Inflammasome activator

Nevit Dilmen / Wikimedia Commons

The paper: S. Mariathasan et al., "Cryopyrin activates the inflammasome in response to toxins and ATP," Nature, 440:228-32, 2006. (Cited in 121 papers)

The finding: By observing mice deficient in the adaptor protein cryopyrin, Vishva Dixit of Genentech and his colleagues discovered cryopyrin's role in activating the inflammasome, a complex of proteins essential for the innate immune response. Cryopyrin, also known as NALP3, causes the release of the cytokines interleukin (IL)-1β and IL-18.

The significance: Mutations in cryopyrin/NALP3 were known to be associated with autoinflammatory diseases characterized by the excessive production of IL-1β. "We knew NALP3 was really important," says Emma Creagh of Trinity College in Dublin, "but we didn't know exactly how." Dixit's findings identified a critical step.

The question: "We don't know what resides between membrane disruption and activation [of the inflammasome] by cryopyrin," says Dixit. Several groups are trying to answer that question. Richard Flavell of Yale University suggests one possibility: The efflux of potassium that accompanies membrane disruption might activate cryopyrin, but the mechanism is not yet known.

The next step: Jurg Tschopp of the University of Lausanne, Switzerland, is looking into the roles of 13 other NALP proteins that have been implicated in diseases. "There is no other protein family that I know of that has so many links to diseases," says Tschopp.