RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signaling
Kaiwen Chen, Benjamin Demarco, Saray Ramos, Rosalie Heilig, Michiel Goris, James P. Grayczyk, Charles‐Antoine Assenmacher, Enrico Radaelli, Leonel Joannas, Jorge Henao‐Mejia, Fabienne Tacchini‐Cottier, Igor E. Brodsky, Petr Brož
Abstract
Significance Pathogenic bacteria subvert host-defense mechanisms by injecting effector proteins into target cells to inhibit NF-κB and MAPK signaling. Detection of such effector proteins, such as YopJ from pathogenic Yersinia , activates RIPK1 and caspase-8–dependent cell death that promotes antibacterial defense. While recent studies demonstrate that caspase-8 cleaves the pore-forming protein gasdermin D to promote anti- Yersinia defense, whether RIPK1 activates other substrates is unclear. Here, we demonstrate that RIPK1 activates gasdermin D in macrophages and the related gasdermin E in neutrophils to promote host defense. Neutralization of IL-1β in vivo promoted host susceptibility to Yersinia infection in wild-type, but not Gsdme −/− , animals, revealing an unexpected role for gasdermin E in IL-1β secretion during bacterial infection.