title: The Salmonella Typhimurium effector SteC inhibits Cdc42-mediated signaling through binding to the exchange factor Cdc24 in Saccharomyces cerevisiae.
abstract: Intracellular survival of Salmonella relies on the activity of proteins translocated into the host cell by type III secretion systems (T3SS). The protein kinase activity of the T3SS effector SteC is required for F-actin remodeling in host cells, although no SteC target has been identified so far. Here we show that expression of the N-terminal non-kinase domain of SteC down-regulates the mating and HOG pathways in Saccharomyces cerevisiae. Epistasis analyses using constitutively active components of these pathways indicate that SteC inhibits signaling at the level of the GTPase Cdc42. We demonstrate that SteC interacts through its N-terminal domain with the catalytic domain of Cdc24, the sole S. cerevisiae Cdc42 guanine nucleotide exchange factor (GEF). SteC also binds to the human Cdc24-like GEF protein Vav1. Moreover, expression of human Cdc42 suppresses growth inhibition caused by SteC. Of interest, the N-terminal SteC domain alters Cdc24 cellular localization, preventing its nuclear accumulation. These data reveal a novel functional domain within SteC, raising the possibility that this effector could also target GTPase function in mammalian cells. Our results also highlight the key role of the Cdc42 switch in yeast mating and HOG pathways and provide a new tool to study the functional consequences of Cdc24 localization.
authors.affiliation: Departamento de Microbiología II, Facultad de Farmacia, Universidad Complutense de Madrid, and Instituto Ramón y Cajal de Investigaciones Sanitarias, 28040 Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Fernandez-Piñar
authors.forename: Ainel
authors.initials: A
authors.lastname: Alemán
authors.forename: John
authors.initials: J
authors.lastname: Sondek
authors.forename: Henrik G
authors.initials: HG
authors.lastname: Dohlman
authors.forename: María
authors.initials: M
authors.lastname: Molina
authors.forename: Humberto
authors.initials: H
authors.lastname: Martín
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D011494:Protein Kinases / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000378:metabolism* / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000378:metabolism; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C073594:CDC24 protein, S cerevisiae; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; C526376:SteC protein, Salmonella typhimurium; D020764:cdc42 GTP-Binding Protein