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

Zhong, Franklin L. and Mamaï, Ons and Sborgi, Lorenzo and Boussofara, Lobna and Hopkins, Richard and Robinson, Kim and Szeverényi, Ildikó and Takeichi, Takuya and Balaji, Reshmaa and Lau, Aristotle and Tye, Hazel and Roy, Keya and Bonnard, Carine and Ahl, Patricia J. and Jones, Leigh Ann and Baker, Paul and Lacina, Lukas and Otsuka, Atsushi and Fournie, Pierre R. and Malecaze, François and Lane, E. Birgitte and Akiyama, Masashi and Kabashima, Kenji and Connolly, John E. and Masters, Seth L. and Soler, Vincent J. and Omar, Salma Samir and McGrath, John A. and Nedelcu, Roxana and Gribaa, Moez and Denguezli, Mohamed and Saad, Ali and Hiller, Sebastian and Reversade, Bruno. (2016) Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation. Cell, 167 (1). pp. 187-202.e17.

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Hiller)
UniBasel Contributors:Hiller Odermatt, Sebastian
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:19 Dec 2017 13:29
Deposited On:26 Oct 2017 12:28

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