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

Research output: Contribution to journalArticle

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 & 14 more 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

Original languageEnglish
Pages (from-to)187–202.e17
JournalCell
Volume167
Issue number1
DOIs
Publication statusPublished - 22 Sep 2016

King's Authors

Abstract

Summary 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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