title: mTOR complex 1 activity is required to maintain the canonical endocytic recycling pathway against lysosomal delivery.
abstract: The plasma membrane of mammalian cells undergoes constitutive endocytosis, endocytic sorting, and recycling, which delivers nutrients to the lysosomes. The receptors, along with membrane lipids, are normally returned to the plasma membrane to sustain this action. It is not known, however, whether this process is influenced by metabolic conditions. Here we report that endocytic recycling requires active mechanistic target of rapamycin (aka mammalian target of rapamycin) (mTORC1), a master metabolic sensor. Upon mTORC1 inactivation, either by starvation or by inhibitor, recycling receptors and plasma membrane lipids, such as transferrin receptors and sphingomyelin, are delivered to the lysosomes. This lysosomal targeting is independent of canonical autophagy: both WT and Atg5-/-mouse embryonic fibroblasts responded similarly. Furthermore, we identify hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), an endosomal sorting complexes required for transport (ESCORT-0) component, as a downstream target of mTORC1. Hrs requires mTORC1 activity to maintain its protein expression level. Silencing Hrs without decreasing mTORC1 activity is sufficient to target transferrin and sphingomyelin to the lysosomes. It is thus evident that the canonical recycling pathway is under the regulation of mTORC1 and likely most predominant in proliferating cells where mTORC1 is highly active.
authors.affiliation: From the Chronic Disease Program, Ottawa Hospital Research Institute and.
authors.forename: Kristin
authors.initials: K
authors.lastname: Dauner
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada and.
authors.forename: Walaa
authors.initials: W
authors.lastname: Eid
authors.affiliation: From the Chronic Disease Program, Ottawa Hospital Research Institute and.
authors.forename: Riya
authors.initials: R
authors.lastname: Raghupathy
authors.affiliation: the Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 0C7, Canada.
authors.forename: John F
authors.initials: JF
authors.lastname: Presley
authors.affiliation: From the Chronic Disease Program, Ottawa Hospital Research Institute and xzha@ohri.ca.|Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada and.
authors.forename: Xiaohui
authors.identifier: 0000-0003-2873-3073
authors.initials: X
authors.lastname: Zha
mesh_terms: D000818:Animals; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism; D001693:Biological Transport, Active / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D013109:Sphingomyelins / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014168:Transferrin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D056827:Endosomal Sorting Complexes Required for Transport; D046912:Multiprotein Complexes; D013109:Sphingomyelins; D014168:Transferrin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Hrs; autophagy; endocytosis; endosomal sorting complexes required for transport (ESCRT); lysosome; mTOR complex (mTORC); membrane recycling; receptor recycling; transferrin