Induction of the ISR by AB5 subtilase cytotoxin drives type-I IFN expression in pDCs via STING activation
- Daniela Barros
- Beatriz H. Ferreira
- Paulina Garcia-Gonzalez
- Francesco Carbone
- Marine Luka
- Fátima Leite-Pinheiro
- Mariana D. Machado
- Theopisti Nikolaou
- Angelo Pilotti
- Eliot Goguet
- Paulo Antas
- Andreia Mendes
- Lichen Zhang
- Marina Cresci
- Lou Galliot
- Julien P. Gigan
- Marisa Reverendo
- Bing Su
- Miwako Narita
- Adrienne W. Paton
- James C. Paton
- Stéphane Rocchi
- Frédéric Rieux-Laucat
- Rafael J. Argüello
- Béatrice Nal
- Yinming Liang
- Mickaël Ménager
- Evelina Gatti
- Catarina R. Almeida
- Philippe Pierre
2025-05-19
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 proinflammatory 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 (PERK) 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 light on how UPR-inducing conditions may regulate the immune system during infection or pathogenesis.