Publication: Induction of the ISR by AB5 subtilase cytotoxin drives type-I IFN expression in pDCs via STING activation

Publié dans: BioRxiv, 2024, ⟨10.1101/2024.10.07.616986⟩

Auteurs: Daniela Barros, Beatriz Ferreira, Paulina Garcia-Gonzalez, Francesco Carbone, Marine Luka, Fátima Leite-Pinheiro, Paulo Antas, Andreia Mendes, Mariana Machado, Lichen Zhang, Marina Cresci, Lou Galliot, Julien Gigan, Marisa Reverendo, Bing Su, Adrienne Paton, James Paton, Stéphane Rocchi, Frédéric Rieux-Laucat, Rafael Argüello, Béatrice Nal, Yinming Liang, Mickaël Ménager, Evelina Gatti, Catarina Almeida, Philippe Pierre

Résumé

SUMMARY We demonstrate that exposure to the AB5 subtilase cytotoxin (SubAB) induces the unfolded protein response (UPR) in human peripheral blood mononuclear cells, concomitant with a pro-inflammatory response across distinct cell subsets. Notably, SubAB selectively induces type-I interferon (IFN) expression in plasmacytoid dendritic cells, acting synergistically with Toll-like receptor 7 stimulation. The induction of type-I IFN in response to SubAB relies on stimulator of interferon genes (STING) activation, coupled with protein synthesis inhibition mediated by protein kinase R-like endoplasmic reticulum kinase and phosphorylation of the eukaryotic translation initiation factor 2 subunit-alpha. By impeding mRNA translation through the integrated stress response, SubAB precipitates the downregulation of the negative innate signaling feedback regulator Tax1-binding protein 1. This downregulation is necessary to unleash TANK-binding kinase 1 signaling associated with STING activation. These findings shed new light on how UPR-inducing conditions may regulate the immune system during infection or pathogenesis.

Lien vers HAL – hal-04793368

Lien vers le DOI – 10.1101/2024.10.07.616986