Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β

Authors


  • Communicated by David N. Cooper

  • Contract grant sponsors: German Research Foundation (DFG, KFO 249, TP1, RO/471-11 and TP2, HO 4510/1-1); Federal Ministry of Education and Research (PID-NET, Project A4); Medical faculty of the University of Technology Dresden, MeDDrive33 (08/09): 60.153 to S.W., Germany; Marie Curie International Reintegration Grant, # 224894 to F.P., European Union.

Correspondence to: Joachim Roesler, Department of Pediatrics, University Medical Center Carl Gustav Carus, Fetscherstr. 74, 01307 Dresden, Germany. E-mail: Roeslerj@rcs.urz.tu-dresden.de

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.

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