CARD8 - Caspase Recruitment Domain Family Member 8

CARD8 - Caspase Recruitment Domain Family Member 8

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<div class="infobox">
| Property | Value |
|----------|-------|
| Symbol | CARD8 |
| Name | Caspase Recruitment Domain Family Member 8 |
| Chromosome | 19q13.33 |
| NCBI Gene ID | 8912 |
| OMIM | 609508 |
| Ensembl | ENSG00000105464 |
| UniProt | Q9Y2585 |
</div>

Overview

CARD8 (Caspase Recruitment Domain Family Member 8) is a critical regulator of the innate immune inflammasome complex. It functions as a key component of both the NLRP1 and NLRP3 inflammasome, cytosolic protein complexes that sense danger signals and activate inflammatory caspase cascades. Through its CARD domain, CARD8 interacts with caspase-1 to trigger the maturation of pro-inflammatory cytokines IL-1β and IL-18, and induces pyroptosis—a form of programmed cell death characterized by membrane pore formation and cell swelling[@johnson2023][@broz2010].

CARD8 - Caspase Recruitment Domain Family Member 8

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background: #f8f9fa;
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margin-left: 20px;
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<div class="infobox">
| Property | Value |
|----------|-------|
| Symbol | CARD8 |
| Name | Caspase Recruitment Domain Family Member 8 |
| Chromosome | 19q13.33 |
| NCBI Gene ID | 8912 |
| OMIM | 609508 |
| Ensembl | ENSG00000105464 |
| UniProt | Q9Y2585 |
</div>

Overview

CARD8 (Caspase Recruitment Domain Family Member 8) is a critical regulator of the innate immune inflammasome complex. It functions as a key component of both the NLRP1 and NLRP3 inflammasome, cytosolic protein complexes that sense danger signals and activate inflammatory caspase cascades. Through its CARD domain, CARD8 interacts with caspase-1 to trigger the maturation of pro-inflammatory cytokines IL-1β and IL-18, and induces pyroptosis—a form of programmed cell death characterized by membrane pore formation and cell swelling[@johnson2023][@broz2010].

In the central nervous system, CARD8 is expressed in [neurons](/entities/neurons), [astrocytes](/entities/astrocytes), and [microglia](/cell-types/microglia-neuroinflammation), where it participates in neuroinflammatory responses. Dysregulated CARD8 signaling contributes to chronic neuroinflammation, a hallmark of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)[@izzo2021][@younkin2023].

Molecular Structure and Function

The CARD8 protein (also known as CARDINAL or TUCAN) is a 541-amino acid protein encoded by the CARD8 gene located on chromosome 19q13.33. The protein contains multiple domains:

• CARD Domain: Located at the N-terminus, this domain mediates protein-protein interactions with other CARD-containing proteins, particularly caspases
• FIIND Domain: The function-to-find domain is required for the autoinflammatory processing of CARD8
• LRR Domain: The leucine-rich repeat domain is involved in pathogen sensing

Inflammasome Pathway

Disease Associations

Alzheimer's Disease

Multiple studies have demonstrated elevated CARD8 expression in AD brain tissue, particularly in regions affected by amyloid-β plaques and neurofibrillary tangles. The NLRP3 inflammasome is activated in AD microglia, and CARD8-mediated inflammasome activation contributes to chronic neuroinflammation and neuronal loss[@heneka2013][@okello2019].

Key mechanisms include:

• Amyloid-β induced activation: Aβ plaques trigger NLRP3 inflammasome assembly in microglia
• Tau pathology: CARD8 activation in tau transgenic mice accelerates pathology[@volpato2021]
• Cytokine release: IL-1β release promotes neuroinflammation and disrupts synaptic plasticity

Parkinson's Disease

CARD8 polymorphisms have been associated with increased PD susceptibility. In dopaminergic neurons, inflammasome activation leads to pyroptotic cell death, contributing to the progressive loss of [neurons in the substantia nigra](/brain-regions/substantia-nigra)[@song2021][@balasus2020].

Mechanisms include:

• α-Synuclein aggregation: Misfolded α-synuclein activates the NLRP3 inflammasome
• Microglial activation: Chronic activation of microglia through CARD8 signaling
• Dopaminergic vulnerability: Inflammasome-mediated death of dopaminergic neurons[@liu2022]

Amyotrophic Lateral Sclerosis

In ALS, CARD8 activation in microglia and astrocytes promotes neuroinflammation that exacerbates motor neuron degeneration. Some studies suggest CARD8 variants may modify disease progression[@greten2017][@prokop2023].

Therapeutic Implications

Targeting CARD8 inflammasome activity represents a promising therapeutic strategy for neurodegenerative diseases[@fernandez2020][@schmidt2022]:

| Therapeutic Approach | Target | Status |
|---------------------|--------|--------|
| NLRP3 Inhibitors | MCC950, Dapansutrile | Phase 2 trials for AD/PD |
| IL-1β Antibodies | Canakinumab | Being tested for neuroprotection |
| CARD8 Peptide Inhibitors | Blocking CARD-CARD interactions | Preclinical |
| Gene Therapy | CRISPR-based knockdowns | Experimental |

Expression Pattern

CARD8 is widely expressed throughout the body, with high expression in immune tissues including spleen, thymus, and bone marrow. In the brain, it is expressed in neurons, astrocytes, and microglia, with elevated expression in regions susceptible to neurodegenerative processes including the hippocampus and substantia nigra[@maurer2020].

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [NLRP3 Inflammasome](/entities/nlrp3-inflammasome)
• [Neuroinflammation](/mechanisms/neuroinflammation)
• [Microglia](/cell-types/microglia-neuroinflammation)
• [Pyroptosis](/mechanisms/pyroptosis)

External Links

• [NCBI Gene: CARD8](https://www.ncbi.nlm.nih.gov/gene/8912)
• [UniProt: Q9Y2585](https://www.uniprot.org/uniprot/Q9Y2585)
• [Ensembl: ENSG00000105464](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000105464)
• [OMIM: 609508](https://www.omim.org/entry/609508)

Pathway Diagram

The following diagram shows the key molecular relationships involving CARD8 - Caspase Recruitment Domain Family Member 8 discovered through SciDEX knowledge graph analysis: