TY - JOUR
T1 - Portimine A toxin causes skin inflammation through ZAKα-dependent NLRP1 inflammasome activation
AU - Gorse, Léana
AU - Plessis, Loïc
AU - Wearne, Stephen
AU - Paradis, Margaux
AU - Pinilla, Miriam
AU - Chua, Rae
AU - Lim, Seong Soo
AU - Pelluz, Elena
AU - TOH, Gee Ann
AU - Mazars, Raoul
AU - Bomfim, Caio
AU - Hervé, Fabienne
AU - Lhaute, Korian
AU - Réveillon, Damien
AU - Suire, Bastien
AU - Ravon-Katossky, Léa
AU - Benoist, Thomas
AU - Fromont, Léa
AU - Péricat, David
AU - Neil Mertens, Kenneth
AU - Derrien, Amélie
AU - Terre-Terrillon, Aouregan
AU - Chomérat, Nicolas
AU - Bilien, Gwenaël
AU - Séchet, Véronique
AU - Carpentier, Liliane
AU - Fall, Mamadou
AU - Sonko, Amidou
AU - Hakim, Hadi
AU - Sadio, Nfally
AU - Bourdeaux, Jessie
AU - Cougoule, Céline
AU - Henras, Anthony K.
AU - Perez-Oliva, Ana Belen
AU - Brehmer, Patrice
AU - Roca, Francisco J.
AU - Zhong, Franklin L.
AU - Common, John
AU - Meunier, Etienne
AU - Hess, Philipp
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025
Y1 - 2025
N2 - 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.
AB - 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.
KW - Environmental Toxins
KW - NLRP1 Inflammasome
KW - Ribotoxic Stress Response
KW - Skin Pathology
UR - http://www.scopus.com/inward/record.url?scp=85217758787&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85217758787&partnerID=8YFLogxK
U2 - 10.1038/s44321-025-00197-4
DO - 10.1038/s44321-025-00197-4
M3 - Article
AN - SCOPUS:85217758787
SN - 1757-4676
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
M1 - 5
ER -
