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. 2025 May 27;122(21):e2421258122.
doi: 10.1073/pnas.2421258122. Epub 2025 May 19.

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

Daniela Barros #  1   2 , Beatriz H Ferreira #  1   3 , Paulina Garcia-Gonzalez  2 , Francesco Carbone  4   5 , Marine Luka  4   5 , Fátima Leite-Pinheiro  1 , Mariana D Machado  1 , Theopisti Nikolaou  2 , Angelo Pilotti  2 , Eliot Goguet  2 , Paulo Antas  1 , Andreia Mendes  1   2 , Lichen Zhang  6 , Marina Cresci  2 , Lou Galliot  2 , Julien P Gigan  2 , Marisa Reverendo  1 , Bing Su  7 , Miwako Narita  8 , Adrienne W Paton  9 , James C Paton  9 , Stéphane Rocchi  10 , Frédéric Rieux-Laucat  11 , Rafael J Argüello  2 , Béatrice Nal  2 , Yinming Liang  6 , Mickaël Ménager  4   5 , Evelina Gatti  1   2 , Catarina R Almeida  1 , Philippe Pierre  1   2   6
Affiliations

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

Daniela Barros et al. Proc Natl Acad Sci U S A. .

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 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.

Keywords: innate immunity; pDC; subtilase cytotoxin; unfolded protein stress response.

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Conflict of interest statement

Competing interests statement:Stéphane Rocchi is the co-founder of BIPER therapeutics.

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