title: Tropheryma whipplei, the agent of Whipple's disease, affects the early to late phagosome transition and survives in a Rab5- and Rab7-positive compartment.
abstract: Tropheryma whipplei, the agent of Whipple's disease, inhibits phago-lysosome biogenesis to create a suitable niche for its survival and replication in macrophages. To understand the mechanism by which it subverts phagosome maturation, we used biochemical and cell biological approaches to purify and characterise the intracellular compartment where Tropheryma whipplei resides using mouse bone-marrow-derived macrophages. We showed that in addition to Lamp-1, the Tropheryma whipplei phagosome is positive for Rab5 and Rab7, two GTPases required for the early to late phagosome transition. Unlike other pathogens, inhibition of PI(3)P production was not the mechanism for Rab5 stabilisation at the phagosome. Overexpression of the inactive, GDP-bound form of Rab5 bypassed the pathogen-induced blockade of phago-lysosome biogenesis. This suggests that Tropheryma whipplei blocks the switch from Rab5 to Rab7 by acting on the Rab5 GTPase cycle. A bio-informatic analysis of the Tropheryma whipplei genome revealed a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) homologous with the GAPDH of Listeria monocytogenes, and this may be the bacterial protein responsible for blocking Rab5 activity. To our knowledge, Tropheryma whipplei is the first pathogen described to induce a "chimeric" phagosome stably expressing both Rab5 and Rab7, suggesting a novel and specific mechanism for subverting phagosome maturation.
authors.affiliation: UMR MD2, Aix-Marseille University and IRBA, Bd P Dramard, Marseille, France ; Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy ; CNRS UMR 7278, IRD198, INSERM U1095, UM63, Aix-Marseille University, Marseille, France.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mottola
authors.affiliation: CNRS UMR 7278, IRD198, INSERM U1095, UM63, Aix-Marseille University, Marseille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boucherit
authors.affiliation: CNRS UMR 7278, IRD198, INSERM U1095, UM63, Aix-Marseille University, Marseille, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Trouplin
authors.affiliation: CNRS UMR 7278, IRD198, INSERM U1095, UM63, Aix-Marseille University, Marseille, France.
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Oury Barry
authors.affiliation: INSERM U1068, CNRS UMR7258, UM105, CRCM-Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Soubeyran
authors.affiliation: CNRS UMR 7278, IRD198, INSERM U1095, UM63, Aix-Marseille University, Marseille, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mege
authors.affiliation: CNRS UMR 7278, IRD198, INSERM U1095, UM63, Aix-Marseille University, Marseille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Ghigo
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D010588:Phagosomes / Q000378:metabolism*; D054851:Tropheryma / Q000378:metabolism*; D008061:Whipple Disease / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D000090802:rab7 GTP-Binding Proteins; C000716465:rab7 GTP-binding proteins, mouse; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins