Induction of the ISR by AB5 subtilase cytotoxin drives type-I IFN expression in pDCs via STING activation
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.
Authors
- Yinming Liang (ORCID: https://orcid.org/0000-0001-9174-4037)
- Paulina A García-González
- Julien P. Gigan
- Stéphane Rocchi (ORCID: https://orcid.org/0000-0002-0943-1304)
- Mickaël Ménager
- Rafael J. Argüello (ORCID: https://orcid.org/0000-0001-9785-3883)
- Bing Su (ORCID: https://orcid.org/0000-0003-0871-7666)
- Marisa Reverendo (ORCID: https://orcid.org/0000-0001-6999-1816)
- Miwako Narita (ORCID: https://orcid.org/0000-0003-2007-1183)
- Adrienne W. Paton (ORCID: https://orcid.org/0000-0002-2996-5733)
- Catarina R. Almeida (ORCID: https://orcid.org/0000-0001-6670-6004)
- Beatriz H. Ferreira (ORCID: https://orcid.org/0000-0002-1497-7440)
- James C. Paton (ORCID: https://orcid.org/0000-0001-9807-5278)
- Béatrice Nal (ORCID: https://orcid.org/0000-0003-3452-7524)
- Paulo Antas (ORCID: https://orcid.org/0000-0002-4361-8164)
- Frédéric Rieux‐Laucat (ORCID: https://orcid.org/0000-0001-7858-7866)
- Daniela Barros (ORCID: https://orcid.org/0000-0002-7104-0267)
- Philippe Pierre (ORCID: https://orcid.org/0000-0003-0863-8255)
- Evelina Gatti (ORCID: https://orcid.org/0000-0002-0667-0799)
- Lou Galliot
- Lichen Zhang (ORCID: https://orcid.org/0000-0002-7810-9941)
- Mariana Fernandes Machado (ORCID: https://orcid.org/0000-0001-6421-9309)
- Andreia Mendes (ORCID: https://orcid.org/0000-0003-1926-376X)
- Francesco Carbone (ORCID: https://orcid.org/0009-0002-0819-4471)
- Fátima Leite-Pinheiro (ORCID: https://orcid.org/0000-0002-8820-8062)
- Angelo Pilotti
- Marine Luka
- Marina Cresci
- Emily Goguet
- Theopisti Nikolaou
Institutions
- Inserm (FR)
- Shanghai Jiao Tong University (CN)
- Université Côte d'Azur (FR)
- Université Paris Cité (FR)
- Aix-Marseille Université (FR)
- Institute for Biomedicine (IT)
- Institute of Immunology (HR)
- Centre d’Immunologie de Marseille-Luminy (FR)
- Institut des Maladies Génétiques Imagine (FR)
- The University of Adelaide (AU)
- University of Aveiro (PT)
- Niigata University (JP)
- Henan Medical University (CN)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-05-19
- DOI
- https://doi.org/10.1073/pnas.2421258122
- Citations
- 1
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- Fundo Regional para a Ciência e Tecnologia
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale