{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:20:10Z","timestamp":1791843610327,"version":"4.3.4"},"reference-count":35,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2003,11,11]]},"abstract":"<jats:p>Pyrin, the familial Mediterranean fever protein, is found in association with the cytoskeleton in myeloid\/monocytic cells and modulates IL-1\u03b2 processing, NF-\u03baB activation, and apoptosis. These effects are mediated in part through cognate interactions with the adaptor protein ASC, which shares an N-terminal motif with pyrin. We sought additional upstream regulators of inflammation by using pyrin as the bait in yeast two-hybrid assays. We now show that proline serine threonine phosphatase-interacting protein [PSTPIP1, or CD2-binding protein 1 (CD2BP1)], a tyrosine-phosphorylated protein involved in cytoskeletal organization, also interacts with pyrin. Recently, PSTPIP1\/CD2BP1 mutations were shown to cause the syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), a dominantly inherited autoinflammatory disorder mediated predominantly by granulocytes. Endogenous PSTPIP1\/CD2BP1 and pyrin are coexpressed in monocytes and granulocytes and can be coimmunoprecipitated from THP-1 cells. The B box segment of pyrin was necessary and the B box\/coiled-coil segment sufficient for this interaction, whereas the SH3 and coiled-coil domains of PSTPIP1\/CD2BP1 were both necessary, but neither was sufficient, for pyrin binding. The Y344F PSTPIP1\/CD2BP1 mutation, which blocks tyrosine phosphorylation, was associated with a marked reduction in pyrin binding in pervanadate-treated cells. PAPA-associated A230T and E250Q PSTPIP1\/CD2BP1 mutations markedly increased pyrin binding as assayed by immunoprecipitation and, relative to WT, these mutants were hyperphosphorylated when coexpressed with c-Abl kinase. Consistent with the hypothesis that these mutations exert a dominant-negative effect on the previously reported activity of pyrin, we found increased IL-1\u03b2 production by peripheral blood leukocytes from a clinically active PAPA patient with the A230T PSTPIP1\/CD2BP1 mutation and in cell lines transfected with both PAPA-associated mutants.<\/jats:p>","DOI":"10.1073\/pnas.2135380100","type":"journal-article","created":{"date-parts":[[2003,11,16]],"date-time":"2003-11-16T15:42:47Z","timestamp":1068997367000},"page":"13501-13506","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":434,"title":["Pyrin binds the PSTPIP1\/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway"],"prefix":"10.1073","volume":"100","author":[{"given":"Nitza G.","family":"Shoham","sequence":"first","affiliation":[{"name":"Genetics and Genomics Branch and Office of the Clinical Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892; and Sarah M. and Charles E. 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