CASP4 Protein
Introduction
Caspase-4 (CASP4) is a member of the cysteine-aspartic protease (caspase) family that plays critical roles in inflammatory responses and programmed cell death. As an inflammatory caspase, CASP4 is uniquely positioned to mediate responses to intracellular pathogens and cellular stress. Unlike inflammatory caspase-1 which requires inflammasome assembly for activation, CASP4 can be directly activated by intracellular lipopolysaccharide (LPS) and endoplasmic reticulum (ER) stress signals. This makes CASP4 particularly important in [neurons](/entities/neurons) and glial cells where it contributes to neuroinflammation and neurodegenerative processes.
--- [@caspasemediated]
title: CASP4 Protein [@stress]
description: Protein page for Caspase-4 [@caspasea]
--- [@gasdermin]
<div class="infobox infobox-protein"> [@casp]
| | | [@caspaseb]
|---|---| [@therapeutic]
| Protein Name | Caspase-4 |
| Gene | [CASP4](/proteins/casp4-protein) |
| UniProt ID | [P49662](https://www.uniprot.org/uniprot/P49662) |
| PDB ID | 4E90, 5NBB |
| Molecular Weight | 45 kDa (proenzyme), 20+10 kDa (active form) |
| Subcellular Localization | Cytoplasm, ER membrane, mitochondria |
| Protein Family | Caspase family, inflammatory caspases (CASP1, CASP4, CASP5) |
| Expression | Broad, high in immune cells, CNS neurons and glia |
</div>
Overview
...CASP4 Protein
Introduction
Caspase-4 (CASP4) is a member of the cysteine-aspartic protease (caspase) family that plays critical roles in inflammatory responses and programmed cell death. As an inflammatory caspase, CASP4 is uniquely positioned to mediate responses to intracellular pathogens and cellular stress. Unlike inflammatory caspase-1 which requires inflammasome assembly for activation, CASP4 can be directly activated by intracellular lipopolysaccharide (LPS) and endoplasmic reticulum (ER) stress signals. This makes CASP4 particularly important in [neurons](/entities/neurons) and glial cells where it contributes to neuroinflammation and neurodegenerative processes.
--- [@caspasemediated]
title: CASP4 Protein [@stress]
description: Protein page for Caspase-4 [@caspasea]
--- [@gasdermin]
<div class="infobox infobox-protein"> [@casp]
| | | [@caspaseb]
|---|---| [@therapeutic]
| Protein Name | Caspase-4 |
| Gene | [CASP4](/proteins/casp4-protein) |
| UniProt ID | [P49662](https://www.uniprot.org/uniprot/P49662) |
| PDB ID | 4E90, 5NBB |
| Molecular Weight | 45 kDa (proenzyme), 20+10 kDa (active form) |
| Subcellular Localization | Cytoplasm, ER membrane, mitochondria |
| Protein Family | Caspase family, inflammatory caspases (CASP1, CASP4, CASP5) |
| Expression | Broad, high in immune cells, CNS neurons and glia |
</div>
Overview
Mermaid diagram (expand to render)
Caspase-4 is an inflammatory caspase involved in both pyroptosis and endoplasmic reticulum (ER) stress responses. It mediates the innate immune response to intracellular LPS and contributes to neurodegeneration through inflammatory cell death pathways. Unlike CASP1 which requires inflammasome assembly, CASP4 can be directly activated by LPS binding and ER stress signals. It cleaves gasdermin D to execute pyroptosis, releasing inflammatory cytokines (IL-1beta, IL-18). CASP4 also contributes to ER stress-induced [apoptosis](/entities/apoptosis) through caspase-3 and caspase-7 activation.
