Caspase-8

UniProt Q14790 Organism Homo sapiens Gene CASP8, MCH5 EC 3.4.22.61

Also known as: CASP8, MCH5

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. Initiator protease that induces extrinsic apoptosis by mediating cleavage and activation of effector caspases responsible for FAS/CD95-mediated and TNFRSF1A-induced cell death. Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. Binding to the adapter molecule FADD recruits it to either receptor FAS/TNFRSF6 or TNFRSF1A. The resulting aggregate called the death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Also cleaves and activates BID, thereby promoting cytochrome C release from mitochrondria (By similarity). 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. Also able to initiate pyroptosis by mediating cleavage and activation of gasdermin-C and -D (GSDMC and GSDMD, respectively): gasdermin cleavage promotes release of the N-terminal moiety that binds to membranes and forms pores, triggering pyroptosis. 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. Cleaves PARP1 and PARP2. Independent of its protease activity, promotes cell migration following phosphorylation at Tyr-380.

Classification

Family (Pfam): PF01335 DED, PF00656 Peptidase_C14
InterPro: Caspase-8_DED1, Caspase-like_dom_sf, Caspase_cys_AS, Caspase_his_AS, DEATH-like_dom_sf, DED_dom, Pept_C14_caspase, Pept_C14_p10, Pept_C14_p20, Pept_C14A
Functional cluster: Zinc-Finger & Chromatin Regulatory Proteins

Experimental structures · PDB · 36

1F9E X-ray 2.90A
1I4E X-ray 3.00A
1QDU X-ray 2.80A
1QTN X-ray 1.20A
2C2Z X-ray 1.95A
2FUN X-ray 3.00A
2K7Z NMR
2Y1L X-ray 1.80A
3H11 X-ray 1.90A
3KJN X-ray 1.80A
3KJQ X-ray 1.80A
4JJ7 X-ray 1.18A
… and 24 more

A predicted model is available from AlphaFold.

Gene Ontology · 61

Disease associations

lung cancer MONDO:0008903
autoimmune lymphoproliferative syndrome type 2B MONDO:0011804

Drugs targeting this protein · 2

EMRICASAN inhibitor
NIVOCASAN inhibitor

Related proteins · sequence + function similarity

Caspase-8 0.94
Caspase-8 0.94
Caspase-10 0.83
Caspase-2 0.83
Caspase-2 0.80
CASP8 and FADD-like apoptosis regulator 0.79
Caspase-2 0.78
CASP8 and FADD-like apoptosis regulator 0.77
CASP8 and FADD-like apoptosis regulator 0.77
Caspase-2 0.76
Caspase b 0.72
Caspase-1-B 0.71

Co-cited proteins · studied together in the literature

Caspase-10 6 shared papers
Viral inhibitor of caspase-8-induced apoptosis 1 shared papers
CASP8-associated protein 2 2 shared papers
B-cell receptor-associated protein 31 2 shared papers
Protein MC160 1 shared papers
CASP8 and FADD-like apoptosis regulator 2 shared papers
Nucleolar protein 3 1 shared papers
Astrocytic phosphoprotein PEA-15 1 shared papers
Effector protein NleF 1 shared papers
FAS-associated death domain protein 3 shared papers
Receptor-interacting serine/threonine-protein kinase 1 4 shared papers
Gasdermin-C 2 shared papers

Literature · 48 cited papers

Calmodulin binding activates chromobacterium CopC effector to ADP-riboxanate host apoptotic caspases. MBio · 2022
Pathogen hijacks programmed cell death signaling by arginine ADPR-deacylization of caspases. Mol. Cell · 2022
The metabolite alpha-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8. Cell Res. · 2021
PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat. Cell Biol. · 2020
Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature · 2020
A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1. Nature · 2020
Coupled Caspase and N-End Rule Ligase Activities Allow Recognition and Degradation of Pluripotency Factor LIN-28 during Non-Apoptotic Development. Dev. Cell · 2017
Caspase-8 tyrosine-380 phosphorylation inhibits CD95 DISC function by preventing procaspase-8 maturation and cycling within the complex. Oncogene · 2016
Herpes simplex virus suppresses necroptosis in human cells. Cell Host Microbe · 2015
The E. coli effector protein NleF is a caspase inhibitor. PLoS ONE · 2013
Intrinsic cleavage of receptor-interacting protein kinase-1 by caspase-6. Cell Death Differ. · 2013
Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
… and 36 more in the literature graph

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