CASP4 Gene

CASP4 Gene

Introduction

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>

Overview

CASP4 Gene

Introduction

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>

Overview

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).

Normal Function

ER Stress Response

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.

Pyroptosis Execution

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.

Innate Immune Sensing

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.

Protein Structure

Caspase-4 contains the canonical caspase domain structure comprising:

• Prodomain: Long prodomain containing death effector domain (DED) for protein-protein interactions
• Large catalytic subunit (p20): Contains the active site cysteine residue
• Small catalytic subunit (p10): Completes the catalytic dimer

Disease Associations

Alzheimer's Disease

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:

• Microglial pyroptosis in response to amyloid-beta
• ER stress-induced neuronal apoptosis
• Inflammatory cytokine release contributing to chronic neuroinflammation

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), CASP4 contributes to:

• Dopaminergic neuron death through ER stress pathways
• Microglial activation and neuroinflammation
• [Alpha-synuclein](/proteins/alpha-synuclein)-induced toxicity

Amyotrophic Lateral Sclerosis

CASP4 is activated in [ALS](/diseases/amyotrophic-lateral-sclerosis) motor neurons and microglia:

• Mediates inflammatory caspase activation in motor neuron degeneration
• Contributes to excitotoxicity-induced cell death
• Participates in the inflammatory response surrounding motor neurons

Stroke and Ischemia

Following cerebral ischemia, CASP4 is activated in neurons and contributes to:

• Ischemic neuronal death through ER stress pathways
• Inflammatory response in the infarct region
• [Blood-brain barrier](/entities/blood-brain-barrier) disruption

Inflammatory Bowel Disease

As a risk gene for [inflammatory bowel disease](/diseases/inflammatory-bowel-disease), CASP4 mediates:

• Gut epithelial cell death
• Inflammatory responses to intestinal microbiota
• Potential [gut-brain axis](/entities/gut-brain-axis) signaling affecting CNS inflammation

Therapeutic Implications

Drug Development

CASP4 represents a therapeutic target for neurodegenerative diseases:

• Small molecule inhibitors: Several CASP4-selective inhibitors are in development
• Natural compounds: Certain flavonoids and polyphenols show CASP4 inhibitory activity
• Gene therapy approaches: RNA interference targeting CASP4 expression

Biomarker Potential

CASP4 activity in cerebrospinal fluid (CSF) may serve as a biomarker for:

• Disease progression in Alzheimer's disease
• Neuroinflammatory status in Parkinson's disease
• Treatment response to anti-inflammatory therapies

Research Directions

Current research focuses on:

• Developing CASP4-selective inhibitors with brain penetration
• Understanding cell-type specific roles of CASP4 in the CNS
• Exploring the gut-brain axis connection via CASP4
• Identifying genetic variants that modify disease risk

See Also

• [Genes Index](/genes)
• [Proteins Index](/proteins)
• [Neuroinflammation Pathway](/mechanisms/neuroinflammation-pathway)
• [Apoptosis Pathway](/mechanisms/apoptosis-neurodegeneration)
• [ER Stress Pathway](/mechanisms/er-stress-pathway)
• [Microglia](/cell-types/microglia)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

Background

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.

External Links

• [NCBI Gene - CASP4](https://www.ncbi.nlm.nih.gov/gene/837)
• [UniProt - CASP4](https://www.uniprot.org/uniprot/P49662)
• [GeneCards - CASP4](https://www.genecards.org/cgi-bin/carddisp.pl?gene=CASP4)
• [OMIM - CASP4](https://www.omim.org/entry/602754)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving CASP4 Gene discovered through SciDEX knowledge graph analysis: