The bacterial toxin ExoU requires a host trafficking chaperone for transportation and to induce necrosis

Vincent Deruelle, Stéphanie Bouillot, Viviana Job, Emmanuel Taillebourg, Marie-Odile Fauvarque, Ina Attrée and Philippe Huber ()
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Vincent Deruelle: Université Grenoble-Alpes, CEA, INSERM, CNRS, Unité de Biologie Cellulaire et Infection
Stéphanie Bouillot: Université Grenoble-Alpes, CEA, INSERM, CNRS, Unité de Biologie Cellulaire et Infection
Viviana Job: Université Grenoble-Alpes, CEA, INSERM, CNRS, Unité de Biologie Cellulaire et Infection
Emmanuel Taillebourg: Université Grenoble-Alpes, CEA, INSERM, CNRS, Unité de Biologie à Grande Echelle
Marie-Odile Fauvarque: Université Grenoble-Alpes, CEA, INSERM, CNRS, Unité de Biologie à Grande Echelle
Ina Attrée: Université Grenoble-Alpes, CEA, INSERM, CNRS, Unité de Biologie Cellulaire et Infection
Philippe Huber: Université Grenoble-Alpes, CEA, INSERM, CNRS, Unité de Biologie Cellulaire et Infection

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Pseudomonas aeruginosa can cause nosocomial infections, especially in ventilated or cystic fibrosis patients. Highly pathogenic isolates express the phospholipase ExoU, an effector of the type III secretion system that acts on plasma membrane lipids, causing membrane rupture and host cell necrosis. Here, we use a genome-wide screen to discover that ExoU requires DNAJC5, a host chaperone, for its necrotic activity. DNAJC5 is known to participate in an unconventional secretory pathway for misfolded proteins involving anterograde vesicular trafficking. We show that DNAJC5-deficient human cells, or Drosophila flies knocked-down for the DNAJC5 orthologue, are largely resistant to ExoU-dependent virulence. ExoU colocalizes with DNAJC5-positive vesicles in the host cytoplasm. DNAJC5 mutations preventing vesicle trafficking (previously identified in adult neuronal ceroid lipofuscinosis, a human congenital disease) inhibit ExoU-dependent cell lysis. Our results suggest that, once injected into the host cytoplasm, ExoU docks to DNAJC5-positive secretory vesicles to reach the plasma membrane, where it can exert its phospholipase activity

Date: 2021
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DOI: 10.1038/s41467-021-24337-9

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