Portimine A toxin causes skin inflammation through ZAK��-dependent NLRP1 inflammasome activation.
L��ana Gorse, Lo��c Plessis, Stephen Wearne, Margaux Paradis, Miriam Pinilla, Rae Chua, Seong Soo Lim, Elena Pelluz, Gee-Ann Toh, Raoul Mazars, Caio Bomfim, Fabienne Herv��, Korian Lhaute, Damien R��veillon, Bastien Suire, L��a Ravon-Katossky, Thomas Benoist, L��a Fromont, David P��ricat, Kenneth Neil Mertens, Am��lie Derrien, Aouregan Terre-Terrillon, Nicolas Chom��rat, Gwena��l Bilien, V��ronique S��chet, Liliane Carpentier, Mamadou Fall, Amidou Sonko, Hadi Hakim, Nfally Sadio, Jessie Bourdeaux, C��line Cougoule, Anthony K Henras, Ana Belen Perez-Oliva, Patrice Brehmer, Francisco J Roca, Franklin L Zhong, John Common, Etienne Meunier, Philipp Hess
Author Information
L��ana Gorse: Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France. ORCID
Lo��c Plessis: Ifremer, PHYTOX Physiologie et Toxines des Microalgues Toxiques et Nuisibles, F-44000, Nantes, France. ORCID
Stephen Wearne: A*STAR Skin Research, Institute of Singapore, Agency for Science, Technology and Research (A*STAR) Skin Research Labs, 138648, Singapore, Singapore.
Margaux Paradis: Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France. ORCID
Miriam Pinilla: Department of Biochemistry and Molecular Biology-B and Immunology, Infectious Disease Pathology, Clinical Microbiology and Tropical Medicine, University of Murcia, Murcia, Spain. ORCID
Rae Chua: LKC School of Medicine, Nanyang Technological University, Singapore, Singapore.
Seong Soo Lim: A*STAR Skin Research, Institute of Singapore, Agency for Science, Technology and Research (A*STAR) Skin Research Labs, 138648, Singapore, Singapore.
Elena Pelluz: Department of Biochemistry and Molecular Biology-B and Immunology, Infectious Disease Pathology, Clinical Microbiology and Tropical Medicine, University of Murcia, Murcia, Spain. ORCID
Gee-Ann Toh: LKC School of Medicine, Nanyang Technological University, Singapore, Singapore. ORCID
Raoul Mazars: Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France.
Caio Bomfim: Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France.
Fabienne Herv��: Ifremer, PHYTOX Physiologie et Toxines des Microalgues Toxiques et Nuisibles, F-44000, Nantes, France. ORCID
Korian Lhaute: Ifremer, PHYTOX Physiologie et Toxines des Microalgues Toxiques et Nuisibles, F-44000, Nantes, France. ORCID
Damien R��veillon: Ifremer, PHYTOX Physiologie et Toxines des Microalgues Toxiques et Nuisibles, F-44000, Nantes, France. ORCID
Bastien Suire: Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France.
L��a Ravon-Katossky: Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France.
Thomas Benoist: Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France. ORCID
L��a Fromont: Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France. ORCID
David P��ricat: Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France.
Kenneth Neil Mertens: Ifremer, COAST Unit, Concarneau, France.
Am��lie Derrien: Ifremer, COAST Unit, Concarneau, France. ORCID
Aouregan Terre-Terrillon: Ifremer, COAST Unit, Concarneau, France.
Nicolas Chom��rat: Ifremer, COAST Unit, Concarneau, France.
Gwena��l Bilien: Ifremer, COAST Unit, Concarneau, France. ORCID
V��ronique S��chet: Ifremer, PHYTOX Physiologie et Toxines des Microalgues Toxiques et Nuisibles, F-44000, Nantes, France. ORCID
Liliane Carpentier: Ifremer, PHYTOX Physiologie et Toxines des Microalgues Toxiques et Nuisibles, F-44000, Nantes, France.
Mamadou Fall: Universit�� Cheikh Anta Diop de Dakar, Laboratoire de Toxicologie et d'hydrologie, Dakar-Fann, Senegal. ORCID
Amidou Sonko: Anti-Poison Centre, Fann University Hospital, Dakar, Senegal.
Hadi Hakim: Private Dermatologist, Dakar, Senegal.
Nfally Sadio: Institut S��n��galais de Recherche Agricole, Centre de Recherche Oc��anographique de Dakar Thiaroye, Dakar, Senegal.
Jessie Bourdeaux: Molecular, Cellular and Developmental (MCD) Unit, Centre for Integrative Biology (CBI), CNRS, University of Toulouse, UPS, Toulouse, France.
C��line Cougoule: Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France. ORCID
Anthony K Henras: Molecular, Cellular and Developmental (MCD) Unit, Centre for Integrative Biology (CBI), CNRS, University of Toulouse, UPS, Toulouse, France. ORCID
Ana Belen Perez-Oliva: Biomedical Research, Institute of Murcia (IMIB)-Pascual Parrilla, Murcia, Spain.
Patrice Brehmer: Institut de Recherche pour le D��veloppement, IRD, Univ Brest, CNRS, Ifremer, Dakar, Senegal. Patrice.Brehmer@ird.fr. ORCID
Francisco J Roca: Department of Biochemistry and Molecular Biology-B and Immunology, Infectious Disease Pathology, Clinical Microbiology and Tropical Medicine, University of Murcia, Murcia, Spain. fjroca@um.es. ORCID
Franklin L Zhong: LKC School of Medicine, Nanyang Technological University, Singapore, Singapore. franklin.zhong@ntu.edu.sg. ORCID
John Common: A*STAR Skin Research, Institute of Singapore, Agency for Science, Technology and Research (A*STAR) Skin Research Labs, 138648, Singapore, Singapore. john.common@newcastle.ac.uk. ORCID
Etienne Meunier: Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France. etienne.meunier@ipbs.fr. ORCID
Philipp Hess: Ifremer, PHYTOX Physiologie et Toxines des Microalgues Toxiques et Nuisibles, F-44000, Nantes, France. philipp.hess@ifremer.fr. ORCID
In 2020-2021, a "mysterious illness" struck Senegalese fishermen, causing severe acute dermatitis in over one thousand individuals following exposure through drift-net fishing activity. Here, by performing deep analysis of the environmental samples we reveal the presence of the marine dinoflagellate Vulcanodinium rugosum and its associated cyclic imine toxins. Specifically, we show that the toxin PortimineA, strongly enriched in environmental samples, impedes ribosome function in human keratinocytes, which subsequently activates the stress kinases ZAK�� and P38 and promotes the nucleation of the human NLRP1 inflammasome, leading to the release of IL-1��/IL-18 pro-inflammatory cytokines and cell death. Furthermore, cell-based models highlight that naturally occurring mutations in the P38-targeted sites of human NLRP1 are unable to respond to PortimineA exposure. Finally, the development and use of human organotypic skins and zebrafish models of PortimineA exposure demonstrate that the ZAK��-NLRP1 axis drives skin necrosis and inflammation. Our results exemplify the threats to human health caused by emerging environmental toxins and identify ZAK�� and NRLP1 as important pharmacological targets to mitigate PortimineA toxicity.
