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The Regulation of MEFV Expression and Its Role in Health and Familial Mediterranean Fever

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The Regulation of MEFV Expression and Its Role in Health and Familial Mediterranean Fever Genes and Immunity (2011) 12, 497–503 & 2011 Macmillan Publishers Limited All rights reserved 1466-4879/11 www.nature.com/gene REVIEW The regulation of MEFV expression and its role in health and familial Mediterranean fever S Grandemange1, I Aksentijevich2, I Jeru3, A Gul4 and I Touitou1 1Unite´ me´dicale des maladies auto-inflammatoires, CHRU de Montpellier, INSERM U844, UM1, Hopital Arnaud de Villeneuve, Montpellier, France; 2National Human Genome Research Institute, Bethesda, MD, USA; 3INSERM U933, Universite´ Pierre et Marie Curie-Paris6 UMR S933, Paris, France and 4Istanbul Faculty of Medicine, Division of Rheumatology, Department of Internal Medicine, Istanbul University, Istanbul, Turkey Familial Mediterranean fever (FMF) is a hereditary recurrent fever associated with mutations in the gene MEFV encoding pyrin. It is expressed mainly in neutrophils and macrophages, and modulates the production of the potent pro-inflammatory cytokine interleukin-1b through regulation of nuclear factor-kB and caspase-1. The MEFV gene expression depends on multiple levels of regulation. Sequence variants located in the promoter and at the 30-untranslated region of the gene modulate this expression. Two studies demonstrated decreased mRNA levels in FMF patients compared with healthy subjects, whereas two others found no significant differences. The diverse experimental settings may have resulted in variable quantification of the 15 splice variants that have been identified recently. Some of these isoforms are regulated by nonsense-mediated decay in both cell- and transcript-specific manner, and may be differentially translated in THP1 cells. In addition, pyrin may be cleaved by caspase 1. The full-length pyrin was less abundant than the cleaved fragment in mononuclear cells from FMF patients than in controls, whereas the opposite was observed in granulocytes. Altogether, the regulation of MEFV expression is more complex than anticipated in both physiological and pathological conditions. Its deregulation is likely to alter the inflammasome function and subsequently result in uncontrolled inflammation as seen in FMF. Genes and Immunity (2011) 12, 497–503; doi:10.1038/gene.2011.53; published online 21 July 2011 Keywords: expression; MEFV; FMF Introduction The gene responsible for FMF, named MEFV, encodes pyrin2 (alternatively known as marenostrin,3) a protein of Familial Mediterranean fever (FMF) is a recessively 781 amino-acids (Figure 1). Initial computer analysis of inherited systemic auto-inflammatory disease. Auto- pyrin/marenostrin sequence revealed that this protein inflammatory diseases are an expanding group of innate contains two putative overlapping nuclear binding immunity diseases that have been recently revisited as a motifs and shows high homology with the B30/2 rfp continuum, which includes diseases with some features transcription factor family. This observation led to the of adaptive immune deregulation. They include heredi- hypothesis that pyrin was a nuclear transcriptional tary recurrent fevers, pyogenic disorders such as the factor. Later, sequence alignments and secondary struc- deficiency of interleukin (IL)-1 receptor and pyogenic ture prediction highlighted that the first 100 N-terminal sterile arthritis pyoderma gangrenosum and acne (PAPA), residues of pyrin constituted a novel protein domain granulomatous diseases such as Crohn’s disease and Blau named PYrin Domain (PYD),4–6 and revealed that PYD syndrome. FMF is considered the prototype among the was the fourth member of the death domain fold hereditary recurrent fevers as the most frequent and the superfamily. PYD orthologs were also identified in first whose gene has been identified. FMF patients suffer several species such as mouse, cow and zebrafish. from recurrent and seemingly unprovoked attacks of The PYD is an N-terminal adapter domain that is found fever, often associated with peritonitis, pleuritis, arthritis in more than 20 human proteins involved in inflamma- and localized erysipelas-like erythema. The attacks tion and apoptosis, such as NLRP3 (NLR family, PYD usually last 12–72 h.1 The inflammatory reaction is containing 3), similar to other death domain fold- characterized by a massive influx of polymorphonuclear containing proteins (for a review see Kohl et al.7) Recent leukocytes into the affected tissues. studies indicate that pyrin modulates the production of the potent pro-inflammatory cytokine IL-1b probably through two major pathways: (i) the N-terminal frag- Correspondence: Professor I Touitou, Unite´ me´dicale des maladies ment of pyrin may regulate nuclear factor (NF)-kB auto-inflammatoires, CHRU de Montpellier, INSERMU844, UM1, activation through interactions with an adapter protein Hopital Arnaud de Villeneuve, Montpellier, 371, Avenue du Doyen named apoptosis-associated speck-like protein with a Giraud 34295, Montpellier cedex 5, France. 