| Caspase-1 | |
|---|---|
| Protein Name | Caspase-1 (ICE, Interleukin-1β Converting Enzyme) |
| Gene | CASP1 |
| UniProt ID | P29466 |
| PDB IDs | 1ICE, 1BMQ, 1RWK, 2H48, 6CL0 |
| Molecular Weight | ~45.2 kDa (zymogen); ~20 kDa (p20) + ~10 kDa (p10) active |
| Subcellular Localization | Cytoplasm; recruited to inflammasome complexes |
| Protein Family | Cysteine-aspartate protease (caspase) family, inflammatory caspase subfamily |
| EC Number | 3.4.22.36 |
Caspase-1 (formerly known as interleukin-1β converting enzyme, ICE) is the founding member of the inflammatory caspase subfamily and a central effector of innate immunity in the central nervous system[1]. Unlike apoptotic caspases (e.g., caspase-9, caspase-3), caspase-1 does not directly participate in programmed cell death via the classical apoptotic pathway. Instead, it serves as the proteolytic engine of inflammasome complexes, cleaving pro-IL-1β and pro-IL-18 into their biologically active forms and processing gasdermin D (GSDMD) to trigger pyroptosis — an inflammatory form of regulated cell death[2].
In the brain, caspase-1 is predominantly expressed in microglia and astrocytes, with induced expression in neurons under pathological conditions. Its activation is a convergence point for multiple danger signals in neurodegeneration, including amyloid-β aggregates, α-synuclein fibrils, oxidized mitochondrial DNA, and extracellular ATP signaling through the P2X7 receptor[3]. Chronic caspase-1 activation is now recognized as a key driver of the sustained neuroinflammation observed in Alzheimer's disease, Parkinson's disease, ALS, and multiple sclerosis[4].
Caspase-1 is synthesized as a 404-amino-acid zymogen (pro-caspase-1) with the following domain architecture:
Mature caspase-1 functions as a dimer of p20/p10 heterodimers, forming a (p20/p10)₂ complex. The crystal structure (PDB: 1ICE) reveals a compact globular fold with four β-sheets forming a central core. The two active sites are oriented on the same face of the molecule, with substrate binding grooves defining the strict preference for aspartate at the P1 position[6].
Caspase-1 employs a cysteine protease mechanism:
The preferred recognition sequence is WEHD↓ (Trp-Glu-His-Asp), distinguishing it from apoptotic caspases which prefer DEVD (caspase-3) or LEHD (caspase-9)[7].
The canonical function of caspase-1 is the proteolytic processing of inflammatory cytokine precursors:
Caspase-1 cleaves gasdermin D (GSDMD) at D275, releasing the N-terminal domain (GSDMD-NT) which oligomerizes in the plasma membrane to form 10–20 nm pores. These pores:
Beyond pyroptosis, caspase-1-generated GSDMD pores serve as conduits for unconventional secretion of leaderless cytoplasmic proteins, representing a regulated secretory pathway independent of the ER-Golgi apparatus[10].
The NLRP3 inflammasome is the most extensively studied caspase-1 activation platform in neurodegeneration:
Caspase-1 activation is a central mechanism linking amyloid pathology to tau pathology and neurodegeneration:
| Compound | Type | Stage | Notes |
|---|---|---|---|
| VX-765 (Belnacasan) | Prodrug → VRT-043198 (active) | Phase II (epilepsy) | Orally bioavailable, BBB-penetrant; shown neuroprotective in AD and PD mouse models |
| VX-740 (Pralnacasan) | Reversible inhibitor | Phase II (RA, discontinued) | Limited CNS penetration |
| Ac-YVAD-CMK | Irreversible peptide inhibitor | Research tool | Not drug-like |
| z-VAD-FMK | Pan-caspase inhibitor | Research tool | Non-selective |
| MCC950 (CRID3) | NLRP3 inhibitor (indirect) | Phase II (multiple) | Blocks upstream of caspase-1 activation |
| Dapansutrile (OLT1177) | NLRP3 inhibitor | Phase II (gout) | Oral, anti-inflammatory |
VX-765 is the most advanced caspase-1 inhibitor with CNS activity, demonstrating efficacy in APP/PS1 and MPTP mouse models[18].
Bhatt DK, et al. Identification and characterization of ICE (interleukin-1β converting enzyme). Cell. 1992. ↩︎
Shi J, Bhatt DK, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015. ↩︎
Heneka MT, Bhatt DK, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurology. 2015. ↩︎
Voet S, Bhatt DK, et al. Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Molecular Medicine. 2019. ↩︎
Walker NPC, Bhatt DK, et al. Crystal structure of the cysteine protease interleukin-1β converting enzyme. Cell. 1994. ↩︎
Wilson KP, Bhatt DK, et al. Structure and mechanism of interleukin-1β converting enzyme. Nature. 1994. ↩︎
Thornberry NA, Bhatt DK, et al. A combinatorial approach defines specificities of members of the caspase family. Journal of Biological Chemistry. 1997. ↩︎
Bhatt DK, et al. Interleukin-1β maturation and release by caspase-1. EMBO Journal. 1994. ↩︎
Ding J, Bhatt DK, et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 2016. ↩︎
Bhatt DK, et al. Unconventional protein secretion via GSDMD pores. Nature. 2018. ↩︎
Swanson KV, Bhatt DK, et al. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nature Reviews Immunology. 2019. ↩︎
Bhatt DK, et al. Inflammasomes: mechanism of assembly, regulation and signalling. Nature Reviews Immunology. 2016. ↩︎
Heneka MT, Bhatt DK, et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013. ↩︎
Venegas C, Bhatt DK, et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease. Nature. 2017. ↩︎
Bhatt DK, et al. Tau cleavage by caspases in neurodegenerative disease. Cell Death & Disease. 2011. ↩︎
Gordon R, Bhatt DK, et al. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Science Translational Medicine. 2018. ↩︎
Zhao W, Bhatt DK, et al. TDP-43 activates microglia through NF-κB and NLRP3 inflammasome. Experimental Neurology. 2015. ↩︎
Flores J, Bhatt DK, et al. Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model. Nature Communications. 2018. ↩︎
Dhimolea E, Bhatt DK. Canakinumab for the treatment of inflammation. Drugs of Today. 2010. ↩︎