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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Hella Luksch - , Department of Paediatrics, University Hospital Carl Gustav Carus Dresden (Author)
  • Michael J. Romanowski - , Sunesis Pharmaceuticals, Novartis USA (Author)
  • Osvaldo Chara - , Center for Information Services and High Performance Computing (ZIH), National Scientific and Technical Research Council Argentina (CONICET) (Author)
  • Victoria Tüngler - , Department of Paediatrics, Division of Neuropediatrics (Author)
  • Ernesto R. Caffarena - , Fundação Oswaldo Cruz (Author)
  • Michael C. Heymann - , TUD Dresden University of Technology (Author)
  • Peter Lohse - , Ludwig Maximilian University of Munich (Author)
  • Ivona Aksentijevich - , National Institutes of Health (NIH) (Author)
  • Elaine F. Remmers - , National Institutes of Health (NIH) (Author)
  • Silvana Flecks - , Department of Paediatrics, University Hospital Carl Gustav Carus Dresden (Author)
  • Nadine Quoos - , TUD Dresden University of Technology (Author)
  • Johannes Gramatté - , TUD Dresden University of Technology (Author)
  • Cathleen Petzold - , Chair of Molecular and Cellular Immunology - focus Immunoregulation, University Hospital Carl Gustav Carus Dresden (Author)
  • Sigrun R. Hofmann - , Department of Paediatrics, University Hospital Carl Gustav Carus Dresden (Author)
  • Stefan Winkler - , Department of Paediatrics, University Hospital Carl Gustav Carus Dresden (Author)
  • Frank Pessler - , TUD Dresden University of Technology, Helmholtz Centre for Infection Research (Author)
  • Tilmann Kallinich - , Charité – Universitätsmedizin Berlin (Author)
  • Gerd Ganser - , St.-Josef-Stift Sendenhorst (Author)
  • Antje Nimtz-Talaska - , Kinderrheumatologie (Author)
  • Ulrich Baumann - , Hannover Medical School (MHH) (Author)
  • Volker Runde - , Wilhelm-Anton-Hospital (Author)
  • Bodo Grimbacher - , University of Freiburg (Author)
  • Jennifer Birmelin - , University of Freiburg (Author)
  • Manfred Gahr - , TUD Dresden University of Technology (Author)
  • Joachim Roesler - , TUD Dresden University of Technology (Author)
  • Angela Rösen-Wolff - , Department of Paediatrics, University Hospital Carl Gustav Carus Dresden (Author)

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 languageEnglish
Pages (from-to)122-131
Number of pages10
JournalHuman Mutation
Volume34
Issue number1
Publication statusPublished - Jan 2013
Peer-reviewedYes

External IDs

researchoutputwizard legacy.publication#51543
Scopus 84871608014
PubMed 22833538
ORCID /0000-0003-3486-2824/work/151436573

Keywords

Keywords

  • Autoinflammatory, Cytokine, Heterozygous, Homozygous, Procaspase, Rheumatic