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 and glial cells where it contributes to neuroinflammation and neurodegenerative processes.
| Protein Name | Caspase-4 |
| Gene | CASP4 |
| UniProt ID | 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 |
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-1β, IL-18). CASP4 also contributes to ER stress-induced apoptosis through caspase-3 and caspase-7 activation.
Caspase-4 contains the canonical caspase domain structure:
The active caspase-4 is a heterotetramer:
| Modification | Site | Functional Impact |
|---|---|---|
| Phosphorylation | Ser277 | Regulatory |
| Ubiquitination | Multiple | Degradation |
| S-nitrosylation | Cys287 | Inhibition |
Caspase-4 is a key mediator of the unfolded protein response (UPR):
Inflammatory cell death pathway:
Cytosolic LPS receptor function:
| Cell Type | Expression | Activation State |
|---|---|---|
| Microglia | High | Chronic activation in disease |
| Neurons | Moderate | Stress-induced |
| Astrocytes | Low | Injury-responsive |
| Oligodendrocytes | Low | Demyelination |
In ALS:
Following cerebral ischemia:
| Compound | Selectivity | Development Stage |
|---|---|---|
| Ac-LEHD-CHO | CASP4 > CASP1 | Research |
| Z-LEHD-FMK | CASP4 | Research |
| VX-765 | CASP1/4 | Clinical trials |
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.