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Lookup NU author(s): Professor John Common
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025. 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.
Author(s): Gorse L, Plessis L, Wearne S, Paradis M, Pinilla M, Chua R, Lim SS, Pelluz E, TOH G-A, Mazars R, Bomfim C, Herve F, Lhaute K, Reveillon D, Suire B, Ravon-Katossky L, Benoist T, Fromont L, Pericat D, Mertens KN, Derrien A, Terre-Terrillon A, Chomerat N, Bilien G, Sechet V, Carpentier L, Fall M, Sonko A, Hakim H, Sadio N, Bourdeaux J, Cougoule C, Henras AK, Perez-Oliva AB, Brehmer P, Roca FJ, Zhong FL, Common J, Meunier E, Hess P
Publication type: Article
Publication status: Published
Journal: EMBO Molecular Medicine
Year: 2025
Volume: 17
Issue: 3
Pages: 535-562
Print publication date: 12/03/2025
Online publication date: 13/02/2025
Acceptance date: 23/01/2025
Date deposited: 23/01/2026
ISSN (print): 1757-4676
ISSN (electronic): 1757-4684
Publisher: Springer Nature
URL: https://doi.org/10.1038/s44321-025-00197-4
DOI: 10.1038/s44321-025-00197-4
Data Access Statement: Experimental dataset of toxin profile in sea samples are availabale in the following database: Plessis et al (2024) Portimine A toxin causes skin pathology through ZAKa-dependent NLRP1 inflammasome activation: LC-MS/MS raw data for Fig. 1C [Data set]. Zenodo https://doi.org/10.5281/zenodo.14254268 The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44321-025-00197-4.
PubMed id: 39948420
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