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Blood, 1 August 2001, Vol. 98, No. 3, pp. 851-859
PHAGOCYTES
The familial Mediterranean fever protein, pyrin, associates with
microtubules and colocalizes with actin filaments
Elizabeth Mansfield,
Jae
Jin Chae,
Hirsh D. Komarow,
Tilmann M. Brotz,
David M. Frucht,
Ivona Aksentijevich, and
Daniel
L. Kastner
From the Genetics Section and the Lymphocyte Cell
Biology Section, Arthritis and Rheumatism Branch, National Institute of
Arthritis and Musculoskeletal and Skin Diseases, and the Experimental
Immunology Branch, National Cancer Institute, National Institutes of
Health, Bethesda, MD.
Familial Mediterranean fever (FMF) is a recessive disorder
characterized by episodes of fever and intense inflammation. FMF attacks are unique in their sensitivity to the microtubule inhibitor colchicine, contrasted with their refractoriness to the
anti-inflammatory effects of glucocorticoids. The FMF gene,
MEFV, was recently identified by positional cloning; it is
expressed at high levels in granulocytes and monocytes. The present
study investigated the subcellular localization of the normal gene
product, pyrin. These experiments did not support previously proposed
nuclear or Golgi localizations. Instead fluorescence microscopy
demonstrated colocalization of full-length GFP- and
epitope-tagged pyrin with microtubules; this was markedly accentuated
in paclitaxel-treated cells. Moreover, immunoblot analysis of
precipitates of stabilized microtubules with recombinant pyrin
demonstrated a direct interaction in vitro. Pyrin expression did not
affect the stability of microtubules. Deletion constructs showed that
the unique N-terminal domain of pyrin is necessary and sufficient for
colocalization, whereas disease-associated mutations in the C-terminal
B30.2 (rfp) domain did not disrupt this interaction. By phalloidin
staining, a colocalization of pyrin with actin was also observed in
perinuclear filaments and in peripheral lamellar ruffles. The proposal
is made that pyrin regulates inflammatory responses at the level of
leukocyte cytoskeletal organization and that the unique therapeutic
effect of colchicine in FMF may be dependent on this interaction.
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