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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1794-1803. Prepublished online as a Blood First Edition Paper on June 24, 2008; DOI 10.1182/blood-2008-01-134932. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-01-134932v1 112/5/1794    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chae, J. J. Articles by Kastner, D. L. Search for Related Content PubMed PubMed Citation Articles by Chae, J. J. Articles by Kastner, D. L. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-B through its N-terminal fragment Jae Jin Chae1, Geryl Wood1, Katharina Richard1, Howard Jaffe2, Nona T. Colburn1, Seth L. Masters1, Deborah L. Gumucio3, Nitza G. Shoham1, and Daniel L. Kastner1 1 Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD; 2 Protein/Peptide Sequencing Facility, National Institute of Neurologic Disorders and Stroke, Bethesda, MD; and 3 Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations in MEFV, which encodes a 781–amino acid protein denoted pyrin. We have previously shown that pyrin regulates caspase-1 activation and IL-1β production through interaction of its N-terminal PYD motif with the ASC adapter protein, and also modulates IL-1β production by interaction of its C-terminal B30.2 domain with the catalytic domains of caspase-1. We now asked whether pyrin might itself be a caspase-1 substrate, and found that pyrin is cleaved by caspase-1 at Asp330, a site remote from the B30.2 domain. Pyrin variants harboring FMF-associated B30.2 mutations were cleaved more efficiently than wild-type pyrin. The N-terminal cleaved fragment interacted with the p65 subunit of NF-B and with IB- through its 15-aa bZIP basic domain and adjacent sequences, respectively, and translocated to the nucleus. The interaction of the N-terminal fragment with p65 enhanced entrance of p65 into the nucleus. The interaction of N-terminal pyrin with IB- induced calpain-mediated degradation of IB-, thus potentiating NF-B activation. Absolute and relative quantities of cleaved pyrin and IB- degradation products were substantially increased in leukocytes from FMF patients compared with healthy controls. Our data support a new pyrin/caspase-1 pathway for NF-B activation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. A. Gavrilin, S. Mitra, S. Seshadri, J. Nateri, F. Berhe, M. W. Hall, and M. D. Wewers Pyrin Critical to Macrophage IL-1{beta} Response to Francisella Challenge J. Immunol., June 15, 2009; 182(12): 7982 - 7989. [Abstract] [Full Text] [PDF]

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