title: Rab5-family guanine nucleotide exchange factors bind retromer and promote its recruitment to endosomes.
abstract: The retromer complex facilitates the sorting of integral membrane proteins from the endosome to the late Golgi. In mammalian cells, the efficient recruitment of retromer to endosomes requires the lipid phosphatidylinositol 3-phosphate (PI3P) as well as Rab5 and Rab7 GTPases. However, in yeast, the role of Rabs in recruiting retromer to endosomes is less clear. We identified novel physical interactions between retromer and the Saccharomyces cerevisiae VPS9-domain Rab5-family guanine nucleotide exchange factors (GEFs) Muk1 and Vps9. Furthermore, we identified a new yeast VPS9 domain-containing protein, VARP-like 1 (Vrl1), which is related to the human VARP protein. All three VPS9 domain-containing proteins show localization to endosomes, and the presence of any one of them is necessary for the endosomal recruitment of retromer. We find that expression of an active VPS9-domain protein is required for correct localization of the phosphatidylinositol 3-kinase Vps34 and the production of endosomal PI3P. These results suggest that VPS9 GEFs promote retromer recruitment by establishing PI3P-enriched domains at the endosomal membrane. The interaction of retromer with distinct VPS9 GEFs could thus link GEF-dependent regulatory inputs to the temporal or spatial coordination of retromer assembly or function.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Bjorn D M
authors.initials: BD
authors.lastname: Bean
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Davey
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S3E1, Canada Department of Biochemistry and Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A8, Canada.
authors.forename: Jamie
authors.initials: J
authors.lastname: Snider
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, SK S4S 0A2, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Jessulat
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, SK S4S 0A2, Canada.
authors.forename: Viktor
authors.initials: V
authors.lastname: Deineko
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Tinney
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S3E1, Canada Department of Biochemistry and Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A8, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Stagljar
authors.affiliation: Department of Biochemistry, Research and Innovation Centre, University of Regina, Regina, SK S4S 0A2, Canada.
authors.forename: Mohan
authors.initials: M
authors.lastname: Babu
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada conibear@cmmt.ubc.ca.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Conibear
mesh_terms: D011992:Endosomes / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C583270:Muk1 protein, S cerevisiae; D018129:Phosphatidylinositol Phosphates; D029701:Saccharomyces cerevisiae Proteins; C099285:VPS9 protein, S cerevisiae; D033921:Vesicular Transport Proteins; C055525:phosphatidylinositol 3-phosphate