The Familial Mediterranean Fever protein interacts and colocalizes with a putative Golgi transporter

The biological function of pyrin, the protein mutated in Familial Mediterra nean Fever (FMF), has not been elucidated. Based on sequence homology, a tr anscription factor activity was proposed for this neutrophil-specific prote in. In a yeast two-hybrid assay, neither transcription activation activity nor any self interaction was detected for pyrin, Screening of an expression cDNA library of peripheral blood leukocytes using as bait the carboxyl por tion of pyrin (amino acids 557-781), which contains most of the FMF mutatio ns, led to the identification of P/M-IP1 (pyrin/ marenostrin interacting pr otein 1). A splice variant of P/M-IP1, GTC-90, had previously been describe d as a component of the 13S hetero-oligomeric protein complex that stimulat es in vitro Golgi transport. We have now shown that P/M-IP1 colocalizes wit h pyrin in the perinuclear cytoplasm of Cos-7 cells and that the interactio n between these two proteins is impaired by FMF causing mutations in pyrin. These data suggest that, at some stage of its functional pathway, pyrin re sides in the cytoplasm and might be involved in, or impacted by, cellular p rotein sorting by the Golgi apparatus. The data also imply that P/M-IP1 may be involved in the abnormal inflammatory response that occurs in patients with FMF.