Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation - PubMed Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2016 Sep 22;167(1):187-202.e17.
doi: 10.1016/j.cell.2016.09.001.

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

Franklin L Zhong  1 , Ons Mamaï  2 , Lorenzo Sborgi  3 , Lobna Boussofara  4 , Richard Hopkins  5 , Kim Robinson  6 , Ildikó Szeverényi  6 , Takuya Takeichi  7 , Reshmaa Balaji  6 , Aristotle Lau  6 , Hazel Tye  8 , Keya Roy  6 , Carine Bonnard  6 , Patricia J Ahl  5 , Leigh Ann Jones  5 , Paul J Baker  8 , Lukas Lacina  6 , Atsushi Otsuka  9 , Pierre R Fournie  10 , François Malecaze  10 , E Birgitte Lane  6 , Masashi Akiyama  11 , Kenji Kabashima  12 , John E Connolly  5 , Seth L Masters  8 , Vincent J Soler  10 , Salma Samir Omar  13 , John A McGrath  14 , Roxana Nedelcu  15 , Moez Gribaa  16 , Mohamed Denguezli  4 , Ali Saad  16 , Sebastian Hiller  3 , Bruno Reversade  17
Affiliations
Free article
Case Reports

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

Franklin L Zhong et al. Cell. .
Free 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.

Keywords: 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.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Publication types

MeSH terms