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

Franklin L. Zhong; Ons Mamaï; Lorenzo Sborgi; Lobna Boussofara; Richard Hopkins; Kim Robinson; Ildikó Szeverényi; Takuya Takeichi; Reshmaa Balaji; Aristotle Lau; Hazel Tye; Keya Roy; Carine Bonnard; Patricia J. Ahl; Leigh Ann Jones; Paul Baker; Lukas Lacina; Atsushi Otsuka; Pierre R. Fournie; François Malecaze; E. Birgitte Lane; Masashi Akiyama; Kenji Kabashima; John E. Connolly; Seth L. Masters; Vincent J. Soler; Salma Samir Omar; John A. McGrath; Roxana Nedelcu; Moez Gribaa; Mohamed Denguezli; Ali Saad; Sebastian Hiller; Bruno Reversade

doi:10.1016/j.cell.2016.09.001

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

Franklin L. Zhong, Ons Mamaï, Lorenzo Sborgi, Lobna Boussofara, Richard Hopkins, Kim Robinson, Ildikó Szeverényi, Takuya Takeichi, Reshmaa Balaji, Aristotle Lau, Hazel Tye, Keya Roy, Carine Bonnard, Patricia J. Ahl, Leigh Ann Jones, Paul Baker, Lukas Lacina, Atsushi Otsuka, Pierre R. Fournie, François MalecazeE. Birgitte Lane, Masashi Akiyama, Kenji Kabashima, John E. Connolly, Seth L. Masters, Vincent J. Soler, Salma Samir Omar, John A. McGrath, Roxana Nedelcu, Moez Gribaa, Mohamed Denguezli, Ali Saad, Sebastian Hiller, Bruno Reversade

Department of Dermatology

Research output: Contribution to journal › Article › peer-review

313 Citations (Scopus)

Abstract

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 inflammasome disorders, 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.

Original language	English
Pages (from-to)	187-202.e17
Journal	Cell
Volume	167
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2016.09.001
Publication status	Published - 2016 Sept 22

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2016.09.001

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Zhong, F. L., Mamaï, O., Sborgi, L., Boussofara, L., Hopkins, R., Robinson, K., Szeverényi, I., Takeichi, T., Balaji, R., Lau, A., Tye, H., Roy, K., Bonnard, C., Ahl, P. J., Jones, L. A., Baker, P., Lacina, L., Otsuka, A., Fournie, P. R., ... Reversade, B. (2016). Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation. Cell, 167(1), 187-202.e17. https://doi.org/10.1016/j.cell.2016.09.001

@article{f57bebe1285d4993ad393a01321579da,

title = "Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation",

abstract = "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 inflammasome disorders, 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.",

author = "Zhong, {Franklin L.} and Ons Mama{\"i} and Lorenzo Sborgi and Lobna Boussofara and Richard Hopkins and Kim Robinson and Ildik{\'o} Szever{\'e}nyi and Takuya Takeichi and Reshmaa Balaji and Aristotle Lau and Hazel Tye and Keya Roy and Carine Bonnard and Ahl, {Patricia J.} and Jones, {Leigh Ann} and Paul Baker and Lukas Lacina and Atsushi Otsuka and Fournie, {Pierre R.} and Fran{\c c}ois Malecaze and Lane, {E. Birgitte} and Masashi Akiyama and Kenji Kabashima and Connolly, {John E.} and Masters, {Seth L.} and Soler, {Vincent J.} and Omar, {Salma Samir} and McGrath, {John A.} and Roxana Nedelcu and Moez Gribaa and Mohamed Denguezli and Ali Saad and Sebastian Hiller and Bruno Reversade",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = sep,

day = "22",

doi = "10.1016/j.cell.2016.09.001",

language = "English",

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Zhong, FL, Mamaï, O, Sborgi, L, Boussofara, L, Hopkins, R, Robinson, K, Szeverényi, I, Takeichi, T, Balaji, R, Lau, A, Tye, H, Roy, K, Bonnard, C, Ahl, PJ, Jones, LA, Baker, P, Lacina, L, Otsuka, A, Fournie, PR, Malecaze, F, Lane, EB, Akiyama, M, Kabashima, K, Connolly, JE, Masters, SL, Soler, VJ, Omar, SS, McGrath, JA, Nedelcu, R, Gribaa, M, Denguezli, M, Saad, A, Hiller, S & Reversade, B 2016, 'Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation', Cell, vol. 167, no. 1, pp. 187-202.e17. https://doi.org/10.1016/j.cell.2016.09.001

TY - JOUR

T1 - Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation

AU - Zhong, Franklin L.

AU - Mamaï, Ons

AU - Sborgi, Lorenzo

AU - Boussofara, Lobna

AU - Hopkins, Richard

AU - Robinson, Kim

AU - Szeverényi, Ildikó

AU - Takeichi, Takuya

AU - Balaji, Reshmaa

AU - Lau, Aristotle

AU - Tye, Hazel

AU - Roy, Keya

AU - Bonnard, Carine

AU - Ahl, Patricia J.

AU - Jones, Leigh Ann

AU - Baker, Paul

AU - Lacina, Lukas

AU - Otsuka, Atsushi

AU - Fournie, Pierre R.

AU - Malecaze, François

AU - Lane, E. Birgitte

AU - Akiyama, Masashi

AU - Kabashima, Kenji

AU - Connolly, John E.

AU - Masters, Seth L.

AU - Soler, Vincent J.

AU - Omar, Salma Samir

AU - McGrath, John A.

AU - Nedelcu, Roxana

AU - Gribaa, Moez

AU - Denguezli, Mohamed

AU - Saad, Ali

AU - Hiller, Sebastian

AU - Reversade, Bruno

PY - 2016/9/22

Y1 - 2016/9/22

N2 - 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 inflammasome disorders, 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.

AB - 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 inflammasome disorders, 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.

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U2 - 10.1016/j.cell.2016.09.001

DO - 10.1016/j.cell.2016.09.001

M3 - Article

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AN - SCOPUS:84988622178

SN - 0092-8674

VL - 167

SP - 187-202.e17

JO - Cell

JF - Cell

IS - 1

ER -

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

Abstract

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