title: Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy.
abstract: Familial Mediterranean fever (FMF) is a systemic autoinflammatory disorder characterized by seemingly unprovoked recurrent episodes of fever and serosal, synovial, or cutaneous inflammation. FMF is caused by recessively inherited mutations in MEFV, which encodes pyrin, and most of the mutations are present in the C-terminal end of the protein encoding B30.2 domain. The FMF carrier frequencies are extremely high in several eastern Mediterranean populations. Pyrin is expressed in granulocytes, monocytes, dendritic cells, and synovial fibroblasts. Pyrin regulates caspase-1 activation and consequently interleukin-1beta production through the interactions of its N-terminal PYRIN domain and C-terminal B30.2 domain with an adaptor protein, apoptosis-associated speck-like protein with a caspase-recruitment domain (ASC) and caspase-1 respectively. Pyrin is cleaved by caspase-1 and the cleaved N-terminal fragment translocates to nucleus and enhances ASC-independent nuclear factor (NF)-kappaB activation through interactions with p65 NF-kappaB and IkappaB-alpha. In addition to the regulatory role of pyrin for caspase-1, the cleavage of pyrin provides an important clue not only in understanding the molecular pathogenesis of FMF but also in developing new therapeutic targets for FMF.
authors.affiliation: Laboratory of Clinical Investigation, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, Genetics and Genomics Branch, Bethesda, MD 20892-1849, USA. chaej@exchange.nih.gov
authors.forename: Jae J
authors.initials: JJ
authors.lastname: Chae
authors.forename: Ivona
authors.initials: I
authors.lastname: Aksentijevich
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
mesh_terms: D020170:Caspase 1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D010505:Familial Mediterranean Fever / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D016166:Free Radical Scavengers / Q000627:therapeutic use; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000071198:Pyrin; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D016166:Free Radical Scavengers; D053583:Interleukin-1beta; C000604192:MEFV protein, human; D016328:NF-kappa B; D000071198:Pyrin; D017382:Reactive Oxygen Species; D020170:Caspase 1