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

Pierre, P.; Barros, D.; Ferreira, B.; Garcia-Gonzalez, P.; Carbone, F.; Luka, M.; Leite-Pinheiro, F. C.; Antas, P.; Mendes, A.; Machado, M.; Zhang, L.; Cresci, M.; Galliot, L.; Gigan, J.; Reverendo, M.; Su, B.; Paton, A. W.; Paton, J. C.; Rocchi, S.; Rieux-laucat, F.; Arguello, R. J.; Nal Rogier, B.; Liang, Y.; Menager, M. M.; Gatti, E.; Almeida, C.

doi:10.1101/2024.10.07.616986

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bioRxiv · 10.1101/2024.10.07.616986

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

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Abstract

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.

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Pierre, P., Barros, D., Ferreira, B., Garcia-Gonzalez, P., Carbone, F., Luka, M., Leite-Pinheiro, F. C., Antas, P., Mendes, A., Machado, M., Zhang, L., Cresci, M., Galliot, L., Gigan, J., Reverendo, M., Su, B., Paton, A. W., Paton, J. C., Rocchi, S., Rieux-laucat, F., Arguello, R. J., Nal Rogier, B., Liang, Y., Menager, M. M., Gatti, E., Almeida, C.. 2024-10-12. Induction of the ISR by AB5 subtilase cytotoxin drives IFN-I expression in pDCs via STING activation. https://doi.org/10.1101/2024.10.07.616986

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