Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation
| Autor: | Carine Bonnard, Mohamed Denguezli, Ali Saad, François Malecaze, John E. Connolly, Seth L. Masters, Hazel Tye, Moez Gribaa, John A. McGrath, Kim S. Robinson, Ons Mamaï, Vincent Soler, Aristotle Lau, Reshmaa Balaji, Ildikó Szeverényi, Atsushi Otsuka, Masashi Akiyama, Pierre Fournié, Richard Hopkins, Keya Roy, Patricia J. Ahl, Sebastian Hiller, Lorenzo Sborgi, Lobna Boussofara, L. A. Jones, Roxana Ioana Nedelcu, Kenji Kabashima, Salma Samir Omar, Takuya Takeichi, E. Birgitte Lane, Franklin L. Zhong, Paul J. Baker, Bruno Reversade, Lukáš Lacina |
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| Přispěvatelé: | Agency for science, technology and research [Singapore] (A*STAR), Farhat Hached University Hospital, University of Basel (Unibas), Nagoya University Graduate School of Medicine, Guy's Hospital [London], The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, Graduate School of Medicine and Faculty of Medicine Kyoto University, Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pierre-Paul Riquet [Toulouse], CHU Toulouse [Toulouse], Alexandria University [Alexandrie], University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Koc University, School of Medicine, Istanbul, National University of Singapore (NUS), ACS - Amsterdam Cardiovascular Sciences, ARD - Amsterdam Reproduction and Development, Center for Reproductive Medicine, Farhat Hached University Hospital [Tunisie], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CARBILLET, Véronique |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
MESH: Signal Transduction Skin Neoplasms MESH: Keratosis / genetics Inflammasomes MESH: Carcinoma / genetics MESH: Amino Acid Sequence germline MESH: Chromosomes Human Pair 17 / genetics Pyrin domain Germline MSPC [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases MESH: Germ-Line Mutation MESH: Skin Neoplasms / genetics MESH: Syndrome MESH: Adaptor Proteins Signal Transducing / chemistry MESH: Skin Neoplasms / pathology MESH: Adaptor Proteins Signal Transducing / genetics integumentary system NLRP1 MESH: Genetic Predisposition to Disease MESH: Epidermis / pathology Inflammasome MESH: Hyperplasia / genetics Syndrome 3. Good health Pedigree MESH: Pyrin / chemistry [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases MESH: Protein Domains genodermatosis medicine.drug Signal Transduction keratinocytes MESH: Hyperplasia / pathology multiple self-healing squamous cell carcinoma MESH: Pedigree NLR Proteins Biology ASC MESH: Apoptosis Regulatory Proteins / genetics General Biochemistry Genetics and Molecular Biology MESH: Inflammasomes / genetics 03 medical and health sciences AIM2 Germline mutation Protein Domains inflammasome skin inflammation Paracrine Communication medicine Humans cancer Genetic Predisposition to Disease MESH: Interleukin-1 / metabolism Amino Acid Sequence MESH: Paracrine Communication Germ-Line Mutation Adaptor Proteins Signal Transducing MESH: Keratosis / pathology Innate immune system Hyperplasia gain-of-function MESH: Humans MESH: Apoptosis Regulatory Proteins / chemistry IL-1 Carcinoma keratosis lichenoides chronica Keratosis Pyrin medicine.disease 030104 developmental biology MESH: Carcinoma / pathology Immunology Cancer research MSSE Skin cancer Epidermis Apoptosis Regulatory Proteins MESH: Inflammasomes / metabolism Chromosomes Human Pair 17 Interleukin-1 |
| Zdroj: | Cell Cell, Elsevier, 2016, 167 (1), pp.187-202.e17. ⟨10.1016/j.cell.2016.09.001⟩ Cell, 167(1), 187-+. Cell Press Cell, 2016, 167 (1), pp.187-202.e17. ⟨10.1016/j.cell.2016.09.001⟩ |
| ISSN: | 0092-8674 1097-4172 |
| DOI: | 10.1016/j.cell.2016.09.001⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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