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Fire and ICE: The role of pyrin domain-containing proteins in inflammation and apoptosis

D.L. Gumucio¹, A. Diaz², P. Schaner¹, N. Richards¹, C. Babcock¹, M. Schaller¹, T. Cesena¹

Department of Cell and Developmental Biology, ²Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

ABSTRACT
The genetic bases for several human autoinflammatory syndromes have recently been identified, and the mutated proteins responsible for these diseases are rapidly being characterized. Here, we examine two of these newly identified proteins, pyrin (also called marenostrin, product of the familial Mediterranean fever locus, MEFV) and cryopyrin (product of the CAIS1 locus, and mutated in familial cold urticaria, Muckle Wells syndrome and chronic infantile neurological cutaneous and articular syndrome). Both pyrin and cryopyrin contain an N-terminal domain that encodes a death domain-related structure, now known as the pyrin domain, or PyD. We trace the molecular interactions mediated by these PyDs, examine the evolution of the family of molecules containing this domain, and discuss the function of PyD-containing proteins and their homologues. Synthesis of the available data indicates that both pyrin and cryopyrin interact via their PyDs with a common adaptor protein, ASC. ASC itself participates in at least three important cellular processes: apoptosis, recruitment and activation of pro-caspase-1 (with associated processing and secretion of IL-1b), and activation of NF-kB (a transcription factor involved in both initiation and resolution of the inflammatory response). Through PyD:PyD interactions, pyrin and cryopyrin, as well as several related, but still uncharacterized PyD containing proteins, appear to modulate the activity of all three of these processes, each of which plays a crucial role in the inflammatory pathways that characterize the innate immune system.

Key words
Hereditary fever syndromes, NF-kB activation, caspase activation, pyrin, crypyrin, Apaf-1 Wlike proteins, innate immunity.

DLG acknowledges support from the Arthritis Foundation; AD is grateful for support from NIH K08 AI50092.
Please address correspondence to: Deborah L. Gumucio, PhD, Department of Cell and Developmental Biology, University of Michigan Medical School, 5704 Medical Science II, Ann Arbor, MI 48109-0616, USA.
E-mail: dgumucio@umich.edu