Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization.

Cell Death Differ 2006 Feb;13(2):236-49

Department of Microbiology and Immunology, Center for Apoptosis Research, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.

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.

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http://dx.doi.org/10.1038/sj.cdd.4401734DOI Listing
February 2006

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