2. Academic Validation
  3. Portimine A toxin causes skin inflammation through ZAKα-dependent NLRP1 inflammasome activation

Portimine A toxin causes skin inflammation through ZAKα-dependent NLRP1 inflammasome activation

  • EMBO Mol Med. 2025 Feb 13. doi: 10.1038/s44321-025-00197-4.
Léana Gorse # 1,  Loïc Plessis # 2 3,  Stephen Wearne # 4,  Margaux Paradis # 1,  Miriam Pinilla # 5 6,  Rae Chua # 7,  Seong Soo Lim 4,  Elena Pelluz 5 6,  Gee-Ann Toh 7,  Raoul Mazars 1,  Caio Bomfim 1,  Fabienne Hervé 2,  Korian Lhaute 2,  Damien Réveillon 2,  Bastien Suire 1,  Léa Ravon-Katossky 1,  Thomas Benoist 1,  Léa Fromont 1,  David Péricat 1,  Kenneth Neil Mertens 8,  Amélie Derrien 8,  Aouregan Terre-Terrillon 8,  Nicolas Chomérat 8,  Gwenaël Bilien 8,  Véronique Séchet 2,  Liliane Carpentier 2,  Mamadou Fall 9 10,  Amidou Sonko 10 11,  Hadi Hakim 12,  Nfally Sadio 13,  Jessie Bourdeaux 14,  Céline Cougoule 1,  Anthony K Henras 14,  Ana Belen Perez-Oliva 6,  Patrice Brehmer # 15 16,  Francisco J Roca # 17 18 17,  Franklin L Zhong # 19 20,  John Common # 21 22 23,  Etienne Meunier # 24 24,  Philipp Hess # 25 25
Affiliations

Affiliations

  • 1 Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France.
  • 2 Ifremer, PHYTOX Physiologie et Toxines des Microalgues Toxiques et Nuisibles, F-44000, Nantes, France.
  • 3 Groupe Rocher, Research-Innovation & Development Department, Issy-les-Moulineaux, France.
  • 4 A*STAR Skin Research, Institute of Singapore, Agency for Science, Technology and Research (A*STAR) Skin Research Labs, 138648, Singapore, Singapore.
  • 5 Department of Biochemistry and Molecular Biology-B and Immunology, Infectious Disease Pathology, Clinical Microbiology and Tropical Medicine, University of Murcia, Murcia, Spain.
  • 6 Biomedical Research, Institute of Murcia (IMIB)-Pascual Parrilla, Murcia, Spain.
  • 7 LKC School of Medicine, Nanyang Technological University, Singapore, Singapore.
  • 8 Ifremer, COAST Unit, Concarneau, France.
  • 9 Université Cheikh Anta Diop de Dakar, Laboratoire de Toxicologie et d'hydrologie, Dakar-Fann, Senegal.
  • 10 Anti-Poison Centre, Fann University Hospital, Dakar, Senegal.
  • 11 Institut de Recherche pour le Développement, IRD, Univ Brest, CNRS, Ifremer, Dakar, Senegal.
  • 12 Private Dermatologist, Dakar, Senegal.
  • 13 Institut Sénégalais de Recherche Agricole, Centre de Recherche Océanographique de Dakar Thiaroye, Dakar, Senegal.
  • 14 Molecular, Cellular and Developmental (MCD) Unit, Centre for Integrative Biology (CBI), CNRS, University of Toulouse, UPS, Toulouse, France.
  • 15 Institut de Recherche pour le Développement, IRD, Univ Brest, CNRS, Ifremer, Dakar, Senegal. Patrice.Brehmer@ird.fr.
  • 16 SRFC, Sub regional Fisheries Commission, Liberté 5, Dakar, Senegal. Patrice.Brehmer@ird.fr.
  • 17 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.
  • 18 Biomedical Research, Institute of Murcia (IMIB)-Pascual Parrilla, Murcia, Spain. fjroca@um.es.
  • 19 LKC School of Medicine, Nanyang Technological University, Singapore, Singapore. franklin.zhong@ntu.edu.sg.
  • 20 A*STAR Skin Research Institute of Singapore, Agency for Science, Technology and Research (A*STAR) Skin Research Labs, 138648, Singapore, Singapore. franklin.zhong@ntu.edu.sg.
  • 21 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.
  • 22 Translational and Clinical Research Institute and NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK. john.common@newcastle.ac.uk.
  • 23 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.
  • 24 Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France. etienne.meunier@ipbs.fr.
  • 25 Ifremer, PHYTOX Physiologie et Toxines des Microalgues Toxiques et Nuisibles, F-44000, Nantes, France. philipp.hess@ifremer.fr.
  • # Contributed equally.
PMID: 39948420 DOI: 10.1038/s44321-025-00197-4
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.

Keywords

Environmental Toxins; NLRP1 Inflammasome; Ribotoxic Stress Response; Skin Pathology.

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