Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation.
Zhong FL., Mamaï O., Sborgi L., Boussofara L., Hopkins R., Robinson K., Szeverényi I., Takeichi T., Balaji R., Lau A., Tye H., Roy K., Bonnard C., Ahl PJ., Jones LA., Baker PJ., 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.
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.