Caspase 8

Immunopharmacology Ligand Target has curated data in GtoImmuPdb

Target id: 1624

Nomenclature: Caspase 8

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	-	479	2q33.1	CASP8	caspase 8
Mouse	-	480	1 29.19 cM	Casp8	caspase 8
Rat	-	482	9q31	Casp8	caspase 8

Previous and Unofficial Names
apoptotic protease Mch-5 \| CAP4 \| CE-like apoptotic protease 5 \| FADD-homologous ICE/CED-3-like protease \| FADD-like ICE \| FLICE \| MACH \| MCH5 \| caspase 8, apoptosis-related cysteine peptidase

Database Links
Specialist databases
MEROPS	C14.009 (Hs)
Other databases
Alphafold	Q14790 (Hs), O89110 (Mm), Q9JHX4 (Rn)
BRENDA	3.4.22.61
ChEMBL Target	CHEMBL3776 (Hs), CHEMBL4630806 (Mm)
Ensembl Gene	ENSG00000064012 (Hs), ENSMUSG00000026029 (Mm), ENSRNOG00000012331 (Rn)
Entrez Gene	841 (Hs), 12370 (Mm), 64044 (Rn)
Human Protein Atlas	ENSG00000064012 (Hs)
KEGG Enzyme	3.4.22.61
KEGG Gene	hsa:841 (Hs), mmu:12370 (Mm), rno:64044 (Rn)
OMIM	601763 (Hs)
Orphanet	ORPHA138851 (Hs)
Pharos	Q14790 (Hs)
RefSeq Nucleotide	NM_033355 (Hs), NM_001080124 (Hs), NM_001228 (Hs), NM_001080125 (Hs), NM_033358 (Hs), NM_033356 (Hs), NM_001080126 (Mm), NM_009812 (Mm), NM_022277 (Rn)
RefSeq Protein	NP_001219 (Hs), NP_203519 (Hs), NP_203520 (Hs), NP_001073593 (Hs), NP_203522 (Hs), NP_001073594 (Hs), NP_001073595 (Mm), NP_033942 (Mm), NP_071613 (Rn)
UniProtKB	Q14790 (Hs), O89110 (Mm), Q9JHX4 (Rn)
Wikipedia	CASP8 (Hs)

Enzyme Reaction

EC Number: 3.4.22.61

Substrates and Reaction Kinetics

Substrate	Sp.	Property	Standard property
BH3 interacting-domain death agonist	Hs	-	-
FLICE-like inhibitory protein	Hs	-	-
caspase 8	Hs	-	-
pro-caspase 3	Hs	-	-
pro-caspase 6	Hs	-	-
pro-caspase 7	Hs	-	-

Endogenous activators (Human)
DISC

Endogenous activators (Human)

DISC

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Inhibitors

Key to terms and symbols

View all chemical structures

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Ligand		Sp.	Action	Value	Parameter	Reference
emricasan		Hs	Inhibition	8.3	pK_i	5
⤷	pK_i 8.3 (K_i 5x10^-9 M) [5]
compound 4 [PMID: 12408711]		Hs	Inhibition	6.1	pK_i	1
⤷	pK_i 6.1 (K_i 8.8x10^-7 M) [1]
Z-IETD-FMK		Hs	Inhibition	-	-	4
⤷	[4]

Immunopharmacology Comments
Roles of apoptotic caspases extending beyond cell death, for example, mediating cellular immune processes such as inflammasome modulation, necroptosis and pro-inflammatory cytokine processing have been reported [7]. Specifically caspase 8 can counteract necroptosis, an inflammatory mode of cell death induced by receptor-interacting protein (RIP)3, and may be involved in IL-1β maturation during fungal and mycobacterial infections [8].

Immunopharmacology Comments

Roles of apoptotic caspases extending beyond cell death, for example, mediating cellular immune processes such as inflammasome modulation, necroptosis and pro-inflammatory cytokine processing have been reported [7]. Specifically caspase 8 can counteract necroptosis, an inflammatory mode of cell death induced by receptor-interacting protein (RIP)3, and may be involved in IL-1β maturation during fungal and mycobacterial infections [8].

