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

Franklin Zhong (1) , Ons Mamaï (1, 2) , Lorenzo Sborgi (3) , Lobna Boussofara (2) , Richard J Hopkins (1) , Kim Robinson (1) , Ildikó Szeverényi (1) , Takuya Takeichi (4, 5) , Reshmaa Balaji (1) , Aristotle Lau (1) , Hazel Tye (6, 7) , Keya Roy (1) , Carine Bonnard (1) , Patricia Ahl (1) , Leigh Ann Jones (1) , Paul Baker (6, 7) , Lukas Lacina (1) , Atsushi Otsuka (8) , Pierre Fournie (9, 10) , François Malecaze (9, 10) , E. Birgitte Lane (1) , Masashi Akiyama (4) , Kenji Kabashima (1, 8) , John Connolly (1) , Seth Masters (6, 7) , Vincent Soler (9, 10) , Salma Samir Omar (11) , John Mcgrath (5) , Roxana Nedelcu (12) , Moez Gribaa (2) , Mohamed Denguezli (2) , Ali Saad (2) , Sebastian Hiller (3) , Bruno Reversade (1, 13, 14)

1 A*STAR - Agency for science, technology and research [Singapore]
2 Farhat Hached University Hospital [Tunisie]
3 Unibas - Université de Bâle = University of Basel = Basel Universität
4 Nagoya University Graduate School of Medicine
5 Guy's Hospital [London]
6 WEHI - The Walter and Eliza Hall Institute of Medical Research
7 University of Melbourne
8 Graduate School of Medicine and Faculty of Medicine Kyoto University
9 UDEAR - Unité différenciation épidermique et auto-immunité rhumatoïde
10 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
11 Alexandria University [Alexandrie]
12 UMPCD - University of Medicine and Pharmacy “Carol Davila” Bucharest
13 Koc University, School of Medicine, Istanbul
14 NUS - National University of Singapore

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.

Mots clés: ASC; IL-1; MSPC; MSSE; NLRP1; cancer; gain-of-function; genodermatosis; germline; inflammasome; keratinocytes; keratosis lichenoides chronica; multiple self-healing squamous cell carcinoma; skin inflammation

Domaines: Maladies infectieuses

Franklin Zhong, Ons Mamaï, Lorenzo Sborgi, Lobna Boussofara, Richard J Hopkins, et al.. Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation. Cell, 2016, 167 (1), pp.187-202.e17. ⟨10.1016/j.cell.2016.09.001⟩. ⟨hal-03158675⟩