title: FAM21 directs SNX27-retromer cargoes to the plasma membrane by preventing transport to the Golgi apparatus.
abstract: The endosomal network maintains cellular homeostasis by sorting, recycling and degrading endocytosed cargoes. Retromer organizes the endosomal sorting pathway in conjunction with various sorting nexin (SNX) proteins. The SNX27-retromer complex has recently been identified as a major endosomal hub that regulates endosome-to-plasma membrane recycling by preventing lysosomal entry of cargoes. Here, we show that SNX27 directly interacts with FAM21, which also binds retromer, within the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complex. This interaction is required for the precise localization of SNX27 at an endosomal subdomain as well as for recycling of SNX27-retromer cargoes. Furthermore, FAM21 prevents cargo transport to the Golgi apparatus by controlling levels of phosphatidylinositol 4-phosphate, which facilitates cargo dissociation at the Golgi. Together, our results demonstrate that the SNX27-retromer-WASH complex directs cargoes to the plasma membrane by blocking their transport to lysosomes and the Golgi.
authors.affiliation: Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Seongju
authors.initials: S
authors.lastname: Lee
authors.affiliation: Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.|Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 443-380, Korea.|Department of Brain Science, Ajou University School of Medicine, Suwon 443-380, Korea.|Neuroscience Graduate Program, Ajou University School of Medicine, Suwon 443-380, Korea.
authors.forename: Jaerak
authors.initials: J
authors.lastname: Chang
authors.affiliation: Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Blackstone
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D028044:Phosphate-Binding Proteins; D021381:Protein Transport; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D058305:Sorting Nexins / Q000235:genetics / Q000378:metabolism*; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D028044:Phosphate-Binding Proteins; D011506:Proteins; C522885:SNX27 protein, human; D058305:Sorting Nexins; C495767:WAS protein, human; C000605267:WASHC2C protein, human; D051316:Wiskott-Aldrich Syndrome Protein