title: Naturally occurring genetic variants of human caspase-1 differ considerably in structure and the ability to activate interleukin-1β.
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.
authors: Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany.
authors: Hella
authors: H
authors: Luksch
authors: Michael J
authors: MJ
authors: Romanowski
authors: Osvaldo
authors: O
authors: Chara
authors: Victoria
authors: V
authors: Tüngler
authors: Ernesto R
authors: ER
authors: Caffarena
authors: Michael C
authors: MC
authors: Heymann
authors: Peter
authors: P
authors: Lohse
authors: Ivona
authors: I
authors: Aksentijevich
authors: Elaine F
authors: EF
authors: Remmers
authors: Silvana
authors: S
authors: Flecks
authors: Nadine
authors: N
authors: Quoos
authors: Johannes
authors: J
authors: Gramatté
authors: Cathleen
authors: C
authors: Petzold
authors: Sigrun R
authors: SR
authors: Hofmann
authors: Stefan
authors: S
authors: Winkler
authors: Frank
authors: F
authors: Pessler
authors: Tilmann
authors: T
authors: Kallinich
authors: Gerd
authors: G
authors: Ganser
authors: Antje
authors: A
authors: Nimtz-Talaska
authors: Ulrich
authors: U
authors: Baumann
authors: Volker
authors: V
authors: Runde
authors: Bodo
authors: B
authors: Grimbacher
authors: Jennifer
authors: J
authors: Birmelin
authors: Manfred
authors: M
authors: Gahr
authors: Joachim
authors: J
authors: Roesler
authors: Angela
authors: A
authors: Rösen-Wolff
mesh_terms: D055162:Biocatalysis; D020170:Caspase 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D020170:Caspase 1