Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation

被引：319

作者：

Zhong, Franklin L. ^{[1
,2
]}

Mamai, Ons ^{[1
,4
]}

Sborgi, Lorenzo ^{[3
]}

Boussofara, Lobna ^{[5
]}

Hopkins, Richard ^{[2
]}

Robinson, Kim ^{[1
]}

Szeverenyi, Ildiko ^{[1
]}

Takeichi, Takuya ^{[6
,13
]}

Balaji, Reshmaa ^{[1
]}

Lau, Aristotle ^{[1
]}

Tye, Hazel ^{[10
,11
]}

Roy, Keya ^{[1
]}

Bonnard, Carine ^{[1
]}

Ahl, Patricia J. ^{[2
]}

Jones, Leigh Ann ^{[2
]}

Baker, Paul J. ^{[11
]}

Lacina, Lukas ^{[1
]}

Otsuka, Atsushi ^{[7
]}

Fournie, Pierre R. ^{[8
,9
]}

Malecaze, Francois ^{[8
,9
]}

Lane, E. Birgitte ^{[1
]}

Akiyama, Masashi ^{[6
]}

Kabashima, Kenji ^{[1
,7
]}

Connolly, John E. ^{[2
]}

Masters, Seth L. ^{[10
,11
]}

Soler, Vincent J. ^{[8
,9
]}

Omar, Salma Samir ^{[1
,12
]}

McGrath, John A. ^{[13
]}

Nedelcu, Roxana ^{[14
]}

Gribaa, Moez

Denguezli, Mohamed ^{[5
]}

Saad, Ali ^{[4
]}

Hiller, Sebastian ^{[3
]}

Reversade, Bruno ^{[1
,2
,15
,16
]}

机构：

[1] ASTAR, Inst Med Biol, Singapore 138632, Singapore

[2] ASTAR, Inst Mol & Cellular Biol, Singapore 138632, Singapore

[3] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland

[4] Farhat Hached Univ Hosp, Lab Human Cytogenet Mol Genet & Reprod Biol, Rue Ibn El Jazzar, Sousse 4000, Tunisia

[5] Farhat Hached Univ Hosp, Dept Dermatol & Venerol, Rue Ibn El Jazzar, Sousse 4000, Tunisia

[6] Nagoya Univ, Grad Sch Med, Dept Dermatol, Nagoya, Aichi 4668550, Japan

[7] Kyoto Univ, Grad Sch Med, Dept Dermatol, Kyoto 6068501, Japan

[8] Univ Toulouse Hosp, Hop Pierre Paul Riquet, Ophthalmol Dept, TSA 40031, Pl Baylac, F-31059 Toulouse 9, France

[9] Univ Toulouse 3, INSERM,UMR 1056,FRE 3742,CNRS,Hop Purpan, Team Epitheliums Physiopathol & Genet Oculaires, Unite Differenciat Epitheliale & Autoimmun Rhumat, FRE 3742 CNRS, F-31059 Toulouse 9, France

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

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

[12] Univ Alexandria, Fac Med, Dept Dermatol Venereol & Androl, Alexandria 21411, Egypt

[13] Kings Coll London, Guys Hosp, St Johns Inst Dermatol, London SE1 4XA, England

[14] Carol Davila Univ Med & Pharm, Natl Inst Infect Dis Matei Bals, Dept Pathophysiol 2, Bucharest 050474, Romania

[15] Koc Univ, Sch Med, Med Genet Dept, TR-34010 Istanbul, Turkey

[16] Natl Univ Singapore, Dept Paediat, Singapore 119228, Singapore

来源：

CELL | 2016年 / 167卷 / 01期

基金：

日本学术振兴会;

关键词：

CAUSES AUTOINFLAMMATION; NLRC4; CAUSES; INTERLEUKIN-1-BETA; APOPTOSIS; VITILIGO; IMMUNITY; NALP1; AIM2;

D O I：

10.1016/j.cell.2016.09.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen-and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasomedisorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.

引用

页码：187 / +

页数：33

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