Stalled but not forgotten: Bacterial exotoxins inhibit translation to activate NLRP1

Abstract

In this issue of JEM, companion articles from Pinilla et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20230104) and Robinson et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20230105) demonstrate that ribotoxic stress induced by Pseudomonas aeruginosa and Corynebacterium diphtheriae EEF2-targeting exotoxins leads to NLRP1 inflammasome activation, representing a new mechanism of effector-triggered immunity.

Insights from Ryan Tibble, Marisa A. Yonemitsu, and Patrick S. Mitchell.

NLRP1 recognizes P. aeruginosa and C. diphtheriae through the RSR. DT and ExoA exotoxins ADP-ribosylate eukaryotic translation elongation factor 2 (EEF2) to inhibit protein synthesis and induce ribosome collisions that activate the MAP kinase kinase kinase ZAKα, initiating a signaling cascade culminating in p38α and p38β phosphorylation. Both ZAKα and p38α/β phosphorylate NLRP1’s N-terminal “tripwire,” leading to its functional degradation. The bioactive C terminus of NLRP1 complexes with ASC and CASP1 to form an active inflammasome and drive subsequent inflammation and pyroptotic cell death.