PUBLICATION
Portimine A toxin causes skin inflammation through ZAKα-dependent NLRP1 inflammasome activation
- Authors
- Gorse, L., Plessis, L., Wearne, S., Paradis, M., Pinilla, M., Chua, R., Lim, S.S., Pelluz, E., Toh, G.A., Mazars, R., Bomfim, C., Hervé, F., Lhaute, K., Réveillon, D., Suire, B., Ravon-Katossky, L., Benoist, T., Fromont, L., Péricat, D., Neil Mertens, K., Derrien, A., Terre-Terrillon, A., Chomérat, N., Bilien, G., Séchet, V., Carpentier, L., Fall, M., Sonko, A., Hakim, H., Sadio, N., Bourdeaux, J., Cougoule, C., Henras, A.K., Perez-Oliva, A.B., Brehmer, P., Roca, F.J., Zhong, F.L., Common, J., Meunier, E., Hess, P.
- ID
- ZDB-PUB-250214-23
- Date
- 2025
- Source
- EMBO Molecular Medicine : (Journal)
- Registered Authors
- Keywords
- Environmental Toxins, NLRP1 Inflammasome, Ribotoxic Stress Response, Skin Pathology
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism
- Skin/drug effects
- Skin/metabolism
- Skin/pathology
- Inflammasomes*/metabolism
- Cell Cycle Proteins
- Transcription Factors
- YAP-Signaling Proteins
- Inflammation/metabolism
- Inflammation/pathology
- Dermatitis/metabolism
- Dermatitis/pathology
- Keratinocytes*/drug effects
- Keratinocytes*/metabolism
- Keratinocytes*/pathology
- Interleukin-1beta/genetics
- Interleukin-1beta/metabolism
- Sulfonamides
- Zebrafish*
- Marine Toxins
- Furans
- Indenes
- Animals
- Humans
- Dinoflagellida
- NLR Proteins/genetics
- NLR Proteins/metabolism
- PubMed
- 39948420 Full text @ EMBO Mol. Med.
Citation
Gorse, L., Plessis, L., Wearne, S., Paradis, M., Pinilla, M., Chua, R., Lim, S.S., Pelluz, E., Toh, G.A., Mazars, R., Bomfim, C., Hervé, F., Lhaute, K., Réveillon, D., Suire, B., Ravon-Katossky, L., Benoist, T., Fromont, L., Péricat, D., Neil Mertens, K., Derrien, A., Terre-Terrillon, A., Chomérat, N., Bilien, G., Séchet, V., Carpentier, L., Fall, M., Sonko, A., Hakim, H., Sadio, N., Bourdeaux, J., Cougoule, C., Henras, A.K., Perez-Oliva, A.B., Brehmer, P., Roca, F.J., Zhong, F.L., Common, J., Meunier, E., Hess, P. (2025) Portimine A toxin causes skin inflammation through ZAKα-dependent NLRP1 inflammasome activation. EMBO Molecular Medicine. :.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping