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.

Fig 1

The structure of pyrin and its interacting proteins. Pyrin is composed of five distinct domains, the PYRIN domain (residues 1–95), bZIP transcription factor basic domain (residues 266–280), B-box zinc finger domain (residues 375–407), α-helical (coiled-coil) domain (residues 408– 594), and B30.2 domain (residues 598–774). Each domain is responsible for various protein-protein interactions of pyrin: the PYRIN domain with ASC (Richards et al, 2001), the bZIP basic domain and adjacent sequences with p65 and IκB-α respectively (Chae et al, 2008), the B-box and α-helical (coiled-coil) domain with the PAPA protein (PSTPIP1, also known as CD2BP1) (Shoham et al, 2003), and the B30.2 domain with caspase-1 (Chae et al, 2006; Papin et al, 2007) and Siva (Balci-Peynircioglu et al, 2008). Pyrin binds to microtubules through the whole N-terminal half of pyrin (Mansfield et al, 2001), while three residues, serines 208, 209, and 242, which are located between the PYRIN domain and the bZIP domain, are critical for the interaction of pyrin with 14.3.3 (Jeru et al, 2005). The caspases-1 mediated cleavage site of pyrin at Asp330 is indicated between the bZIP basic domain and the B-box zinc finger domain.

Fig 2

Proposed role of pyrin and pathogenesis of FMF. As a representative inflammasome, structural organization of the NLRP3 inflammasome is shown. In the inflammasome, p20 and p10, active caspase-1 subunits are produced by induced proximity-mediated autocatalysis. The wild-type B30.2 domain of pyrin interacts with the p20 and p10 subunits, and consequently preventing their assembly into active p20/p10 heterodimer. FMF-associated pyrin B30.2 mutants interacts with p20 and p10 less than WT pB30.2 domain, thereby permitting p20/p10 heterodimer assembly, IL-1β activation, and induction of inflammation. The active p20/p10 heterodimer cleaves pyrin at Asp330 which is located between the bZIP basic domain and the B-box zinc finger domain. The N-terminal cleaved fragment interacts with p65 and IκB-α through the bZIP basic domain and adjacent sequences respectively, by which NF-κB is activated and the expression of inflammatory genes are induced.