The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments

Citation
E. Mansfield et al., The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments, BLOOD, 98(3), 2001, pp. 851-859
Citations number
68
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Hematology,"Cardiovascular & Hematology Research
Journal title
BLOOD
ISSN journal
0006-4971 → ACNP
Volume
98
Issue
3
Year of publication
2001
Pages
851 - 859
Database
ISI
SICI code
0006-4971(20010801)98:3<851:TFMFPP>2.0.ZU;2-2
Abstract
Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever and intense inflammation. FMF attacks are unique in thei r sensitivity to the microtubule inhibitor colchicine, contrasted with thei r refractoriness to the anti-Inflammatory effects of glucocorticoids. The F MF gene, MEFV was recently identified by positional cloning; it Is expresse d at high levels in granulocytes and monocytes. The present study investiga ted the subeelfular localization of the normal gene product, pyrin. These e xperiments did not support previously proposed nuclear or Golgi localizatio ns. In-stead fluorescence microscopy demonstrated colocalization of full-le ngth GFP-and epitope-tagged pyrin with microtubules; this was markedly acce ntuated in paclitaxel-treated cells. Moreover, immunoblot analysis of preci pitates of stabilized microtubules with recombinant pyrin demonstrated a di rect 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-a ssociated mutations in the C-terminal B30.2 (rfp) domain did not disrupt th is interaction. By phalloidin staining, a colocalization of pyrin with acti n was also observed in perinuclear filaments and in peripheral lamellar ruf fles. The proposal is made that pyrin regulates inflammatory responses at t he level of leukocyte cytoskeletal organization and that the unique therape utic effect of colchicine in FMF may be dependent on this interaction. (C) 2001 by The American Society of Hematology.