Léana Gorse

Institut de Pharmacologie et de Biologie Structurale

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Miriam Pinilla

Institut de Pharmacologie et de Biologie Structurale

ÉM

Étienne Meunier

Institut de Pharmacologie et de Biologie Structurale

Gee Ann Toh

Nanyang Technological University

David Péricat

Institut de Pharmacologie et de Biologie Structurale

Céline Cougoule

Institut de Pharmacologie et de Biologie Structurale

Franklin L. Zhong

Nanyang Technological University

Julien M. Buyck

Université de Poitiers

Audrey Hessel

Institut de Pharmacologie et de Biologie Structurale

Kim S. Robinson

Agency for Science, Technology and Research

Anthony K. Henras

Centre National de la Recherche Scientifique

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Centre National de la Recherche Scientifique

Institut de Pharmacologie et de Biologie Structurale

Université de Toulouse

Université Toulouse III - Paul Sabatier

Ifremer

Inserm

Nanyang Technological University

Agency for Science, Technology and Research

Université de Bretagne Occidentale

Universidad de Murcia

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EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption uponPseudomonasinfection

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Miriam Pinilla Raoul Mazars Romain Vergé Léana Gorse Karin Santoni

ABSTRACT The intracellular inflammasome complex have been implicated in the maladaptive tissue damage and inflammation observed in chronic Pseudomonas aeruginosa infection. Human airway and corneal epithelial cells, which are critically altered during chronic infections mediated by P. aeruginosa , specifically express the inflammasome sensor NLRP1. Here, together with a companion study, we report that the NLRP1 inflammasome detects Exotoxin A (EXOA), a ribotoxin released by P. aeruginosa Type 2 Secretion System (T2SS) during chronic infection. Mechanistically, EXOA-driven Eukaryotic Elongation Factor 2 (EEF2) ribosylation and covalent inactivation promotes ribotoxic stress and subsequent NLRP1 inflammasome activation, a process shared with other EEF2-inactivating toxins, Diphtheria Toxin and Cholix Toxin. Biochemically, irreversible EEF2 inactivation triggers ribosome stress-associated kinases ZAKα- and P38-dependent NLRP1 phosphorylation and subsequent proteasome-driven functional degradation. Finally, Cystic Fibrosis cells from patients exhibit exacerbated P38 activity and hypersensitivity to EXOA-induced ribotoxic stress-dependent NLRP1 inflammasome activation, a process inhibited by the use of ZAKα inhibitors. Altogether, our results show the importance of P. aeruginosa virulence factor EXOA at promoting NLRP1-dependent epithelial damage and identify ZAKα as a critical sensor of virulence-inactivated EEF2. KEY POINTS P. aeruginosa induces NLRP1-dependent pyroptosis in human corneal and nasal epithelial cells P. aeruginosa Exotoxin A (EXOA) and other EEF2-inactivating bacterial exotoxins activate the human NLRP1 inflammasome EEF2 inactivation promotes ribotoxic stress response and ZAKα kinase-dependent NLRP1 inflammasome activation. Bronchial epithelial cells from Cystic Fibrosis patients show extreme sensitivity to ribotoxic stress-dependent NLRP1 inflammasome activation in response to Exotoxin A P38 and ZAKα inhibition protects Cystic Fibrosis epithelial cell from EXOA-induced pyroptosis

Pseudomonas exotoxin

Pyroptosis

Exotoxin

NLRP1

10.1101/2023.01.16.524164

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Citations (2)

Mechanistic basis for potassium efflux–driven activation of the human NLRP1 inflammasome

Proceedings of the National Academy of Sciences (2024)

Pritisha Rozario Miriam Pinilla Léana Gorse Anna Vind Kim S. Robinson

Nigericin, an ionophore derived from Streptomyces hygroscopicus , is arguably the most commonly used tool compound to study the NLRP3 inflammasome. Recent findings, however, showed that nigericin also activates the NLRP1 inflammasome in human keratinocytes. In this study, we resolve the mechanistic basis of nigericin-driven NLRP1 inflammasome activation. In multiple nonhematopoietic cell types, nigericin rapidly and specifically inhibits the elongation stage of the ribosome cycle by depleting cytosolic potassium ions. This activates the ribotoxic stress response (RSR) sensor kinase ZAKα, p38, and JNK, as well as the hyperphosphorylation of the NLRP1 linker domain. As a result, nigericin-induced pyroptosis in human keratinocytes is blocked by extracellular potassium supplementation, ZAKα knockout, or pharmacologic inhibitors of ZAKα and p38 kinase activities. By surveying a panel of ionophores, we show that electroneutrality of ion movement is essential to activate ZAKα-driven RSR and a greater extent of K+ depletion is necessary to activate ZAKα-NLRP1 than NLRP3. These findings resolve the mechanism by which nigericin activates NLRP1 in nonhematopoietic cell types and demonstrate an unexpected connection between RSR, perturbations of potassium ion flux, and innate immunity.

