Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Chae, J.J. et al.

Chae, Wood, Masters, Richard, Park, Smith, Kastner,

The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production.

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-1beta 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-1beta production in cells transfected with a caspase-1/IL-1beta 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 M680I pyrin mutations. Consistent with a net inhibitory effect of pyrin on IL-1beta activation, small interfering RNA (siRNA)-mediated pyrin knockdown in THP-1 cells augmented IL-1beta 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-1beta activation and suggest heightened IL-1 responsiveness as one factor selecting for pyrin mutations.[1]

References

The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production. Chae, J.J., Wood, G., Masters, S.L., Richard, K., Park, G., Smith, B.J., Kastner, D.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]

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