Portimine A toxin causes skin inflammation through ZAKα-dependent NLRP1 inflammasome activation
Year: 2025
Type: article
Abstract: 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 ZAKα and P38 and promotes the nucleation of the human NLRP1 inflammasome, leading to the release of IL-1β/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 ZAKα-NLRP1 axis drives skin necrosis and inflammation. Our results exemplify the threats to human health caused by emerging environmental toxins and identify ZAKα and NRLP1 as important pharmacological targets to mitigate PortimineA toxicity.
Source: EMBO Molecular Medicine
Authors: Léana Gorse, Loïc Plessis, Stephen Wearne, Margaux Paradis, Miriam Pinilla, Rae Chua, Seong Soo Lim, Elena Pelluz, Gee-Ann TOH, Raoul Mazars, Caio Bomfim, Fabienne Hervé, Korian Lhaute, Damien Réveillon, Bastien Suire, Léa Ravon-Katossky, Thomas Benoist, Léa Fromont, David Péricat, Kenneth Neil Mertens, Amélie Derrien, Aouregan Terre-Terrillon, Nicolas Chomérat, Gwenaël Bilien, Véronique Séchet, Liliane Carpentier, Mamadou Fall, Amidou Sonko, Hadi Hakim, Nfally Sadio, Jessie Bourdeaux, Céline Cougoule, Anthony K Henras, Ana Belen Perez-Oliva, Patrice Brehmer, Francisco J Roca, Franklin L Zhong, John Common, Etienne Meunier, Philipp Hess
Institutions: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Ifremer, Agency for Science, Technology and Research, Skin Research Institute of Singapore, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, Nanyang Technological University, Centre Hospitalier National Universitaire de Fann, Cheikh Anta Diop University, Institut de Recherche pour le Développement, Institut de Recherche pour le Développement, Institut Sénégalais de Recherches Agricoles, Université Toulouse III - Paul Sabatier, Unité de biologie Moléculaire, Cellulaire et du Développement, Centre de Biologie Intégrative de Toulouse, Sub-Regional Fisheries Commission, Institut Universitaire Européen de la Mer, Laboratoire des Sciences de l'Environnement Marin, NIHR Newcastle Biomedical Research Centre, Newcastle University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $7,990
Funders: Institut Français de Recherche pour l'Exploitation de la Mer, “la Caixa” Foundation, Institut de Recherche pour le Développement, Alliance Nationale pour les Sciences de la Vie et de la Santé, National Institute for Health and Care Research, Agence Nationale de la Recherche, Bundesministerium für Bildung und Forschung, Fondation pour la Recherche Médicale, Association Nationale de la Recherche et de la Technologie, Ministry of Education, India, Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona, Medical Research Council, National Medical Research Council, NIHR Newcastle Biomedical Research Centre, European Social Fund, HORIZON EUROPE European Research Council
Awards: PathophySiological impact of Inflammasome COntrol by PAK-kinases in psoriasis, G2131186200, ImportanCe of inflammasOmes in eMerging Environmental Toxin-driven patHologies, G3535982825, G489645366, G5120647007, G5458040483, G5486664426, Functional conservation and divergence in INFLAmmasomes of MArine organisms towards bio-inspired anti-TOXins molecules, G6820774512, G6983695657, G7586750453, Verbundprojekt: Der Ökosystemansatz im Fischerei- und Umweltmanagement der Meeresgebiete Westafrikas (AWA), Teilprojekt: TPG1 - GEOMAR - Beobachtung und Modellierung der Ozeanphysik und Biogeochemie für einen Ökosystemansatz im Management der Fischerei und der Meeresumwelt, G8441356214
OpenAlex ID: W4407550331