Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation

被引：247

作者：

Masters, Seth L. ^{[1
,2
]}

Lagou, Vasiliki ^{[3
,4
,5
]}

Jeru, Isabelle ^{[6
,7
,8
]}

Baker, Paul J. ^{[1
,2
]}

Van Eyck, Lien ^{[4
,5
]}

Parry, David A. ^{[9
]}

Lawless, Dylan ^{[10
]}

De Nardo, Dominic ^{[1
,2
]}

Garcia-Perez, Josselyn E. ^{[4
,5
]}

Dagley, Laura F. ^{[1
,2
,11
]}

Holley, Caroline L. ^{[12
,13
]}

Dooley, James ^{[4
,5
]}

Moghaddas, Fiona ^{[1
,2
]}

Pasciuto, Emanuela ^{[4
,5
]}

Jeandel, Pierre-Yves ^{[14
]}

Sciot, Raf ^{[15
,16
]}

Lyras, Dena ^{[17
]}

Webb, Andrew I. ^{[2
,11
]}

Nicholson, Sandra E. ^{[1
,2
]}

De Somer, Lien ^{[16
]}

van Nieuwenhove, Erika ^{[4
,5
,16
]}

Ruuth-Praz, Julia ^{[7
,8
]}

Copin, Bruno ^{[8
]}

Cochet, Emmanuelle ^{[8
]}

Medlej-Hashim, Myrna ^{[18
]}

Megarbane, Andre ^{[19
]}

Schroder, Kate ^{[12
,13
]}

Savic, Sinisa ^{[20
,21
,22
]}

Goris, An

Amselem, Serge ^{[6
,7
,8
]}

Wouters, Carine ^{[4
,16
]}

Liston, Adrian ^{[4
,5
]}

机构：

[1] Walter & Eliza Hall Inst Med Res, Inflammat Div, Parkville, Vic 3052, Australia

[2] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia

[3] Katholieke Univ Leuven, Dept Neurosci, B-3000 Leuven, Belgium

[4] Katholieke Univ Leuven, Dept Microbiol & Immunol, B-3000 Leuven, Belgium

[5] VIB, Translat Immunol Lab, B-3000 Leuven, Belgium

[6] INSERM, UMR S933, F-75012 Paris, France

[7] Univ Paris 06, UMR S933, F-75012 Paris, France

[8] Hop Trousseau, AP HP, Serv Genet & Embryol Med, F-75012 Paris, France

[9] Univ Edinburgh, Inst Genet & Mol Med, Western Gen Hosp, Ctr Genom & Expt Med, Crewe Rd South, Edinburgh LS7 4SA, Midlothian, Scotland

[10] Univ Leeds, Leeds Inst Biomed & Clin Sci, St Jamess Univ Hosp, Wellcome Trust Brenner Bldg, Leeds LS7 4SA, W Yorkshire, England

[11] Walter & Eliza Hall Inst Med Res, Syst Biol & Personalised Med Div, Parkville, Vic 3052, Australia

[12] Univ Queensland, IMB, Brisbane, Qld 4072, Australia

[13] Univ Queensland, IMB Ctr Inflammat & Dis Res, Brisbane, Qld 4072, Australia

[14] Univ Nice Sophia Antipolis, Dept Med Interne, Hop Archet 1, F-06202 Nice, France

[15] Katholieke Univ Leuven, Dept Pathol, B-3000 Leuven, Belgium

[16] Univ Hosp Leuven, B-3000 Leuven, Belgium

[17] Monash Univ, Dept Microbiol, Melbourne, Vic 3800, Australia

[18] Lebanese Univ, Fac Sci 2, Dept Life & Earth Sci, Beirut 11022801, Lebanon

[19] Arabian Gulf Univ, Al Jawhara Ctr, Manama 26671, Bahrain

[20] St James Univ Hosp, Dept Allergy & Clin Immunol, Leeds LS9 7TF, W Yorkshire, England

[21] St James Univ Hosp, Leeds Musculoskeletal Biomed Res Unit, Natl Inst Hlth Res, Wellcome Trust Brenner Bldg,Beckett St, Leeds LS9 7TF, W Yorkshire, England

[22] St James Univ Hosp, Leeds Inst Rheumat & Musculoskeletal Med, Wellcome Trust Brenner Bldg,Beckett St, Leeds LS9 7TF, W Yorkshire, England

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2016年 / 8卷 / 332期

基金：

英国医学研究理事会; 澳大利亚研究理事会;

关键词：

MEDITERRANEAN FEVER; SEQUENCING DATA; MEFV MUTATIONS; INFLAMMASOME; DISEASE; PROTEIN; GENE; PHOSPHORYLATION; VARIANTS; ACTIN;

D O I：

10.1126/scitranslmed.aaf1471

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1 beta (IL-1 beta). Mutations in the B30.2/SPRY domain cause pathogen-independent activation of pyrin and are responsible for the autoinflammatory disease familialMediterranean fever (FMF). We studied a family with a dominantly inherited autoinflammatory disease, distinct from FMF, characterized by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. The disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The mutation results in the loss of a 14-3-3 binding motif at phosphorylated S242, which was not perturbed by FMF mutations in the B30.2/SPRY domain. However, loss of both S242 phosphorylation and 14-3-3 binding was observed for bacterial effectors that activate the pyrin inflammasome, such as Clostridium difficile toxin B (TcdB). The S242R mutation thus recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1b production. Successful therapy targeting IL-1b has been initiated in one patient, resolving pyrin-associated autoinflammation with neutrophilic dermatosis. This disease provides evidence that a guard-likemechanism of pyrin regulation, originally identified for Nod-like receptors in plant innate immunity, also exists in humans.

引用

页数：9

共 33 条

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