Induction of the ISR by AB5 subtilase cytotoxin drives type-I IFN expression in pDCs via STING activation
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (30)
Daniela Barros
Institute of Biomedicine, Department of Medical Sciences, University of Aveiro
Beatriz H. Ferreira
Institute of Biomedicine, Department of Medical Sciences, University of Aveiro
Paulina Garcia-Gonzalez
Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML)
Francesco Carbone
Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM U1163
Marine Luka
Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM U1163
Fátima Leite-Pinheiro
Institute of Biomedicine, Department of Medical Sciences, University of Aveiro
Mariana D. Machado
Institute of Biomedicine, Department of Medical Sciences, University of Aveiro
Theopisti Nikolaou
Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML)
Angelo Pilotti
Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML)
Eliot Goguet
Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML)
Paulo Antas
Institute of Biomedicine, Department of Medical Sciences, University of Aveiro
Andreia Mendes
Institute of Biomedicine, Department of Medical Sciences, University of Aveiro
Lichen Zhang
School of Medical Technology, Henan Key Laboratory of Immunology and Targeted Therapy, Xinxiang Medical University
Marina Cresci
Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML)
Lou Galliot
Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML)
Julien P. Gigan
Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML)
Marisa Reverendo
Institute of Biomedicine, Department of Medical Sciences, University of Aveiro
Bing Su
Miwako Narita
Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University
Adrienne W. Paton
Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide
James C. Paton
Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide
Stéphane Rocchi
Université Côte d’Azur, INSERM
Frédéric Rieux-Laucat
Université de Paris Cité, Imagine Institute Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163
Rafael J. Argüello
Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML)
Béatrice Nal
Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML)
Yinming Liang
School of Medical Technology, Henan Key Laboratory of Immunology and Targeted Therapy, Xinxiang Medical University
Mickaël Ménager
Université de Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM U1163
Evelina Gatti
Institute of Biomedicine, Department of Medical Sciences, University of Aveiro
Catarina R. Almeida
Institute of Biomedicine, Department of Medical Sciences, University of Aveiro
Philippe Pierre
Institute of Biomedicine, Department of Medical Sciences, University of Aveiro