Caspase-8
Introduction
Caspase 8 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
Caspase-8 is encoded by the [CASP8](/proteins/casp8-protein) gene. It is a Caspase family, initiator caspases involved in caspase-8 mediates extrinsic [apoptosis](/entities/apoptosis) by death receptors (fas/cd95, trail-r1/2, tnfr1). it can also... [@tummers2022]
<div class="infobox infobox-protein"> [@dickens2021]
<table> [@schleich2020]
<tr><th colspan="2" style="background:#f0f0f0;">Caspase-8</th></tr> [@han2019]
<tr><td><strong>Protein Name</strong></td><td>Caspase-8</td></tr> [@fricker2018]
<tr><td><strong>Gene</strong></td><td>[CASP8](/genes/casp8)</td></tr> [@kantari2021]
<tr><td><strong>UniProt ID</strong></td><td>[Q14790](https://www.uniprot.org/uniprot/Q14790)</td></tr> [@mcilwain2015]
<tr><td><strong>PDB ID(s)</strong></td><td>1K7J, 1K8A, 2C7E, 2C7F, 3K7E, 4JJU, 4PSV</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>55.4 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cytoplasm, Cell Membrane</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Caspase family, initiator caspases</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>
Structure
...Caspase-8
Introduction
Caspase 8 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
Caspase-8 is encoded by the [CASP8](/proteins/casp8-protein) gene. It is a Caspase family, initiator caspases involved in caspase-8 mediates extrinsic [apoptosis](/entities/apoptosis) by death receptors (fas/cd95, trail-r1/2, tnfr1). it can also... [@tummers2022]
<div class="infobox infobox-protein"> [@dickens2021]
<table> [@schleich2020]
<tr><th colspan="2" style="background:#f0f0f0;">Caspase-8</th></tr> [@han2019]
<tr><td><strong>Protein Name</strong></td><td>Caspase-8</td></tr> [@fricker2018]
<tr><td><strong>Gene</strong></td><td>[CASP8](/genes/casp8)</td></tr> [@kantari2021]
<tr><td><strong>UniProt ID</strong></td><td>[Q14790](https://www.uniprot.org/uniprot/Q14790)</td></tr> [@mcilwain2015]
<tr><td><strong>PDB ID(s)</strong></td><td>1K7J, 1K8A, 2C7E, 2C7F, 3K7E, 4JJU, 4PSV</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>55.4 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cytoplasm, Cell Membrane</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Caspase family, initiator caspases</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>
Structure
Caspase-8 exists as two isoforms (Caspase-8a and Caspase-8b) that differ by 2 amino acids. It has a long prodomain with two death effector domains (DEDs).
Normal Function
Caspase-8 mediates extrinsic apoptosis by death receptors (Fas/CD95, TRAIL-R1/2, TNFR1). It can also initiate a caspase cascade independent of mitochondria (Type I cells) or cleave Bid to engage the intrinsic pathway (Type II cells). Caspase-8 also has non-apoptotic roles in cell proliferation and differentiation.
Role in Disease
Alzheimer's Disease
Death receptor signaling contributes to neuronal apoptosis in AD.
Parkinson's Disease
Caspase-8 is activated by DJ-1 loss and contributes to dopaminergic neuron death.
Stroke
Extrinsic apoptotic pathway contributes to ischemic neuronal injury.
Traumatic Brain Injury
Death receptor-mediated caspase-8 activation contributes to secondary injury.
Therapeutic Targeting
Caspase-8 inhibitors (IETD-FMK) have shown neuroprotective potential in preclinical models of stroke and TBI.
Key Publications
[@stupack2022] Protein information and structure. UniProt Database.