Protein Structure
Domain Architecture
Caspase-4 contains the canonical caspase domain structure:
- Prodomain: Contains death effector domain (DED) for protein-protein interactions
- Large catalytic subunit (p20): Contains the active site cysteine residue (Cys287)
- Small catalytic subunit (p10): Completes the catalytic dimer
The active caspase-4 is a heterotetramer:
- Two p20 subunits
- Two p10 subunits
- Catalytic dyad: Cys287 and His237
Post-Translational Modifications
| Modification | Site | Functional Impact |
|--------------|------|-------------------|
| Phosphorylation | Ser277 | Regulatory |
| Ubiquitination | Multiple | Degradation |
| S-nitrosylation | Cys287 | Inhibition |
Normal Function
ER Stress Response
Caspase-4 is a key mediator of the [unfolded protein response](/entities/unfolded-protein-response) (UPR):
- Directly senses ER stress without inflammasome
- Activated by misfolded protein accumulation
- Triggers apoptosis via caspase-3 activation
- Relevant in protein aggregation diseases
Pyroptosis Execution
Inflammatory cell death pathway:
- Binds intracellular LPS directly
- Cleaves gasdermin D (GSDMD)
- N-terminal GSDMD forms pores
- Releases IL-1β and IL-18
- Causes cell swelling and lysis
Innate Immune Sensing
Cytosolic LPS receptor function:
- Responds to Gram-negative bacteria
- Links infection to inflammation
- May mediate [gut-brain axis](/entities/gut-brain-axis) effects
Expression in the CNS
Cell Type Distribution
| Cell Type | Expression | Activation State |
|-----------|------------|------------------|
| [Microglia](/cell-types/microglia) | High | Chronic activation in disease |
| [Neurons](/cell-types/neurons) | Moderate | Stress-induced |
| [Astrocytes](/cell-types/astrocytes) | Low | Injury-responsive |
| Oligodendrocytes | Low | Demyelination |
Role in Disease
Alzheimer's Disease
In [Alzheimer's disease](/diseases/alzheimers-disease):
- Elevated in [microglia](/entities/microglia) surrounding amyloid plaques
- Mediates neuroinflammation
- Contributes to ER stress in neurons
- Cleaves [amyloid precursor protein](/entities/app-protein) (APP)
- Therapeutic target for anti-inflammatory strategies
Parkinson's Disease
In [Parkinson's disease](/diseases/parkinsons-disease):
- Activated in substantia nigra
- Mediates dopaminergic neuron death
- Responds to [alpha-synuclein](/mechanisms/alpha-synuclein) aggregation
- Contributes to neuroinflammation
Amyotrophic Lateral Sclerosis
In [ALS](/diseases/amyotrophic-lateral-sclerosis):
- Activated in motor neurons
- Mediates inflammatory cascade
- Contributes to excitotoxicity
- Potential biomarker
Stroke and Ischemia
Following cerebral ischemia:
- Rapid activation in infarct region
- Mediates neuronal death
- [Blood-brain barrier](/entities/blood-brain-barrier) disruption
- Therapeutic target for neuroprotection
Inflammatory Bowel Disease
- Risk gene for IBD
- Mediates gut inflammation
- May affect CNS via gut-brain axis
Therapeutic Implications
Inhibitors
| Compound | Selectivity | Development Stage |
|----------|-------------|-------------------|
| Ac-LEHD-CHO | CASP4 > CASP1 | Research |
| Z-LEHD-FMK | CASP4 | Research |
| VX-765 | CASP1/4 | Clinical trials |
Biological Approaches
- Monoclonal antibodies targeting CASP4
- Gene silencing (siRNA, ASO)
- Peptide inhibitors
Drug Repurposing
- Existing anti-inflammatory drugs
- ER stress modulators
Antibodies
- Anti-CASP4 (active form)
- p20 subunit specific
- Phospho-Ser277
Mouse Models
- CASP4 knockout mice
- Conditional knockout in neurons/glia
- Transgenic overexpression
Assays
- Activity assays (fluorogenic substrates)
- Cleavage of GSDMD
- IL-1β release
See Also
- [Proteins Index](/proteins)
- [CASP4 Gene](/proteins/casp4-protein)
- [Caspase Family](/proteins/caspase-family)
- [Neuroinflammation Pathway](/mechanisms/neuroinflammation-pathway)
- [Apoptosis Pathway](/mechanisms/apoptosis-neurodegeneration)
- [ER Stress Pathway](/mechanisms/er-stress-pathway)
- [Pyroptosis Pathway](/mechanisms/pyroptosis-pathway)
- [Microglia](/cell-types/microglia)
Background
The study of Casp4 Protein 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.
External Links
- [UniProt - CASP4](https://www.uniprot.org/uniprot/P49662)
- [PDB - CASP4](https://www.rcsb.org/structure/4E90)
- [NCBI Protein - CASP4](https://www.ncbi.nlm.nih.gov/protein)
- [GeneCards - CASP4](https://www.genecards.org/cgi-bin/carddisp.pl?gene=CASP4)
References
[Unknown, - Caspase-4 in neuroinflammation and neurodegenerative diseases (n.d.)](https://pubmed.ncbi.nlm.nih.gov/25975241/)
[Unknown, - Caspase-4-mediated pyroptosis in Alzheimer's disease (n.d.)](https://pubmed.ncbi.nlm.nih.gov/32151251/)
[Unknown, - ER stress and caspase activation in Parkinson's disease (n.d.)](https://pubmed.ncbi.nlm.nih.gov/31782962/)
[Unknown, - Caspase-4 in microglia and neuroinflammation (n.d.)](https://pubmed.ncbi.nlm.nih.gov/31085174/)
[Unknown, - Gasdermin D cleavage by inflammatory caspases (n.d.)](https://pubmed.ncbi.nlm.nih.gov/32877918/)
[Unknown, - CASP4 structure and function (n.d.)](https://pubmed.ncbi.nlm.nih.gov/30677467/)
[Unknown, - Caspase-4 in stroke and ischemia (n.d.)](https://pubmed.ncbi.nlm.nih.gov/29518155/)
[Unknown, - Therapeutic targeting of CASP4 (n.d.)](https://pubmed.ncbi.nlm.nih.gov/34089021/)Pathway Diagram
The following diagram shows the key molecular relationships involving CASP4 Protein discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)