Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis

Patients with familial Mediterranean fever suffer sporadic inflammatory att acks characterized by fever and intense pain (in joints, abdomen, or chest) . Pyrin, the product of the MEFV locus, is a cytosolic protein whose functi on is unknown. Using pyrin as a "bait" to probe a yeast two-hybrid library made from neutrophil cDNA, we isolated apoptotic deck protein containing a caspase recruitment domain (CARD) (ASC), a proapoptotic protein that induce s 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-p ositive cells is found, and speck-positive cells show increased survival. I mmunofluorescence 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 exo n 1 of ASC show 42% sequence similarity and resemble death domain-related s tructures in modeling studies. These findings link pyrin to apoptosis pathw ays and suggest that the modulation of cell survival may be a component of the pathophysiology of familial Mediterranean fever.