See Also
- [CASP8 Gene](/proteins/casp8-protein)
- [Apoptosis Pathway](/mechanisms/apoptosis-neurodegeneration)
- [Mitochondrial Dysfunction Pathway](/mechanisms/mitochondrial-dysfunction-pathway)
- [Autophagy-Lysosomal Pathway](/mechanisms/autophagy-lysosomal-pathway)
External Links
- [UniProt: Caspase-8](https://www.uniprot.org/uniprot/Q14790)
- [PDB: Caspase-8](https://www.rcsb.org/)
- [Human Protein Atlas: CASP8](https://www.proteinatlas.org/)
Molecular Mechanisms
Death Receptor Signaling
Caspase-8 is activated by the death receptor pathway through a well-characterized cascade:
Ligand binding: FasL, TRAIL, or TNF-α binds to their respective death receptors (Fas/CD95, TRAIL-R1/R2, TNFR1)
DISC formation: Death-inducing signaling complex (DISC) assembles at the receptor
Pro-caspase-8 recruitment: Pro-caspase-8 binds to the DISC via FADD adapter protein
Auto-activation: Pro-caspase-8 undergoes autocatalytic cleavage to form active caspase-8
Downstream execution: Active caspase-8 cleaves downstream effector caspases (caspase-3, -6, -7)Non-Apoptotic Functions
Caspase-8 has important non-apoptotic roles:
- Cell proliferation: Required for [NF-κB](/entities/nf-kb) activation and cell survival signaling
- Differentiation: Essential for T-cell differentiation and macrophage function
- Migration: Regulates actin cytoskeleton dynamics and cell motility
- Inflammation: Processes pro-inflammatory cytokines
Signaling Pathways
Extrinsic Apoptosis Pathway
Cross-Talk with Other Pathways
- NF-κB pathway: Caspase-8 can activate NF-κB, promoting cell survival
- ERK pathway: Involved in cell survival signaling
- JNK pathway: Stress-activated kinase signaling
Disease-Specific Mechanisms
Alzheimer's Disease
- [Aβ](/proteins/amyloid-beta) oligomers can activate death receptors (Fas, TNFR1)
- Caspase-8 activation contributes to synaptic loss
- Elevated caspase-8 levels in AD brain tissue
- Death receptor signaling amplifies neuroinflammation
Parkinson's Disease
- DJ-1 loss-of-function increases caspase-8 activation
- Dopaminergic [neurons](/entities/neurons) are particularly vulnerable to extrinsic apoptosis
- [α-Synuclein](/proteins/alpha-synuclein) can sensitize cells to death receptor signaling
- Mitochondrial dysfunction cross-talk with extrinsic pathway
Stroke and Ischemia
- Oxygen-glucose deprivation activates death receptors
- TNF-α and FasL release during ischemia
- Caspase-8 contributes to penumbra expansion
- Dual inhibition of caspase-8 and caspase-9 provides neuroprotection
Traumatic Brain Injury
- Secondary injury involves death receptor activation
- Caspase-8 mediates inflammatory responses
- Inhibition reduces both apoptotic and necrotic cell death
Huntington's Disease
- Mutant [huntingtin](/proteins/huntingtin-protein) can interact with death receptor components
- Caspase-8 activation in striatal neurons
- Cross-talk with mitochondrial apoptotic pathway
Amyotrophic Lateral Sclerosis
- Death receptor signaling in motor neuron degeneration
- Astrocyte-mediated caspase-8 activation
- Potential therapeutic target
Therapeutic Approaches
Caspase-8 Inhibitors
| Compound | Type | Status | Notes |
|----------|------|--------|-------|
| Z-IETD-FMK | Peptide inhibitor | Research tool | Selective for caspase-8 |
| A-385,358 | Small molecule | Preclinical | Brain-penetrant |
| Emricasan | Pan-caspase inhibitor | Clinical trials | Not specific to caspase-8 |
Death Receptor Antagonists
- Fas/FasL blocking antibodies: Tested in preclinical models
- TRAIL receptor decoys: Potential for neuroprotection
- TNF-α inhibitors: Used in neurodegenerative disease models
Gene Therapy Approaches
- Dominant-negative caspase-8 mutants
- RNAi targeting caspase-8 expression
- Viral vector delivery of protective genes
Biomarkers
Caspase-8 as Biomarker
- CSF caspase-8: Elevated in AD, PD, and ALS
- Peripheral blood mononuclear cells: Caspase-8 activation state
- Therapeutic response marker: Inhibition efficacy monitoring
Caspase-8 Cleavage Products
- Active caspase-8 fragments in patient samples
- Correlates with disease progression
- Potential for diagnostic and prognostic use
Detection Methods
- Activity assays: Fluorometric substrates (IETD-AFC)
- Western blot: Pro-caspase-8 and cleaved forms
- Immunohistochemistry: Tissue localization
- Flow cytometry: Cell surface death receptor analysis
Mouse Models
- Caspase-8 conditional knockout mice
- Transgenic overexpression models
- Humanized mouse models for drug testing
Background
The study of Caspase 8 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
See Also
- [CASP8 Gene](/mechanisms/dopaminergic-neuron-vulnerability)
- [Caspase](/proteins/caspase-9)
- [Extrinsic Apoptosis Pathway](/mechanisms/dopaminergic-neuron-vulnerability)
- [Intrinsic Apoptosis Pathway](/mechanisms/intrinsic-apoptosis-neurodegeneration)
- [Death Receptor Signaling](/mechanisms/dopaminergic-neuron-vulnerability)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Stroke](/diseases/stroke)
- [Apoptosis](/mechanisms/apoptosis-pathways-neurodegeneration)
External Links
- [UniProt: Q14790](https://www.uniprot.org/uniprot/Q14790)
- [PDB: 1K7J](https://www.rcsb.org/structure/1K7J)
- [GeneCards: CASP8](https://www.genecards.org/cgi-bin/carddisp.pl?gene=CASP8)
- [PubMed: Caspase-8 Neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/?term=caspase-8+neurodegeneration)
References
Pathway Diagram
The following diagram shows the key molecular relationships involving Caspase-8 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)
Pathway Diagram
The following diagram shows the key molecular relationships involving Caspase-8 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)