Recent studies have identified a family of cytosolic proteins (named NODs) that has been implicated in the detection of bacterial components in the cytosol. NOD family members including NOD1, NOD2 and Cryopyrin contain remarkable structural homology to plant disease-resistance gene products that mediate protective immunity against invading pathogens. Two members of the NOD protein family, NOD1 and NOD2, detect conserved structures derived from bacterial peptidoglycan and upon activation activate NF-KB leading to the secretion of pro-inflammatory cytokines/chemokines. Mutations of NOD2 are associated with Crohn's disease and Blau syndrome, two diseases characterized by granulomatous inflamamation. Genetic studies have shown that missense mutations of Cryopyrin cause the autoinflammatory disorders familial cold autoinflammatory syndrome (FACS), Muckle-Wells syndrome (MWS), and neonatal-onset multiple-system inflammatory disease (NOMID). Although most of these diseases are rare, understanding of their pathogenesis may provide critical insight into the mechanisms mediating inflammation and innate immunity. Recent work from several laboratories including our own suggest that Cryopyrin is involved in the regulation of IL-1B secretion, NF-KB activation and apoptosis through its interaction with the adaptor molecule ASC. We have obtained evidence that Cryopyrin mutations found in patients with autoinflammatory disease function as activating mutations in that they induce increased NF-KB activity and IL-1B secretion when compared to the wild-type protein. Furthermore, we find that pyrin, the product of familial fever (FMF), another inherited autoinflammatory disorder, negatively regulates Cryopyrin/ASC signaling by inhibiting the interaction between Cryopyrin and ASC. Thus, we hypothesize that several of the autoinflammatory diseases may be caused by dysregulation of the Cryopyrin/ASC signaling pathway.
The aim of this proposal is to provide a better understanding of the molecular mechanisms and physiological role of Cryopyrin in responses to inflammatory stimuli and infectious agents. Biochemical, genetic, and cellular approaches will be employed for gaining a better understanding of the function and signaling pathway mediated by Cryopyrin. The studies proposed may provide novel insight into the physiological role and regulation of the Cryopyring signaling pathway and into the pathogenesis of autoinflammatory disorders.
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