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The B30.2 Domain of Pyrin, the Familial Mediterranean Fever Protein, Interacts Directly with Caspase-1 to Modulate IL-1β Production

Proceedings of the National Academy of Sciences - PNAS, 2006-06, Vol.103 (26), p.9982-9987 [Peer Reviewed Journal]

Copyright 2006 National Academy of Sciences of the United States of America ;2006 by The National Academy of Sciences of the USA 2006 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.0602081103 ;PMID: 16785446

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  • Title:
    The B30.2 Domain of Pyrin, the Familial Mediterranean Fever Protein, Interacts Directly with Caspase-1 to Modulate IL-1β Production
  • Author: Chae, Jae Jin ; Wood, Geryl ; Masters, Seth L. ; Richard, Katharina ; Park, Grace ; Smith, Brian J. ; Kastner, Daniel L.
  • Subjects: Biological Sciences ; Cell culture techniques ; Cell lines ; Genetic mutation ; Kidney cells ; Proteins ; Receptors ; Secretion ; Small interfering RNA ; Transfection ; Western blotting
  • Is Part Of: Proceedings of the National Academy of Sciences - PNAS, 2006-06, Vol.103 (26), p.9982-9987
  • Description: Familial Mediterranean fever (FMF) is a recessively inherited autoinflammatory disorder with high carrier frequencies in the Middle East. Pyrin, the protein mutated in FMF, regulates caspase-1 activation and consequently IL-1β production through cognate interaction of its N-terminal PYRIN motif with the ASC adaptor protein. However, the preponderance of mutations reside in pyrin's C-terminal B30.2 domain. Here we demonstrate direct interaction of this domain with caspase-1. In lysates from cells not expressing ASC, reciprocal GST pull-downs demonstrated the interaction of pyrin with the p20 and p10 catalytic subunits of caspase-1. Coimmunoprecipitations of pyrin and caspase-1 from THP-1 human monocytic cells were consistent with the interaction of endogenous proteins. The C-terminal B30.2 domain of pyrin is necessary and sufficient for the interaction, and binding was reduced by FMF-associated B30.2 mutations. Full-length pyrin attenuated IL-1β production in cells transfected with a caspase-1/ IL-1β construct, an effect diminished by FMF-associated B30.2 mutations and in B30.2 deletion mutants. Modeling of the crystal structure of caspase-1 with the deduced structure of the pyrin B30.2 domain corroborated both the interaction and the importance of M694V and M6801 pyrin mutations. Consistent with a net inhibitory effect of pyrin on IL-1β activation, small interfering RNA (siRNA)-mediated pyrin knockdown in THP-1 cells augmented IL-1β production in response to bacterial LPS. Moreover, the IL-1 receptor antagonist anakinra suppressed acute-phase proteins in a patient with FMF and amyloidosis. Our data support a direct, ASC-independent effect of pyrin on IL-1β activation and suggest heightened IL-1 responsiveness as one factor selecting for pyrin mutations.
  • Publisher: National Academy of Sciences
  • Language: English
  • Identifier: ISSN: 0027-8424
    EISSN: 1091-6490
    DOI: 10.1073/pnas.0602081103
    PMID: 16785446
  • Source: PubMed Central (Open access)
    GFMER Free Medical Journals
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