Naturally occurring genetic variants of human caspase-1 differ considerably in structure and the ability to activate interleukin-1β

LUKSCH H; ROMANOWSKI M J; CHARA O; TUENGLER V; CAFFARENA E R; HEYMANN M C; LOHSE P; AKSENTIJEVICH I; REMMERS E F; FLECKS S; QUOOS N; GRAMATTÉ J; PETZOLD C; HOFMANN S R; WINKLER S; PESSLER F; KALLINICH T; GANSER G; NIMTZ-TALASKA A; BAUMANN U; RUNDE V; GRIMBACHER B; BIRMELIN J; GAHR M; ROESLER J; RÖSEN-WOLFF A

HUMAN MUTATION

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: New York; Año: 2013 vol. 34 p. 122 - 131

1059-7794

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.