Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
Abstract
Caspase-1 (Interleukin-1 Converting Enzyme, ICE) is a proinflammatory enzyme that plays pivotal roles in innate immunity and many inflammatory conditions such as periodic fever syndromes and gout. Inflammation is often mediated by enzymatic activation of interleukin (IL)-1β and IL-18. We detected seven naturally occurring human CASP1 variants with different effects on protein structure, expression, and enzymatic activity. Most mutations destabilized the caspase-1 dimer interface as revealed by crystal structure analysis and homology modeling followed by molecular dynamics simulations. All variants demonstrated decreased or absent enzymatic and IL-1β releasing activity in vitro, in a cell transfection model, and as low as 25% of normal ex vivo in a whole blood assay of samples taken from subjects with variant CASP1, a subset of whom suffered from unclassified autoinflammation. We conclude that decreased enzymatic activity of caspase-1 is compatible with normal life and does not prevent moderate and severe autoinflammation.
Details
Original language | English |
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Pages (from-to) | 122-131 |
Number of pages | 10 |
Journal | Human Mutation |
Volume | 34 |
Issue number | 1 |
Publication status | Published - Jan 2013 |
Peer-reviewed | Yes |
External IDs
researchoutputwizard | legacy.publication#51543 |
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Scopus | 84871608014 |
PubMed | 22833538 |
ORCID | /0000-0003-3486-2824/work/151436573 |
Keywords
Keywords
- Autoinflammatory, Cytokine, Heterozygous, Homozygous, Procaspase, Rheumatic