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

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. In- flammation 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.Fil: Luksch, Hella. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Romanowski, Michael J.. Sunesis Pharmaceuticals. Department of Structural Biology; Estados UnidosFil: Chara, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Technische Universitat Dresden. Center for Information Services and High-Performance Computing; AlemaniaFil: Tuengler, Victoria. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Caffarena, Ernesto Raúl. Escola Nacional de Saude Publica Sergio Arouca. Fundación Oswaldo Cruz; BrasilFil: Heymann, Michael C.. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Lohse, Peter. Ludwig-Maximilians-Universit; AlemaniaFil: Aksentijevich, Ivona. Inflammatory Disease Section; Estados UnidosFil: Remmers, Elaine F.. Inflammatory Disease Section; Estados UnidosFil: Flecks, Silvana. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Quoos, Nadine. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Gramatté, Johannes. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Petzold, Cathleen. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Hofmann, Sigrun R.. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Winkler, Stefan. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Pessler, Frank. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania. Helmholtz Centre for Infection Research; AlemaniaFil: Kallinich, Tilmann. Universität zu Berlin; AlemaniaFil: Ganser, Gerd. Sendenhorst. St. Josef-Stift; AlemaniaFil: Nimtz-Talaska, Antje. Kinderrheumatologie; AlemaniaFil: Baumann, Ulrich. Hannover Medical School; AlemaniaFil: Runde, Volker. Wilhelm-Anton-Hospital; AlemaniaFil: Grimbacher, Bodo. University Hospital Freiburg; AlemaniaFil: Birmelin, Jennifer. University Hospital Freiburg; AlemaniaFil: Gahr, Manfred. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Roesler, Joachim. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Rösen-Wolff, Angela. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemani