Human procaspase-1 variants with decreased enzymatic activity are associated with febrile episodes and may contribute to inflammation via RIP2 and NF-κB signaling.
The proinflammatory enzyme caspase-1 plays an important role in the innate immune system and is involved in a variety of inflammatory conditions. Rare naturally occurring human variants of the caspase-1 gene (CASP1) lead to different protein expression and structure and to decreased or absent enzymatic activity. Paradoxically, a significant number of patients with such variants suffer from febrile episodes despite decreased IL-1β production and secretion. In this study, we investigate how variant (pro)caspase-1 can possibly contribute to inflammation. In a transfection model, such variant procaspase-1 binds receptor interacting protein kinase 2 (RIP2) via Caspase activation and recruitment domain (CARD)/CARD interaction and thereby activates NF-κB, whereas wild-type procaspase-1 reduces intracellular RIP2 levels by enzymatic cleavage and release into the supernatant. We approach the protein interactions by coimmunoprecipitation and confocal microscopy and show that NF-κB activation is inhibited by anti-RIP2-short hairpin RNA and by the expression of a RIP2 CARD-only protein. In conclusion, variant procaspase-1 binds RIP2 and thereby activates NF-κB. This pathway could possibly contribute to proinflammatory signaling.
Klinik und Poliklinik für Kinder- und Jugendmedizin, Medizinische Fakultät der Technischen Universität Dresden, 01307 Dresden, Germany;
Michael C
MC
Heymann
Stefan
S
Winkler
Hella
H
Luksch
Silvana
S
Flecks
Marcus
M
Franke
Susanne
S
Ruß
Seza
S
Ozen
Engin
E
Yilmaz
Christoph
C
Klein
Tilmann
T
Kallinich
Dirk
D
Lindemann
Sebastian
S
Brenner
Gerd
G
Ganser
Joachim
J
Roesler
Angela
A
Rösen-Wolff
Sigrun R
SR
Hofmann
D015153:Blotting, Western; D020170:Caspase 1 / Q000235:genetics* / Q000378:metabolism; D005334:Fever / Q000201:enzymology / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014161:Transduction, Genetic; D014162:Transfection
D016328:NF-kappa B; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D020170:Caspase 1