1. Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization.
- Author
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Yu JW, Wu J, Zhang Z, Datta P, Ibrahimi I, Taniguchi S, Sagara J, Fernandes-Alnemri T, and Alnemri ES
- Subjects
- Baculoviridae, CARD Signaling Adaptor Proteins, Carrier Proteins genetics, Caspase 1 genetics, Cell Line, Cytoskeletal Proteins chemistry, Cytoskeletal Proteins genetics, Enzyme Activation, Gene Expression Regulation, Humans, Immunoprecipitation, Inflammation genetics, Inflammation physiopathology, Microscopy, Confocal, Mutation, NF-kappa B genetics, NLR Family, Pyrin Domain-Containing 3 Protein, Protein Structure, Tertiary, Pyrin, Carrier Proteins physiology, Caspase 1 metabolism, Cytoskeletal Proteins physiology, NF-kappa B physiology
- Abstract
Mutations in cryopyrin and pyrin proteins are responsible for several autoinflammatory disorders in humans, suggesting that these proteins play important roles in regulating inflammation. Using a HEK293 cell-based reconstitution system that stably expresses ASC and procaspase-1 we demonstrated that neither cryopyrin nor pyrin or their corresponding disease-associated mutants could significantly activate NF-kappaB in this system. However, both cryopyrin and two disease-associated cryopyrin mutants induced ASC oligomerization and ASC-dependent caspase-1 activation, with the disease-associated mutants being more potent than the wild-type (WT) cryopyrin, because of increased self-oligomerization. Contrary to the proposed anti-inflammatory activity of WT pyrin, our results demonstrated that pyrin, like cryopyrin, can also assemble an inflammasome complex with ASC and procaspase-1 leading to ASC oligomerization, caspase-1 activation and interleukin-1beta processing. Thus, we propose that pyrin could function as a proinflammatory molecule.
- Published
- 2006
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