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

• 成果类型: Article
• 署名作者: Barros, Daniela; Ferreira, Beatriz H.; Garcia-Gonzalez, Paulina; Carbone, Francesco; Luka, Marine; Leite-Pinheiro, Fatima; Machado, Mariana D.; Nikolaou, Theopisti; Pilotti, Angelo; Goguet, Eliot; Antas, Paulo; Mendes, Andreia; Zhang, Lichen; Cresci, Marina; Galliot, Lou; Gigan, Julien P.; Reverendo, Marisa; Su, Bing; Narita, Miwako; Paton, Adrienne W.; Paton, James C.; Rocchi, Stephane; Rieux-Laucat, Frederic; Arguello, Rafael J.; Nal, Beatrice; Liang, Yinming; Menager, Mickael; Gatti, Evelina; Almeida, Catarina R.; Pierre, Philippe
• 署名单位: Universidade de Aveiro; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Aix-Marseille Universite; Universidade de Aveiro; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Henan Medical University; Shanghai Jiao Tong University; Chinese Academy of Sciences; Niigata University; University of Adelaide; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Cote d'Azur; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8479
• DOI: 10.1073/pnas.2421258122
• 发表日期: 2025-05-19
• 关键词: endoplasmic-reticulum stress; set enrichment analysis; transcription factor; inflammatory responses; protein-kinase; ab(5) toxin; inhibitor; reveals; potent; characterizes

摘要

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.