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J. Biol. Chem., Vol. 276, Issue 42, 39320-39329, October 19, 2001
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From the Departments of Patients with familial Mediterranean fever
suffer sporadic inflammatory attacks characterized by fever and intense
pain (in joints, abdomen, or chest). Pyrin, the product of the
MEFV locus, is a cytosolic protein whose function is
unknown. Using pyrin as a "bait" to probe a yeast two-hybrid
library made from neutrophil cDNA, we isolated
apoptotic speck protein containing a caspase recruitment domain (CARD) (ASC), a proapoptotic protein
that induces the formation of large cytosolic "specks" in
transfected cells. We found that when HeLa cells are transfected with
ASC, specks are formed. After co-transfection of cells with ASC plus
wild type pyrin, an increase in speck-positive cells is found, and speck-positive cells show increased survival. Immunofluorescence studies show that pyrin co-localizes with ASC in specks. Speck localization requires exon 1 of pyrin, but exon 1 alone of pyrin does
not result in an increase in the number of specks. Exon 1 of pyrin and
exon 1 of ASC show 42% sequence similarity and resemble death
domain-related structures in modeling studies. These findings link
pyrin to apoptosis pathways and suggest that the modulation of cell
survival may be a component of the pathophysiology of familial
Mediterranean fever.
Interaction between Pyrin and the Apoptotic Speck
Protein (ASC) Modulates ASC-induced Apoptosis*
§¶,§
¶¶,,,,, and§§
Cell and Developmental
Biology, ** Internal Medicine, and
Biochemistry and the
¶¶ Graduate Program in Cellular and Molecular Biology, The
University of Michigan Medical School, Ann Arbor, Michigan,
48109-0616
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by Organogenesis Training Grant T32-HD07505.
§§
Supported by a grant from the Arthritis Foundation. To whom
correspondence should be addressed: Dept. of Cell and Developmental Biology, University of Michigan Medical School, 5704 Medical Science II, Ann Arbor, MI 48109-0616. Tel.: 734-647-0172; Fax: 734-647-9559; E-mail: dgumucio@umich.edu.
Supported by Rheumatology Training Grant
T32-AR07080.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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