Human Procaspase-1 Variants with Decreased Enzymatic Activity Are Associated with Febrile Episodes and May Contribute to Inflammation via RIP2 and NF-kB Signaling


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Heymann M. C., Winkler S., Luksch H., Flecks S., Franke M., Russ S., ...More

JOURNAL OF IMMUNOLOGY, vol.192, no.9, pp.4379-4385, 2014 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 192 Issue: 9
  • Publication Date: 2014
  • Doi Number: 10.4049/jimmunol.1203524
  • Journal Name: JOURNAL OF IMMUNOLOGY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.4379-4385
  • Hacettepe University Affiliated: Yes

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-1 beta 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-kB, 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-kB 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-kB. This pathway could possibly contribute to proinflammatory signaling.