Human procaspase-1 variants with decreased enzymatic activity are associated with febrile episodes and may contribute to inflammation via RIP2 and NF-κB signaling.

Abstract

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.

• Authors: Michael C Heymann, Stefan Winkler, Hella Luksch, Silvana Flecks, Marcus Franke, Susanne Ruß, Seza Ozen, Engin Yilmaz, Christoph Klein, Tilmann Kallinich, Dirk Lindemann, Sebastian Brenner, Gerd Ganser, Joachim Roesler, Angela Rösen-Wolff, Sigrun R Hofmann
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 9 Pg. 4379-85 (May 01 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24706726 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• RIPK2 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinase 2
• Caspase 1

Topics

• Blotting, Western
• Caspase 1 (genetics, metabolism)
• Fever (enzymology, genetics)
• Fluorescent Antibody Technique
• Gene Knockdown Techniques
• Genetic Variation
• HEK293 Cells
• Humans
• Immunoprecipitation
• Inflammation (genetics, immunology, metabolism)
• NF-kappa B (metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinase 2 (metabolism)
• Signal Transduction (physiology)
• Transduction, Genetic
• Transfection