title: Rac and Rab GTPases dual effector Nischarin regulates vesicle maturation to facilitate survival of intracellular bacteria.
abstract: The intracellular pathogenic bacterium Salmonella enterica serovar typhimurium (Salmonella) relies on acidification of the Salmonella-containing vacuole (SCV) for survival inside host cells. The transport and fusion of membrane-bound compartments in a cell is regulated by small GTPases, including Rac and members of the Rab GTPase family, and their effector proteins. However, the role of these components in survival of intracellular pathogens is not completely understood. Here, we identify Nischarin as a novel dual effector that can interact with members of Rac and Rab GTPase (Rab4, Rab14 and Rab9) families at different endosomal compartments. Nischarin interacts with GTP-bound Rab14 and PI(3)P to direct the maturation of early endosomes to Rab9/CD63-containing late endosomes. Nischarin is recruited to the SCV in a Rab14-dependent manner and enhances acidification of the SCV. Depletion of Nischarin or the Nischarin binding partners--Rac1, Rab14 and Rab9 GTPases--reduced the intracellular growth of Salmonella. Thus, interaction of Nischarin with GTPases may regulate maturation and subsequent acidification of vacuoles produced after phagocytosis of pathogens.
authors: Genentech Inc., South San Francisco, CA 94080, USA. kuijlc@gene.com
authors: Coenraad
authors: C
authors: Kuijl
authors: Manohar
authors: M
authors: Pilli
authors: Suresh K
authors: SK
authors: Alahari
authors: Hans
authors: H
authors: Janssen
authors: Poh-Sim
authors: PS
authors: Khoo
authors: Karen E
authors: KE
authors: Ervin
authors: Monica
authors: M
authors: Calero
authors: Sobhanaditya
authors: S
authors: Jonnalagadda
authors: Richard H
authors: RH
authors: Scheller
authors: Jacques
authors: J
authors: Neefjes
authors: Jagath R
authors: JR
authors: Junutula
mesh_terms: D001692:Biological Transport; D015153:Blotting, Western; D011992:Endosomes / Q000378:metabolism / Q000382:microbiology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D054755:Imidazoline Receptors / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism / Q000382:microbiology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012480:Salmonella Infections / Q000382:microbiology; D012486:Salmonella typhimurium / Q000254:growth & development*; D020798:Two-Hybrid System Techniques; D014617:Vacuoles / Q000378:metabolism / Q000382:microbiology*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D054755:Imidazoline Receptors; D047908:Intracellular Signaling Peptides and Proteins; C458505:NISCH protein, human; D018129:Phosphatidylinositol Phosphates; D012333:RNA, Messenger; C055525:phosphatidylinositol 3-phosphate; D006160:Guanosine Triphosphate; C079856:RAB9A protein, human; C553411:Rab14 protein, human; D020691:rab GTP-Binding Proteins; D020744:rac GTP-Binding Proteins
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