Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation

Zhong, FL; Mamai, O; Sborgi, L; Boussofara, L; Hopkins, R; Robinson, K; Szeverenyi, 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

Author(s): Zhong, FL; Mamai, O; Sborgi, L; Boussofara, L; Hopkins, R; Robinson, K; Szeverenyi, 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;
Details: Publication Year 2016-09-22,Volume 167,Issue #1,Page 187-202 e17
Journal Title: Cell
Publication Type: Journal Article
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.
Publisher: Cell Press
Research Division(s): Inflammation
PubMed ID: 27662089
Publisher's Version: https://doi.org/10.1016/j.cell.2016.09.001
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2016-10-04 09:29:45

Last Modified: 2016-10-04 12:05:07