title: Salmonella inhibits retrograde trafficking of mannose-6-phosphate receptors and lysosome function.
abstract: Salmonella enterica is an intracellular bacterial pathogen that replicates within membrane-bound vacuoles through the action of effector proteins translocated into host cells. Salmonella vacuoles have characteristics of lysosomes but are reduced in hydrolytic enzymes transported by mannose-6-phosphate receptors (MPRs). We found that the effector SifA subverted Rab9-dependent retrograde trafficking of MPRs, thereby attenuating lysosome function. This required binding of SifA to its host cell target SKIP/PLEKHM2. Furthermore, SKIP regulated retrograde trafficking of MPRs in noninfected cells. Translocated SifA formed a stable complex with SKIP and Rab9 in infected cells. Sequestration of Rab9 by SifA-SKIP accounted for the effect of SifA on MPR transport and lysosome function. Growth of Salmonella increased in cells with reduced lysosomal activity and decreased in cells with higher lysosomal activity. These results suggest that Salmonella vacuoles undergo fusion with lysosomes whose potency has been reduced by SifA.
authors.affiliation: Section of Microbiology, Centre for Molecular Microbiology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
authors.forename: Kieran
authors.initials: K
authors.lastname: McGourty
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Thurston
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Matthews
authors.forename: Laurie
authors.initials: L
authors.lastname: Pinaud
authors.forename: Luís Jaime
authors.initials: LJ
authors.lastname: Mota
authors.forename: David W
authors.initials: DW
authors.lastname: Holden
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008561:Membrane Fusion; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D019779:Salmonella enterica / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001426:Bacterial Proteins; D006023:Glycoproteins; D034741:RNA, Small Interfering; D017527:Receptor, IGF Type 2; C466999:SPHKAP protein, human; C421862:SifA protein, Salmonella; C079856:RAB9A protein, human; D020691:rab GTP-Binding Proteins