| UniProt ID | [P29466](https://www.uniprot.org/uniprot/P29466) |
| Molecular Weight | 45 kDa (pro-form), 20/10 kDa (cleaved subunits) |
| Subcellular Localization | Cytosol, inflammasome complex |
| PDB Structures | 1BMF, 1SC1, 6VHZ |
| Gene | [CASP1](/entities/casp1) |
Inflammatory caspase-1, processes pro-IL-1β and pro-IL-18, mediates pyroptosis via gasdermin D cleavage.
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
Canonical Substrates
- 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)
Inflammasome Assembly
- Priming signal: TLR/NF-κB activation upregulates NLRP3 and pro-IL-1β
- Activation signal: DAMPs, PAMPs trigger inflammasome assembly
- Complex formation: NLRP3 → ASC → pro-caspase-1
- Caspase-1 activation: Auto-cleavage within complex
Physiological Functions
- Host defense against bacterial, viral, fungal pathogens
- Clearance of damaged cells via pyroptosis
- Coordination of inflammatory responses
- Tissue repair and regeneration
Caspase-1 activation and inflammasome signaling contribute to neurodegeneration across multiple disorders:
Alzheimer's Disease
- NLRP3 inflammasome activated by Aβ aggregates
- Active caspase-1 detected in microglia 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
Parkinson's Disease
- α-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
Multiple Sclerosis
- 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
Stroke and Ischemia
- Rapid NLRP3 inflammasome activation post-ischemia
- Caspase-1-dependent pyroptosis contributes to infarct expansion
- IL-1β exacerbates blood-brain barrier disruption
- Early caspase-1 inhibition reduces infarct size
Traumatic Brain Injury
- 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
ALS
- Caspase-1 activation in SOD1 mutant models
- IL-1β contributes to motor neuron death
- Inflammasome components upregulated in ALS spinal cord
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
Inflammasome Inhibitors
- 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
Downstream Targeting
- 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
Gasdermin D Targeting
- Inhibit pore formation (necrosulfonamide analogs)
- Block caspase-1 cleavage of GSDMD
- Maintain IL-1β processing while preventing pyroptosis
Challenges
- Maintaining host defense while inhibiting inflammation
- Timing: Chronic vs. acute inhibition
- CNS penetration for many compounds limited
- Need for biomarker-guided patient selection