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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\n                    <jats:italic>Drosophila<\/jats:italic>\n                    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\n                  <\/jats:p>","DOI":"10.1038\/s41467-021-24337-9","type":"journal-article","created":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T06:06:39Z","timestamp":1624946799000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["The bacterial toxin ExoU requires a host trafficking chaperone for transportation and to induce necrosis"],"prefix":"10.1038","volume":"12","author":[{"given":"Vincent","family":"Deruelle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Bouillot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Job","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Taillebourg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5020-3701","authenticated-orcid":false,"given":"Marie-Odile","family":"Fauvarque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2580-764X","authenticated-orcid":false,"given":"Ina","family":"Attr\u00e9e","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4153-7694","authenticated-orcid":false,"given":"Philippe","family":"Huber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,29]]},"reference":[{"key":"24337_CR1","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1111\/2049-632X.12033","volume":"67","author":"SL Gellatly","year":"2013","unstructured":"Gellatly, S. L. & Hancock, R. E. Pseudomonas aeruginosa: new insights into pathogenesis and host defenses. Pathog. Dis. 67, 159\u2013173 (2013).","journal-title":"Pathog. Dis."},{"key":"24337_CR2","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1038\/nrmicro2199","volume":"7","author":"AR Hauser","year":"2009","unstructured":"Hauser, A. R. The type III secretion system of Pseudomonas aeruginosa: infection by injection. Nat. Rev. Microbiol 7, 654\u2013665 (2009).","journal-title":"Nat. Rev. Microbiol"},{"key":"24337_CR3","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1111\/j.1440-1843.2010.01819.x","volume":"15","author":"BJ Williams","year":"2010","unstructured":"Williams, B. J., Dehnbostel, J. & Blackwell, T. S. Pseudomonas aeruginosa: host defence in lung diseases. Respirology 15, 1037\u20131056 (2010).","journal-title":"Respirology"},{"key":"24337_CR4","doi-asserted-by":"publisher","first-page":"100640","DOI":"10.1016\/j.drup.2019.07.002","volume":"44","author":"J Botelho","year":"2019","unstructured":"Botelho, J., Grosso, F. & Peixe, L. Antibiotic resistance in Pseudomonas aeruginosa\u2014mechanisms, epidemiology and evolution. Drug Resist Updat. 44, 100640 (2019).","journal-title":"Drug Resist Updat."},{"key":"24337_CR5","doi-asserted-by":"publisher","unstructured":"Horcajada, J. P. et al. Epidemiology and treatment of multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa infections. Clin. Microbiol. Rev. 32, https:\/\/doi.org\/10.1128\/CMR.00031-19 (2019).","DOI":"10.1128\/CMR.00031-19"},{"key":"24337_CR6","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.gendis.2019.04.001","volume":"6","author":"P Pachori","year":"2019","unstructured":"Pachori, P., Gothalwal, R. & Gandhi, P. Emergence of antibiotic resistance Pseudomonas aeruginosa in intensive care unit; a critical review. Genes Dis. 6, 109\u2013119 (2019).","journal-title":"Genes Dis."},{"key":"24337_CR7","doi-asserted-by":"publisher","first-page":"S44","DOI":"10.1093\/infdis\/jiw299","volume":"215","author":"C Juan","year":"2017","unstructured":"Juan, C., Pena, C. & Oliver, A. Host and Pathogen Biomarkers for Severe Pseudomonas aeruginosa Infections. J. Infect. Dis. 215, S44\u2013S51 (2017).","journal-title":"J. Infect. Dis."},{"key":"24337_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13582","volume":"7","author":"A Belyy","year":"2016","unstructured":"Belyy, A. et al. Actin activates Pseudomonas aeruginosa ExoY nucleotidyl cyclase toxin and ExoY-like effector domains from MARTX toxins. Nat. Commun. 7, 13582 (2016).","journal-title":"Nat. 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Ubiquitin and ubiquitin-modified proteins activate the Pseudomonas aeruginosa T3SS cytotoxin, ExoU. Mol. Microbiol. 82, 1454\u20131467 (2011).","journal-title":"Mol. Microbiol."},{"key":"24337_CR12","doi-asserted-by":"publisher","first-page":"19012","DOI":"10.1074\/jbc.RA119.010278","volume":"294","author":"TI Springer","year":"2019","unstructured":"Springer, T. I., Reid, T. E., Gies, S. L. & Feix, J. B. Interactions of the effector ExoU from Pseudomonas aeruginosa with short-chain phosphatidylinositides provide insights into ExoU targeting to host membranes. J. Biol. Chem. 294, 19012\u201319021 (2019).","journal-title":"J. Biol. Chem."},{"key":"24337_CR13","doi-asserted-by":"publisher","first-page":"2919","DOI":"10.1074\/jbc.M114.611251","volume":"290","author":"GH Tyson","year":"2015","unstructured":"Tyson, G. H. et al. A novel phosphatidylinositol 4,5-bisphosphate binding domain mediates plasma membrane localization of ExoU and other patatin-like phospholipases. J. Biol. 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