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

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Pinilla, Miriam | Mazars, Raoul | Vergé, Romain | Gorse, Leana | Paradis, Margaux | Suire, Bastien | Santoni, Karin | Robinson, Kim Samirah | Toh, Gee Ann | Prouvensier, Laure | Leon-Icaza, Stephen Adonai | Hessel, Audrey | Péricat, David | Murris, Marlène | Guet-Revillet, Hélène | Henras, Anthony | Buyck, Julien | Ravet, Emmanuel | Zhong, Franklin, L | Cougoule, Céline | Planès, Rémi | Meunier, Etienne

Edité par CCSD ; Rockefeller University Press -

International audience. 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.

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