caspase-8; ICE-like apoptotic protease 5; MACH; MORT-1 associated CED-3 homolog; FLICE; FADD-like ICE; Mch5 (CASP8)
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Introduction
Multiple isoforms; 2 subunits: p18 & p10.
Function
- most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated & TNFRSF1A induced cell death
- binding to the adapter molecule FADD recruits it to either receptor
- the resulting aggregate, death-inducing signaling complex (DISC), performs CASP8 proteolytic activation
- the active dimeric enzyme is then liberated from the DISC & free to activate downstream apoptotic proteases
- proteolytic fragments of the N-terminal propeptide (CAP3, CAP5 & CAP6) are likely retained in the DISC
- cleaves & activates CASP3, CASP4, CASP6, CASP7, CASP9 & CASP10
- may participate in the GZMB apoptotic pathways
- cleaves ADPRT
- hydrolyzes small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC
- likely target for cowpox virus CRMA death inhibitory protein
- isoforms 5, 6, 7 & 8 lack the catalytic site & may interfere with the pro-apoptotic activity of the complex
- interacts with FADD, CFLAR & PEA15
- isoform 9 interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 &/or BCL2L1
- generation of the subunits requires association with the death-inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease
- GZMB & CASP10 can be involved in these processing events
- phosphorylated upon DNA damage, probably by ATM or ATR
- strict requirement for Asp at position P1 & has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(gly/Ser/Ala)
Structure
- heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kD (p18) & a 10 kD (p10) subunit
- isoform 9 contains a N-terminal extension that is required for interaction with the BCAP31 complex
- belongs to the peptidase C14 family
- contains 2 DED (death effector) domains
Compartment
Alternative splicing
named isoforms=9
Expression
- isoforms 1, 5 & 7 are expressed in a wide variety of tissues
- highest expression in peripheral blood leukocytes, spleen, thymus, & liver
- barely detectable in brain, testis, & skeletal muscle
Pathology
- defects in CASP8 are the cause of caspase-8 deficiency
- gene is deleted or silenced preferentially in childhood neuroblastomas with N-myc amplification.[3]
Polymorphism
- genetic vaiations in CASP8 are associated with diminished risk of lung cancer in a population of Han chinese subjects
- genetic vaiations are also associated with decreased risk of cancer of various other forms including esophageal cqncer, gastric cancer, colorectal cancer, cervical cancer, & breast cancer, acting in an allele dose-dependent manner
Notes
- may be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay
More general terms
References
- ↑ Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. 1996 Jun 14;85(6):803-15. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8681376
- ↑ Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell. 1996 Jun 14;85(6):817-27. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8681377
- ↑ 3.0 3.1 Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM, Kidd VJ. Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN. Nat Med. 2000 May;6(5):529-35. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10802708
- ↑ CASP8base, CASP8 mutation db http://bioinf.uta.fi/CASP8base/
- ↑ GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=CASP8
- ↑ UniProt http://www.uniprot.org/uniprot/Q14790.html
Database
- UniProt: http://www.uniprot.org/uniprot/Q14790.html
- Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:841
- OMIM: https://mirror.omim.org/entry/211980
- OMIM: https://mirror.omim.org/entry/601763
- OMIM: https://mirror.omim.org/entry/607271
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=841
- Kegg: http://www.genome.jp/dbget-bin/www_bget?