Journal
JOURNAL OF IMMUNOLOGY
Volume 192, Issue 9, Pages 4379-4385Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1203524
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Funding
- German Research Foundation (Deutsche Forschungs-gemeinschaft) [KFO249, TP1, RO/471-11, TP2, HO 4510/1-1]
- Federal Ministry of Education and Research (PID-NET)
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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.
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