8–10 E-mail: [email protected] caspase-recruitment domain (ASC) and/or with Received 20 May 2011; accepted 27 June 2011; published online 21 NFkB-p65,11 and (ii) pyrin regulates caspase-1/IL-1b July 2011 activation through its interaction with ASC.12 Addition- MEFV expression in FMF S Grandemange et al 498 MEFV DNA: 14600bp 5’flanking 3’ flanking 1 2 3 4 5 6 7 8 9 10 mRNA: 3499bp 1 2 3 4 5 67 8 9 10 Protein: 781aa PyD B-Box CC B30.2/SPRY TRIM20 DDF TRIpartite Motif family Viral Proteins? Inflammasome Figure 1 Schematic representation of the FMF gene (MEFV) and its expression products at the RNA and protein levels. Exons are boxed, introns are depicted as lines. The protein domains are illustrated along with their putative functions. The death domain fold at the N-terminal domain is involved in regulating inflammation via homotypic interactions with inflammasomes. Interestingly, residues (680 and 694) important for the conservation of the pyrin structure are precisely those which, when mutated, are associated with a severe form of the disease.39 The SPRY domain is present in several proteins of the tripartite motif family. This domain may interact with viral components. A full colour version of this figure is available at the Genes and Immunity journal online. ally, the C-terminal B30.2 domain of pyrin, also known as FMF mutations may also lead to dysregulation in the SPRY, directly interacts with caspase-1 to modulate IL-1b MEFV expression affecting pyrin level. production.13,14 This domain, together with the B-Box The past decade has witnessed the explosion of and coiled-coil domains, constitutes a tripartite motif, reviews on auto-inflammatory diseases written by which is contained in proteins involved in viral recogni- scientists and clinicians from a variety of disciplines. tion. Thus, pyrin is also known as TRIM20.15 Most of them attempted to correlate clinical features with The MEFV gene contains 10 exons. Nearly 200 genotypes in patients with auto-inflammatory diseases, sequence variants, almost all single-nucleotide substitu- or to dissect the underlying inflammatory pathways. tions, have been recorded in Infevers,16 a database However, there has been no review on the regulation of dedicated to auto-inflammatory mutations (http:// MEFV gene expression in physiological or pathological fmf.igh.cnrs.fr/ISSAID/infevers/). Only a small number conditions. In this manuscript, we review the complex of these variants are unambiguously pathogenic, such as regulation of MEFV expression at the RNA and protein M694V, a severe mutation with a founder effect, and no levels, summarize the data obtained from various cell more than half of the reported MEFV variations are lines along with expression data from FMF patients, and associated with the FMF phenotype. The vast majority of discuss impaired regulation of MEFV expression as a genuine FMF-associated mutations are found in the possible mechanism of the disease. SPRY domain of the protein. How mutations in the MEFV gene can result in so variable an inflammatory phenotype has been only partially elucidated.17 Most MEFV expression at the mRNA level molecular mechanisms that have been hypothesized suggest an impaired or dysregulated interaction of Cellular expression mutant pyrin protein with its partners, resulting in Initial expression studies using northern blot experi- activation of the NLRP3 inflammasomes.18 Inflamma- ments detected MEFV mRNA only in peripheral blood somes are cytoplasmic multiprotein complexes essential leukocytes (PBLs) and in a colorectal adenocarcinoma 2 for the maturation of proinflammatory cytokines IL-1b, cell line, SW480. Specific analysis of leukocyte fractions IL-18 and IL-33. Several inflammasomes have been from bone marrow and PBLs showed that MEFV was described on the basis of their constituent stress-sensing highly expressed in neutrophils, and to some extent in 20,21 components. In NLRP inflammasomes, ASC works as an eosinophils and monocytes, but not in lymphocytes. adapter molecule that connects the stress-sensing com- MEFV is also expressed in dendritic cells and in ponent and pro-caspase-1 through its N-terminal PyD fibroblasts from synovium, peritoneum and to a lesser 22 domain and C-terminal CARD domain, respectively (for extent from skin. This highly specific cellular expres- reviews see Chae et al.18 and Schroder and Tschopp19). sion pattern likely accounts for the predilection of FMF This brings two molecules of procaspase-1 into close patients to develop inflammation in serosal, synovial and proximity, leading to proteolytic activation and the skin tissues. subsequent release of the active catalytic
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