EEF2-inactivating Toxins Engage the NLRP1 Inflammasome and Promote Epithelial Barrier Disruption

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2023 Aug 29

PMID 37642996

Authors

Miriam Pinilla

Raoul Mazars

Romain Verge

Leana Gorse

Margaux Paradis

Bastien Suire

Karin Santoni

Kim Samirah Robinson

Gee Ann Toh

Laure Prouvensier

Stephen Adonai Leon-Icaza

Audrey Hessel

David Pericat

Marlene Murris

Helene Guet-Revillet

Anthony Henras

Julien Buyck

Emmanuel Ravet

Franklin L Zhong

Celine Cougoule

Remi Planes

Etienne Meunier

Affiliations

Soon will be listed here.

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.

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