title: Salmonella Disrupts Host Endocytic Trafficking by SopD2-Mediated Inhibition of Rab7.
abstract: Intracellular bacterial pathogens of a diverse nature share the ability to evade host immunity by impairing trafficking of endocytic cargo to lysosomes for degradation, a process that is poorly understood. Here, we show that the Salmonella enterica type 3 secreted effector SopD2 mediates this process by binding the host regulatory GTPase Rab7 and inhibiting its nucleotide exchange. Consequently, this limits Rab7 interaction with its dynein- and kinesin-binding effectors RILP and FYCO1 and thereby disrupts host-driven regulation of microtubule motors. Our study identifies a bacterial effector capable of directly binding and thereby modulating Rab7 activity and a mechanism of endocytic trafficking disruption that may provide insight into the pathogenesis of other bacteria. Additionally, we provide a powerful tool for the study of Rab7 function, and a potential therapeutic target.
authors: Cell Biology Program, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors: Vanessa M
authors: VM
authors: D'Costa
authors: Cell Biology Program, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors: Virginie
authors: V
authors: Braun
authors: Department of Molecular Genetics, University of Toronto, ON M5S 1A8, Canada.
authors: Marija
authors: M
authors: Landekic
authors: Département de Biochimie, de Microbiologie et de Bio-informatique, PROTEO et IBIS, Université Laval, Québec City, QC G1V 0A6, Canada.
authors: Rong
authors: R
authors: Shi
authors: Department of Biochemistry, McGill University, Montreal, QC H3G 0B1, Canada.
authors: Ariane
authors: A
authors: Proteau
authors: Department of Chemistry and Biochemistry, Concordia University, Montreal, QC H4B 1R6, Canada.
authors: Laura
authors: L
authors: McDonald
authors: Department of Biochemistry, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors: Miroslaw
authors: M
authors: Cygler
authors: Cell Biology Program, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Biochemistry, University of Toronto, ON M5S 1A8, Canada; Institute of Medical Science, University of Toronto, ON M5S 1A8, Canada.
authors: Sergio
authors: S
authors: Grinstein
authors: Cell Biology Program, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, ON M5S 1A8, Canada; Institute of Medical Science, University of Toronto, ON M5S 1A8, Canada; Sickkids IBD Centre, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. Electronic address: john.brumell@sickkids.ca.
authors: John H
authors: JH
authors: Brumell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism* / Q000382:microbiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D019779:Salmonella enterica / Q000378:metabolism / Q000472:pathogenicity; D014157:Transcription Factors / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C460141:FYCO1 protein, human; D008869:Microtubule-Associated Proteins; C423317:RILP protein, human; C116105:SopD protein, Salmonella; D014157:Transcription Factors; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; D020691:rab GTP-Binding Proteins