Immuno Process Associations

Immuno Process:

Immuno Process:

Immuno Process:

Immuno Process:

Immuno Process:

Immune system development

Immuno Process:

Cytokine production & signalling

Immuno Process:

Cellular signalling

Clinically-Relevant Mutations and Pathophysiology

Disease:

Autoimmune lymphoproliferative syndrome with recurrent viral infections

Synonyms:	Autoimmune lymphoproliferative syndrome [Disease Ontology: DOID:6688] Autoimmune lymphoproliferative syndrome, type IIB; ALPS2B [OMIM: 607271] Caspase 8 deficiency [OMIM: 607271]
Disease Ontology:	DOID:6688
OMIM:	607271
Orphanet:	ORPHA275517

Disease:

Breast cancer

Disease Ontology:	DOID:1612
OMIM:	114480

Role:

A single nucleotide polymorphism in CASP8 is associated with protection against breast cancer.

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Type	Species	Amino acid change	Nucleotide change	Description	Reference
Missense	Human	D302H		rs1045485	2-3,6

Disease:

Hepatocellular carcinoma

Disease Ontology:	DOID:684
OMIM:	114550

Disease:

Lung cancer

Disease Ontology:	DOID:1324
OMIM:	211980

Role:

A deletion allele in CASP8 is associated with reduced risk of lung cancer

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Type	Species	Amino acid change	Nucleotide change	Description	Reference
Deletion	Human		-652 6Ndel	6 nucleotide deletion variant in the promotor region of CASP8 was found to be associated with reduced risk of lung cancer in a Han Chinese population.	9

References

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1. Choong IC, Lew W, Lee D, Pham P, Burdett MT, Lam JW, Wiesmann C, Luong TN, Fahr B, DeLano WL et al.. (2002) Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design. J Med Chem, 45 (23): 5005-22. [PMID:12408711]

2. Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MW, Pooley KA, Scollen S, Baynes C, Ponder BA, Chanock S et al.. (2007) A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet, 39 (3): 352-8. [PMID:17293864]

3. Frank B, Bermejo JL, Hemminki K, Klaes R, Bugert P, Wappenschmidt B, Schmutzler RK, Burwinkel B. (2005) Re: Association of a common variant of the CASP8 gene with reduced risk of breast cancer. J Natl Cancer Inst, 97 (13): 1012; author reply 1012-3. [PMID:15998955]

4. Gregoli PA, Bondurant MC. (1999) Function of caspases in regulating apoptosis caused by erythropoietin deprivation in erythroid progenitors. J Cell Physiol, 178 (2): 133-43. [PMID:10048577]

5. Linton SD, Aja T, Armstrong RA, Bai X, Chen LS, Chen N, Ching B, Contreras P, Diaz JL, Fisher CD et al.. (2005) First-in-class pan caspase inhibitor developed for the treatment of liver disease. J Med Chem, 48 (22): 6779-82. [PMID:16250635]

6. MacPherson G, Healey CS, Teare MD, Balasubramanian SP, Reed MW, Pharoah PD, Ponder BA, Meuth M, Bhattacharyya NP, Cox A. (2004) Association of a common variant of the CASP8 gene with reduced risk of breast cancer. J Natl Cancer Inst, 96 (24): 1866-9. [PMID:15601643]

7. Man SM, Kanneganti TD. (2016) Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat Rev Immunol, 16 (1): 7-21. [PMID:26655628]

8. Rodrigue-Gervais IG, Saleh M. (2013) Caspases and immunity in a deadly grip. Trends Immunol, 34 (2): 41-9. [PMID:23069594]

9. Sun T, Gao Y, Tan W, Ma S, Shi Y, Yao J, Guo Y, Yang M, Zhang X, Zhang Q et al.. (2007) A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers. Nat Genet, 39 (5): 605-13. [PMID:17450141]