp-8, FLICE, MACH, MCH5
• Chromosome: 2
• Chromosome location: 2q33.1
• Summary: This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. [provided by RefSeq, Jul 2008]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs17860424	C>T	Pathogenic	Coding sequence variant, missense variant, non coding transcript variant
rs587776665	GT>-	Pathogenic	Downstream transcript variant, genic downstream transcript variant, frameshift variant, non coding transcript variant, coding sequence variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT005293	hsa-let-7a-5p	Western blot	18758960
MIRT006278	hsa-miR-19b-1-5p	Luciferase reporter assay	22197821
MIRT029158	hsa-miR-26b-5p	Microarray	19088304
MIRT204830	hsa-miR-106b-5p	Luciferase reporter assay	24166509
MIRT527671	hsa-miR-5682	PAR-CLIP	22012620
MIRT527672	hsa-miR-767-5p	PAR-CLIP	22012620
MIRT527673	hsa-miR-6871-3p	PAR-CLIP	22012620
MIRT527674	hsa-miR-29c-3p	PAR-CLIP	22012620
MIRT527675	hsa-miR-29b-3p	PAR-CLIP	22012620
MIRT527676	hsa-miR-29a-3p	PAR-CLIP	22012620
MIRT527677	hsa-miR-5688	PAR-CLIP	22012620
MIRT527678	hsa-miR-495-3p	PAR-CLIP	22012620
MIRT682653	hsa-miR-665	HITS-CLIP	23706177
MIRT682654	hsa-miR-6771-5p	HITS-CLIP	23706177
MIRT682655	hsa-miR-6735-3p	HITS-CLIP	23706177
MIRT682656	hsa-miR-7160-5p	HITS-CLIP	23706177
MIRT682657	hsa-miR-4722-5p	HITS-CLIP	23706177
MIRT682658	hsa-miR-6884-5p	HITS-CLIP	23706177
MIRT682659	hsa-miR-485-5p	HITS-CLIP	23706177
MIRT682660	hsa-miR-1827	HITS-CLIP	23706177
MIRT682661	hsa-miR-4649-3p	HITS-CLIP	23706177
MIRT682662	hsa-miR-6746-5p	HITS-CLIP	23706177
MIRT682663	hsa-miR-4768-3p	HITS-CLIP	23706177
MIRT682664	hsa-miR-4478	HITS-CLIP	23706177
MIRT682665	hsa-miR-4419b	HITS-CLIP	23706177
MIRT682666	hsa-miR-3929	HITS-CLIP	23706177
MIRT682667	hsa-miR-940	HITS-CLIP	23706177
MIRT682668	hsa-miR-6893-5p	HITS-CLIP	23706177
MIRT682669	hsa-miR-6808-5p	HITS-CLIP	23706177
MIRT731940	hsa-miR-376a-3p	Luciferase reporter assay, qRT-PCR, Western blot	27979415
MIRT731940	hsa-miR-376a-3p	PAR-CLIP	27292025
MIRT733978	hsa-miR-34a-5p	PCR array	28097098
MIRT734976	hsa-miR-296-5p	Immunoprecipitaion, Luciferase reporter assay, qRT-PCR	27927008
MIRT735309	hsa-miR-21-5p	In situ hybridization, Luciferase reporter assay, Northern blot, qRT-PCR, Western blot	26080425
MIRT764003	hsa-miR-2392	PAR-CLIP	27292025
MIRT766174	hsa-miR-362-5p	PAR-CLIP	27292025
MIRT766765	hsa-miR-3682-5p	PAR-CLIP	27292025
MIRT767341	hsa-miR-376b-3p	PAR-CLIP	27292025
MIRT771350	hsa-miR-4704-3p	PAR-CLIP	27292025
MIRT771388	hsa-miR-4710	PAR-CLIP	27292025
MIRT772455	hsa-miR-4793-5p	PAR-CLIP	27292025
MIRT772896	hsa-miR-5000-5p	PAR-CLIP	27292025
MIRT773002	hsa-miR-500b-5p	PAR-CLIP	27292025
MIRT773634	hsa-miR-5196-3p	PAR-CLIP	27292025
MIRT781708	hsa-miR-744-3p	PAR-CLIP	27292025
MIRT782262	hsa-miR-7855-5p	PAR-CLIP	27292025