Nigericin

Pyroptosis

10.1073/pnas.2309579121

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Citations (14)

EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption

The Journal of Experimental Medicine (2023)

Miriam Pinilla Raoul Mazars Romain Vergé Léana Gorse M. Paradis

Human airway and corneal epithelial cells, which are critically altered during chronic infections mediated by Pseudomonas aeruginosa, specifically express the inflammasome sensor NLRP1. Here, together with a companion study, we report that the NLRP1 inflammasome detects exotoxin A (EXOA), a ribotoxin released by P. aeruginosa type 2 secretion system (T2SS), during chronic infection. Mechanistically, EXOA-driven eukaryotic elongation factor 2 (EEF2) ribosylation and covalent inactivation promote ribotoxic stress and subsequent NLRP1 inflammasome activation, a process shared with other EEF2-inactivating toxins, diphtheria toxin and cholix toxin. Biochemically, irreversible EEF2 inactivation triggers ribosome stress–associated kinases ZAKα- and P38-dependent NLRP1 phosphorylation and subsequent proteasome-driven functional degradation. Finally, cystic fibrosis cells from patients exhibit exacerbated P38 activity and hypersensitivity to EXOA-induced ribotoxic stress–dependent NLRP1 inflammasome activation, a process inhibited by the use of ZAKα inhibitors. Altogether, our results show the importance of P. aeruginosa virulence factor EXOA at promoting NLRP1-dependent epithelial damage and identify ZAKα as a critical sensor of virulence-inactivated EEF2.

Pseudomonas exotoxin

Virulence factor

Elongation factor

NLRP1

10.1084/jem.20230104

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Citations (18)

Détection immunitaire des toxines bactériennes inhibitrices de la traduction dans les cellules épithéliales

médecine/sciences (2025)

Miriam Pinilla Léana Gorse Étienne Meunier

10.1051/medsci/2024186

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

EMBO Molecular Medicine (2025)

Léana Gorse L. Plessis Stephen Wearne M. Paradis Miriam Pinilla

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.

NLRP1

Human skin

NALP3

Pyroptosis

10.1038/s44321-025-00197-4

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Citations (0)

Caspase-1-driven neutrophil pyroptosis and its role in host susceptibility to Pseudomonas aeruginosa

PLoS Pathogens (2022)

Karin Santoni David Péricat Léana Gorse Julien M. Buyck Miriam Pinilla

Multiple regulated neutrophil cell death programs contribute to host defense against infections. However, despite expressing all necessary inflammasome components, neutrophils are thought to be generally defective in Caspase-1-dependent pyroptosis. By screening different bacterial species, we found that several Pseudomonas aeruginosa ( P . aeruginosa ) strains trigger Caspase-1-dependent pyroptosis in human and murine neutrophils. Notably, deletion of Exotoxins U or S in P . aeruginosa enhanced neutrophil death to Caspase-1-dependent pyroptosis, suggesting that these exotoxins interfere with this pathway. Mechanistically, P . aeruginosa Flagellin activates the NLRC4 inflammasome, which supports Caspase-1-driven interleukin (IL)-1β secretion and Gasdermin D (GSDMD)-dependent neutrophil pyroptosis. Furthermore, P . aeruginosa -induced GSDMD activation triggers Calcium-dependent and Peptidyl Arginine Deaminase-4-driven histone citrullination and translocation of neutrophil DNA into the cell cytosol without inducing extracellular Neutrophil Extracellular Traps. Finally, we show that neutrophil Caspase-1 contributes to IL-1β production and susceptibility to pyroptosis-inducing P . aeruginosa strains in vivo . Overall, we demonstrate that neutrophils are not universally resistant for Caspase-1-dependent pyroptosis.

Pyroptosis

Neutrophil Extracellular Traps

NLRC4

AIM2

10.1371/journal.ppat.1010305

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Citations (34)