| Title: |
EEF2-inactivating toxins engage the NLRP1 inflammasome and promote epithelial barrier disruption |
| Authors: |
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 |
| Source: |
The Journal of Experimental Medicine; October 2023, Vol. 220 Issue: 10 pe20230104-e20230104, 1p |
| 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. |
| Database: |
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