CASP4 (Caspase-4) is a member of the cysteine-aspartic protease family that plays critical roles in inflammatory responses and cell death pathways. Originally characterized for its involvement in endoplasmic reticulum (ER) stress-induced [apoptosis](/entities/apoptosis) and pyroptosis, CASP4 has emerged as a key mediator in neuroinflammation and neurodegenerative diseases. Unlike caspase-1 which requires inflammasome assembly for activation, CASP4 can be directly activated by intracellular lipopolysaccharide (LPS) and ER stress signals, making it uniquely positioned to respond to cellular stress in [neurons](/entities/neurons) and glial cells.
--- [@neural]
title: CASP4 Gene [@kir]
description: Gene page for Caspase-4 [@katp]
--- [@atga]
<div class="infobox infobox-gene"> [@caspasemediated]
| | | [@stress]
|---|---| [@caspasea]
| Gene Symbol | CASP4 |
| Full Name | Caspase-4 |
| Chromosomal Location | 11q22.2 |
| NCBI Gene ID | [837](https://www.ncbi.nlm.nih.gov/gene/837) |
| OMIM | [602754](https://www.omim.org/entry/602754) |
| Ensembl ID | ENSG00000100994 |
| UniProt ID | [P49662](https://www.uniprot.org/uniprot/P49662) |
</div>
CASP4 (Caspase-4) is a member of the cysteine-aspartic protease family that plays critical roles in inflammatory responses and cell death pathways. Originally characterized for its involvement in endoplasmic reticulum (ER) stress-induced [apoptosis](/entities/apoptosis) and pyroptosis, CASP4 has emerged as a key mediator in neuroinflammation and neurodegenerative diseases. Unlike caspase-1 which requires inflammasome assembly for activation, CASP4 can be directly activated by intracellular lipopolysaccharide (LPS) and ER stress signals, making it uniquely positioned to respond to cellular stress in [neurons](/entities/neurons) and glial cells.
--- [@neural]
title: CASP4 Gene [@kir]
description: Gene page for Caspase-4 [@katp]
--- [@atga]
<div class="infobox infobox-gene"> [@caspasemediated]
| | | [@stress]
|---|---| [@caspasea]
| Gene Symbol | CASP4 |
| Full Name | Caspase-4 |
| Chromosomal Location | 11q22.2 |
| NCBI Gene ID | [837](https://www.ncbi.nlm.nih.gov/gene/837) |
| OMIM | [602754](https://www.omim.org/entry/602754) |
| Ensembl ID | ENSG00000100994 |
| UniProt ID | [P49662](https://www.uniprot.org/uniprot/P49662) |
</div>
Caspase-4 is an inflammatory caspase that executes pyroptotic cell death in response to intracellular LPS from Gram-negative bacteria and ER stress. It is predominantly expressed in immune cells, including [microglia](/cell-types/microglia), as well as in [neurons](/cell-types/neurons) and [astrocytes](/cell-types/astrocytes) within the central nervous system (CNS). CASP4 mediates both gasdermin D-dependent pyroptosis and caspase-3-dependent apoptosis, depending on the cellular context and stimulus. Its activation contributes to neuroinflammation through the release of pro-inflammatory cytokines and damage-associated molecular patterns (DAMPs).
Caspase-4 is a key mediator of the [unfolded protein response](/entities/unfolded-protein-response) (UPR) in the ER. Under conditions of ER stress, such as accumulation of misfolded proteins, CASP4 can be activated directly without inflammasome assembly. Activated CASP4 cleaves downstream executioner caspases, including caspase-3 and caspase-7, leading to apoptosis. In neurodegenerative diseases characterized by protein misfolding, such as Alzheimer's disease and Parkinson's disease, ER stress is a common pathological feature that triggers CASP4 activation.
Inflammatory caspases including CASP4 can execute pyroptotic cell death by cleaving gasdermin D. The N-terminal fragment of gasdermin D forms pores in the plasma membrane, leading to cell swelling, membrane rupture, and release of intracellular contents including interleukin-1β (IL-1β) and interleukin-18 (IL-18). This form of cell death is particularly relevant in [microglia](/entities/microglia), where excessive pyroptosis contributes to chronic neuroinflammation.
CASP4 directly binds to intracellular LPS from Gram-negative bacteria, serving as a cytosolic LPS sensor. This function links bacterial infection risk to inflammatory responses in the brain. Given the proposed role of gut microbiota in neurodegenerative diseases, CASP4 may mediate the effects of peripheral bacterial signals on CNS inflammation.
Caspase-4 contains the canonical caspase domain structure comprising:
CASP4 is upregulated in [Alzheimer's disease](/diseases/alzheimers-disease) brains, particularly in [microglia](/cell-types/microglia-neuroinflammation) surrounding [amyloid-beta](/proteins/amyloid-beta) plaques. Studies show that CASP4 mediates:
In [Parkinson's disease](/diseases/parkinsons-disease), CASP4 contributes to:
CASP4 is activated in [ALS](/diseases/amyotrophic-lateral-sclerosis) motor neurons and microglia:
Following cerebral ischemia, CASP4 is activated in neurons and contributes to:
As a risk gene for [inflammatory bowel disease](/diseases/inflammatory-bowel-disease), CASP4 mediates:
CASP4 represents a therapeutic target for neurodegenerative diseases:
CASP4 activity in cerebrospinal fluid (CSF) may serve as a biomarker for:
Current research focuses on:
The study of Casp4 Gene 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.
The following diagram shows the key molecular relationships involving CASP4 Gene discovered through SciDEX knowledge graph analysis: