Portimine A toxin causes skin inflammation through ZAKα-dependent NLRP1 inflammasome activation
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.
Authors
- Gee Ann Toh (ORCID: https://orcid.org/0000-0002-7417-8376)
- Franklin L. Zhong (ORCID: https://orcid.org/0000-0002-0516-6021)
- Véronique Séchet (ORCID: https://orcid.org/0000-0002-7085-3215)
- Amélie Derrien (ORCID: https://orcid.org/0000-0001-9656-7850)
- Kenneth Neil Mertens (ORCID: https://orcid.org/0000-0003-2005-9483)
- Raoul Mazars (ORCID: https://orcid.org/0000-0002-9102-7916)
- Caio César Barbosa Bomfim (ORCID: https://orcid.org/0000-0003-1998-9237)
- David Péricat (ORCID: https://orcid.org/0009-0001-0428-8211)
- Francisco J. Roca (ORCID: https://orcid.org/0000-0002-6744-148X)
- Rae Chua (ORCID: https://orcid.org/0000-0002-3150-6368)
- M. Paradis (ORCID: https://orcid.org/0009-0008-4423-4147)
- Étienne Meunier (ORCID: https://orcid.org/0000-0002-3651-4877)
- Philipp Heß (ORCID: https://orcid.org/0000-0002-9047-1345)
- H A Nazmul Hakim
- Damien Réveillon (ORCID: https://orcid.org/0000-0002-6706-6077)
- Anthony K. Henras (ORCID: https://orcid.org/0000-0001-7785-9938)
- Fabienne Hervé (ORCID: https://orcid.org/0000-0002-5485-7611)
- Gwenaël Bilien (ORCID: https://orcid.org/0000-0002-8633-3441)
- Amidou Sonko (ORCID: https://orcid.org/0000-0001-5482-8186)
- Jessie Bourdeaux
- Thomas Benoist (ORCID: https://orcid.org/0000-0003-0116-2629)
- Ana B. Pérez‐Oliva (ORCID: https://orcid.org/0000-0002-2596-0871)
- Aourégan Terre-Terrillon (ORCID: https://orcid.org/0009-0001-7410-4780)
- Léa Fromont (ORCID: https://orcid.org/0000-0001-6747-2705)
- Céline Cougoule (ORCID: https://orcid.org/0000-0002-6795-5448)
- Liliane Carpentier (ORCID: https://orcid.org/0009-0004-1796-3855)
- John Common (ORCID: https://orcid.org/0000-0002-3280-7365)
- L. Plessis
- Korian Lhaute
- Nicolas Chomérat (ORCID: https://orcid.org/0000-0001-9691-6344)
- Mamadou Fall (ORCID: https://orcid.org/0000-0001-8588-8309)
- Patrice Brehmer (ORCID: https://orcid.org/0000-0001-8949-9095)
- Léana Gorse (ORCID: https://orcid.org/0009-0009-3149-9784)
- Miriam Pinilla
- Bastien Suire (ORCID: https://orcid.org/0009-0003-1414-7804)
- Nfally Sadio
- Seong Soo Lim
- Stephen Wearne (ORCID: https://orcid.org/0009-0003-0320-7402)
- Léa Ravon‐Katossky
- Elena Pelluz
Institutions
- Agency for Science, Technology and Research (SG)
- Centre National de la Recherche Scientifique (FR)
- Université Toulouse III - Paul Sabatier (FR)
- Ifremer (FR)
- Université de Bretagne Occidentale (FR)
- Nanyang Technological University (SG)
- Gulf States Marine Fisheries Commission (US)
- Institut de Pharmacologie et de Biologie Structurale (FR)
- Institut de Recherche pour le Développement (SN)
- NIHR Newcastle Biomedical Research Centre (GB)
- Centre Hospitalier National Universitaire de Fann (SN)
- Instituto Murciano de Investigación Biosanitaria (ES)
- Hôpital Principal de Dakar (SN)
- Issy Media (France) (FR)
- Institut Universitaire Européen de la Mer (FR)
- Institut Sénégalais de Recherches Agricoles (SN)
- Laboratoire des Sciences de l'Environnement Marin (FR)
- Institut de Recherche pour le Développement (FR)
- Universidad de Murcia (ES)
- Cheikh Anta Diop University (SN)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-02-13
- DOI
- https://doi.org/10.1038/s44321-025-00197-4
- Citations
- 7
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 5.64
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