1. EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption.
- Author
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Pinilla M, Mazars R, Vergé R, Gorse L, Paradis M, Suire B, Santoni K, Robinson KS, Toh GA, Prouvensier L, Leon-Icaza SA, Hessel A, Péricat D, Murris M, Guet-Revillet H, Henras A, Buyck J, Ravet E, Zhong FL, Cougoule C, Planès R, and Meunier E
- Subjects
- Humans, Peptide Elongation Factor 2, Inflammasomes, Cytoplasm, NLR Proteins, Eukaryota, Cystic Fibrosis
- Abstract
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., (© 2023 Pinilla et al.)
- Published
- 2023
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