title: Shigella flexneri infection generates the lipid PI5P to alter endocytosis and prevent termination of EGFR signaling.
abstract: The phosphoinositide metabolic pathway, which regulates cellular processes implicated in survival, motility, and trafficking, is often subverted by bacterial pathogens. Shigella flexneri, a bacterium that causes dysentery, injects IpgD, a phosphoinositide phosphatase that generates the lipid phosphatidylinositol 5-phosphate (PI5P), into host cells, thereby activating the phosphoinositide 3-kinase-Akt survival pathway. We show that epidermal growth factor receptor (EGFR) is required for PI5P-dependent activation of Akt in infected HeLa cells or cells ectopically expressing IpgD. Cells treated with PI5P had increased numbers of early endosomes with activated EGFR, no detectable EGFR in the late endosomal or lysosomal compartments, and prolonged EGFR signaling. Endosomal recycling and retrograde pathways were spared, indicating that the effect of PI5P on the degradative route to the late endocytic compartments was specific. Thus, we identified PI5P, which was enriched in endosomes, as a regulator of vesicular trafficking that alters growth factor receptor signaling by impairing lysosomal degradation, a property used by S. flexneri to favor survival of host cells.
authors.affiliation: INSERM, U1048, Université Toulouse 3, I2MC and Hôpital de Toulouse, Avenue Jean Poulhès BP84225, 31432 Toulouse Cedex 04, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Ramel
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lagarrigue
authors.forename: Véronique
authors.initials: V
authors.lastname: Pons
authors.forename: Joëlle
authors.initials: J
authors.lastname: Mounier
authors.forename: Sophie
authors.initials: S
authors.lastname: Dupuis-Coronas
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Chicanne
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Sansonetti
authors.forename: Frédérique
authors.initials: F
authors.lastname: Gaits-Iacovoni
authors.forename: Hélène
authors.initials: H
authors.lastname: Tronchère
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
mesh_terms: D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D002470:Cell Survival; D004405:Dysentery, Bacillary / Q000201:enzymology* / Q000235:genetics; D004705:Endocytosis; D011992:Endosomes / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D004789:Enzyme Activation / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012763:Shigella flexneri / Q000201:enzymology* / Q000235:genetics; D015398:Signal Transduction
chemical_list: D001426:Bacterial Proteins; D018129:Phosphatidylinositol Phosphates; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C425774:IpgD protein, Shigella flexneri; D010744:Phosphoric Monoester Hydrolases