Caspase-1 (CASP1)

Caspase-1 (CASP1)

<div class="infobox">
<h3>Caspase-1</h3>
<table>
<tr><td><strong>UniProt ID</strong></td><td>[P29466](https://www.uniprot.org/uniprot/P29466)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>45 kDa (pro-form), 20/10 kDa (cleaved subunits)</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cytosol, inflammasome complex</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>1BMF, 1SC1, 6VHZ</td></tr>
<tr><td><strong>Gene</strong></td><td>[CASP1](/entities/casp1)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

Inflammatory caspase-1, processes pro-IL-1beta and pro-IL-18, mediates pyroptosis via gasdermin D cleavage.

Normal Function

Caspase-1 (CASP1)

<div class="infobox">
<h3>Caspase-1</h3>
<table>
<tr><td><strong>UniProt ID</strong></td><td>[P29466](https://www.uniprot.org/uniprot/P29466)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>45 kDa (pro-form), 20/10 kDa (cleaved subunits)</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cytosol, inflammasome complex</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>1BMF, 1SC1, 6VHZ</td></tr>
<tr><td><strong>Gene</strong></td><td>[CASP1](/entities/casp1)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

Inflammatory caspase-1, processes pro-IL-1beta and pro-IL-18, mediates pyroptosis via gasdermin D cleavage.

Normal Function

Caspase-1 (interleukin-1β-converting enzyme, ICE) is the prototypical inflammatory caspase, playing a central role in innate immunity and inflammatory cell death (pyroptosis):

Structure and Activation

• Synthesized as inactive 45 kDa pro-enzyme
• Activated within multiprotein inflammasome complexes
• Canonical inflammasomes: NLRP3, NLRP1, NLRC4, AIM2, Pyrin
• Pro-caspase-1 recruited via CARD-CARD interactions
• Auto-cleavage generates p20/p10 heterodimer[@martinon2009]

• Pro-IL-1β (31 kDa) → mature IL-1β (17 kDa)
• Pro-IL-18 (24 kDa) → mature IL-18 (18 kDa)
• Gasdermin D (53 kDa) → N-terminal fragment (31 kDa) + C-terminal fragment (22 kDa)
• N-terminal fragment forms membrane pores → pyroptosis
• IL-33: Processed to active form (context-dependent)

Physiological Functions

• Host defense against bacterial, viral, fungal pathogens
• Clearance of damaged cells via pyroptosis
• Coordination of inflammatory responses
• Tissue repair and regeneration

Role in Neurodegeneration

Caspase-1 activation and inflammasome signaling contribute to neurodegeneration across multiple disorders:

Alzheimer's Disease

• [NLRP3 inflammasome](/entities/nlrp3-inflammasome) activated by [Aβ](/proteins/amyloid-beta) aggregates
• Active caspase-1 detected in [microglia](/cell-types/microglia-neuroinflammation) surrounding plaques
• IL-1β and IL-18 promote neuroinflammation and synaptic dysfunction
• Caspase-1-mediated pyroptosis releases DAMPs, amplifying inflammation
• Genetic ablation of Nlrp3 or Casp1 reduces pathology in AD models[@heneka2013]

• [α-synuclein](/proteins/alpha-synuclein) fibrils activate NLRP3 inflammasome in microglia
• Dopaminergic neuron death exacerbated by caspase-1/IL-1β axis
• MPTP models show inflammasome activation
• IL-1 receptor antagonist reduces neurodegeneration[@gordon2018]

• Caspase-1 upregulated in active MS lesions
• IL-1β and IL-18 contribute to demyelination
• Experimental autoimmune encephalomyelitis (EAE) attenuated in Casp1⁻/⁻ mice
• IL-18 drives Th1/Th17 responses

• Rapid NLRP3 inflammasome activation post-ischemia
• Caspase-1-dependent pyroptosis contributes to infarct expansion
• IL-1β exacerbates [blood-brain barrier](/entities/blood-brain-barrier) disruption
• Early caspase-1 inhibition reduces infarct size[@fann2018]

• Mechanical damage triggers inflammasome activation
• Caspase-1 and IL-1β elevated in CSF after TBI
• Chronic neuroinflammation perpetuates secondary injury
• Potential therapeutic window for inflammasome inhibitors

• Caspase-1 activation in SOD1 mutant models
• IL-1β contributes to motor neuron death
• Inflammasome components upregulated in ALS spinal cord[@johann2015]

Therapeutic Targeting

Caspase-1 and inflammasome targeting strategies in neurodegeneration:

Direct Caspase-1 Inhibitors

• VX-765 (belnacasan): Oral prodrug of VRT-043198; entered Phase II for epilepsy and psoriasis; good safety profile; brain penetration limited
• Emricasan: Pan-caspase inhibitor with caspase-1 activity; trials in liver disease
• Pralnacasan: Discontinued due to toxicity concerns in animal studies[@wannamaker2007]

• MCC950/CRID3: Potent NLRP3 inhibitor; blocks inflammasome assembly; neuroprotective in AD, PD, MS models
• OLT1177 (dapansutrile): NLRP3 inhibitor; Phase II trials for heart failure
• Tranilast: Repurposed drug with NLRP3 inhibitory activity

• IL-1 receptor antagonist (anakinra): Approved for RA; repurposing in stroke, AD trials
• Canakinumab: Anti-IL-1β antibody; reduced lung cancer in CANTOS trial
• IL-18 binding protein: Neutralizes IL-18; in trials for inflammatory conditions[@dinarello2013]

• Inhibit pore formation (necrosulfonamide analogs)
• Block caspase-1 cleavage of GSDMD
• Maintain IL-1β processing while preventing pyroptosis

• Maintaining host defense while inhibiting inflammation
• Timing: Chronic vs. acute inhibition
• CNS penetration for many compounds limited
• Need for biomarker-guided patient selection

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

• [UniProt: P29466](https://www.uniprot.org/uniprot/P29466)
• [PDB structures](https://www.rcsb.org/search?q=uniprot:P29466)

References