Transcription factors

Transcription factor	Regulation	Reference
CEBPD	Unknown	24810056
CREB1	Activation	18342014
DNMT1	Repression	20398055
MEN1	Activation	17766243
RUNX3	Activation	15930301

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0001525	Process	Angiogenesis	ISS
GO:0004197	Function	Cysteine-type endopeptidase activity	IDA	16920334, 19240112
GO:0004197	Function	Cysteine-type endopeptidase activity	TAS
GO:0005123	Function	Death receptor binding	IEA
GO:0005164	Function	Tumor necrosis factor receptor binding	IEA
GO:0005515	Function	Protein binding	IPI	9208847, 9334338, 9343261, 9560245, 10442631, 12198154, 12884866, 12887920, 12888622, 14612908, 15069192, 15509781, 16498403, 16936772, 17047155, 17159907, 17170703, 17245429, 17479112, 18086677, 18245485, 18328427, 18485876, 18846110, 19060883, 19176810, 19427028, 19524512, 1952451
GO:0005654	Component	Nucleoplasm	IDA
GO:0005737	Component	Cytoplasm	IBA	21873635
GO:0005739	Component	Mitochondrion	TAS	10891503
GO:0005741	Component	Mitochondrial outer membrane	TAS
GO:0005829	Component	Cytosol	IDA	17167422
GO:0005829	Component	Cytosol	TAS
GO:0005856	Component	Cytoskeleton	TAS	10891503
GO:0006508	Process	Proteolysis	IDA	12888622
GO:0006915	Process	Apoptotic process	IBA	21873635
GO:0006915	Process	Apoptotic process	IGI	17599062
GO:0006915	Process	Apoptotic process	IMP	22891283
GO:0006919	Process	Activation of cysteine-type endopeptidase activity involved in apoptotic process	IBA	21873635
GO:0006919	Process	Activation of cysteine-type endopeptidase activity involved in apoptotic process	TAS
GO:0007166	Process	Cell surface receptor signaling pathway	TAS
GO:0007507	Process	Heart development	ISS
GO:0008233	Function	Peptidase activity	IDA	19740745
GO:0008233	Function	Peptidase activity	IMP	17047155
GO:0008234	Function	Cysteine-type peptidase activity	TAS	8681376
GO:0008625	Process	Extrinsic apoptotic signaling pathway via death domain receptors	IBA	21873635
GO:0009409	Process	Response to cold	IEA
GO:0010803	Process	Regulation of tumor necrosis factor-mediated signaling pathway	TAS
GO:0030101	Process	Natural killer cell activation	TAS	18309324
GO:0030225	Process	Macrophage differentiation	IBA	21873635
GO:0030225	Process	Macrophage differentiation	TAS	18309324
GO:0031264	Component	Death-inducing signaling complex	IDA	11101870, 21803845
GO:0031265	Component	CD95 death-inducing signaling complex	IDA	11717445
GO:0031625	Function	Ubiquitin protein ligase binding	IPI	15069192
GO:0032025	Process	Response to cobalt ion	IEA
GO:0032355	Process	Response to estradiol	IEA
GO:0032496	Process	Response to lipopolysaccharide	IEA
GO:0032731	Process	Positive regulation of interleukin-1 beta production	IMP	22267217
GO:0032991	Component	Protein-containing complex	IDA	22267217
GO:0034138	Process	Toll-like receptor 3 signaling pathway	TAS
GO:0034612	Process	Response to tumor necrosis factor	IMP	10521396
GO:0035666	Process	TRIF-dependent toll-like receptor signaling pathway	TAS
GO:0035877	Function	Death effector domain binding	IBA	21873635
GO:0035877	Function	Death effector domain binding	IPI	11717445
GO:0036462	Process	TRAIL-activated apoptotic signaling pathway	IDA	21785459
GO:0039650	Process	Suppression by virus of host cysteine-type endopeptidase activity involved in apoptotic process	TAS
