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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.

Original publication

DOI

10.1016/j.cell.2016.09.001

Type

Journal

Cell

Publication Date

09/2016

Volume

167

Pages

187 - 202.e17

Addresses

Institute of Medical Biology, A(∗)STAR, Singapore 138632, Singapore; Institute of Molecular and Cellular Biology, A(∗)STAR, Singapore 138632, Singapore. Electronic address: franklin.zhong@reversade.com.

Keywords

Epidermis, Chromosomes, Human, Pair 17, Humans, Carcinoma, Skin Neoplasms, Keratosis, Syndrome, Genetic Predisposition to Disease, Hyperplasia, Adaptor Proteins, Signal Transducing, Interleukin-1, Pedigree, Paracrine Communication, Signal Transduction, Amino Acid Sequence, Germ-Line Mutation, Apoptosis Regulatory Proteins, Inflammasomes, Pyrin, Protein Domains, NLR Proteins