GO:0042110	Process	T cell activation	TAS	18309324
GO:0042113	Process	B cell activation	TAS	18309324
GO:0042802	Function	Identical protein binding	IPI	16169070, 17170703
GO:0043005	Component	Neuron projection	IEA
GO:0043065	Process	Positive regulation of apoptotic process	ISS
GO:0043123	Process	Positive regulation of I-kappaB kinase/NF-kappaB signaling	IEP	12761501
GO:0043123	Process	Positive regulation of I-kappaB kinase/NF-kappaB signaling	IMP	12884866
GO:0043124	Process	Negative regulation of I-kappaB kinase/NF-kappaB signaling	IMP	17047155
GO:0044297	Component	Cell body	IEA
GO:0044877	Function	Protein-containing complex binding	IEA
GO:0045121	Component	Membrane raft	IEA
GO:0045471	Process	Response to ethanol	IEA
GO:0045651	Process	Positive regulation of macrophage differentiation	IMP	17047155
GO:0045862	Process	Positive regulation of proteolysis	IDA	18387192
GO:0046677	Process	Response to antibiotic	IEA
GO:0051603	Process	Proteolysis involved in cellular protein catabolic process	IMP	10521396
GO:0060544	Process	Regulation of necroptotic process	TAS
GO:0060546	Process	Negative regulation of necroptotic process	IDA	31827280
GO:0060546	Process	Negative regulation of necroptotic process	ISS
GO:0060715	Process	Syncytiotrophoblast cell differentiation involved in labyrinthine layer development	TAS	18309324
GO:0070269	Process	Pyroptosis	ISS
GO:0070423	Process	Nucleotide-binding oligomerization domain containing signaling pathway	TAS
GO:0071260	Process	Cellular response to mechanical stimulus	IEP	19593445
GO:0071407	Process	Cellular response to organic cyclic compound	IEA
GO:0071550	Process	Death-inducing signaling complex assembly	TAS
GO:0097110	Function	Scaffold protein binding	IPI	21785459
GO:0097153	Function	Cysteine-type endopeptidase activity involved in apoptotic process	IBA	21873635
GO:0097153	Function	Cysteine-type endopeptidase activity involved in apoptotic process	IDA	31827280
GO:0097153	Function	Cysteine-type endopeptidase activity involved in apoptotic process	IMP	21737330
GO:0097190	Process	Apoptotic signaling pathway	IMP	11101870
GO:0097190	Process	Apoptotic signaling pathway	TAS
GO:0097191	Process	Extrinsic apoptotic signaling pathway	IDA	21785459
GO:0097194	Process	Execution phase of apoptosis	IMP	21737330
GO:0097194	Process	Execution phase of apoptosis	ISS
GO:0097194	Process	Execution phase of apoptosis	TAS
GO:0097199	Function	Cysteine-type endopeptidase activity involved in apoptotic signaling pathway	IBA	21873635
GO:0097199	Function	Cysteine-type endopeptidase activity involved in apoptotic signaling pathway	IMP	11717445, 21980415
GO:0097200	Function	Cysteine-type endopeptidase activity involved in execution phase of apoptosis	IBA	21873635
GO:0097202	Process	Activation of cysteine-type endopeptidase activity	IDA	18387192
GO:0097264	Process	Self proteolysis	ISS
GO:0097296	Process	Activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway	TAS
GO:0097342	Component	Ripoptosome	IDA	21737330
GO:1900740	Process	Positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway	TAS
GO:1901216	Process	Positive regulation of neuron death	IEA
GO:1902041	Process	Regulation of extrinsic apoptotic signaling pathway via death domain receptors	TAS
GO:1902042	Process	Negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	TAS

Other IDs

• MIM: 601763
• HGNC: 1509
• e!Ensembl: ENSG00000064012

Protein

• UniProt ID: Q14790
• Protein name: Caspase-8 (CASP-8) (EC 3.4.22.61) (Apoptotic cysteine protease) (Apoptotic protease Mch-5) (CAP4) (FADD-homologous ICE/ced-3-like protease) (FADD-like ICE) (FLICE) (ICE-like apoptotic protease 5) (MORT1-associated ced-3 homolog) (MACH) [Cleaved into: Caspase-8 subunit p18; Caspase-8 subunit p10]
• Protein function: Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood (By similarity). Initiator protease that induces extrinsic apoptosis by mediating cleavage and activation of effector caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death (PubMed:23516580, PubMed:8681376, PubMed:8681377, PubMed:9006941, PubMed:9184224, PubMed:8962078). Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10 (PubMed:8962078, PubMed:9006941). Binding to the adapter molecule FADD recruits it to either receptor TNFRSF6/FAS mediated or TNFRSF1A (PubMed:8681376, PubMed:8681377). The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation (PubMed:9184224). The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases (PubMed:9184224). Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC (PubMed:9184224). In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-324', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response (PubMed:31827280, PubMed:31827281). Also able to initiate pyroptosis by mediating cleavage and activation of gasdermin-D (GSDMD): GSDMD cleavage promoting release of the N-terminal moiety (Gasdermin-D, N-terminal) that binds to membranes and forms pores, triggering pyroptosis (By similarity). Initiates pyroptosis following inactivation of MAP3K7/TAK1 (By similarity). Also acts as a regulator of innate immunity by mediating cleavage and inactivation of N4BP1 downstream of TLR3 or TLR4, thereby promoting cytokine production (By similarity). May participate in the Granzyme B (GZMB) cell death pathways (PubMed:8755496). Cleaves PARP1 (PubMed:8681376). ; [Isoform 5]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. ; [Isoform 6]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. ; [Isoform 7]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex (Probable). Acts as an inhibitor of the caspase cascade (PubMed:12010809). ; [Isoform 8]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.
• PDB: 1F9E, 1I4E, 1QDU, 1QTN, 2C2Z, 2FUN, 2K7Z, 2Y1L, 3H11, 3KJN, 3KJQ, 4JJ7, 4PRZ, 4PS1, 4ZBW, 5H31, 5H33, 5JQE, 5L08, 6AGW, 6PX9
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF01335	DED	3 → 84	Death effector domain	Domain
  PF01335	DED	101 → 180	Death effector domain	Domain
  PF00656	Peptidase_C14	234 → 476		Domain

• Sequence:

  MDFSRNLYDIGEQLDSEDLASLKFLSLDYIPQRKQEPIKDALMLFQRLQEKRMLEESNLS
  FLKELLFRINRLDLLITYLNTRKEEMERELQTPGRAQISAYRVMLYQISEEVSRSELRSF
  KFLLQEEISKCKLDDDMNLLDIFIEMEKRVILGEGKLDILKRVCAQINKSLLKIINDYEE
  FSKERSSSLEGSPDEFSNGEELCGVMTISDSPREQDSESQTLDKVYQMKSKPRGYCLIIN
  NHNFAKAREKVPKLHSIRDRNGTHLDAGALTTTFEELHFEIKPHDDCTVEQIYEILKIYQ
  LMDHSNMDCFICCILSHGDKGIIYGTDGQEAPIYELTSQFTGLKCPSLAGKPKVFFIQAC
  QGDNYQKGIPVETDSEEQPYLEMDLSSPQTRYIPDEADFLLGMATVNNCVSYRNPAEGTW
  YIQSLCQSLRERCPRGDDILTILTEVNYEVSNKDDKKNMGKQMPQPTFTLRKKLVFPSD

• Sequence length: 479