title: Selective Lysosomal Transporter Degradation by Organelle Membrane Fusion.
abstract: Lysosomes rely on their resident transporter proteins to return products of catabolism to the cell for reuse and for cellular signaling, metal storage, and maintaining the lumenal environment. Despite their importance, little is known about the lifetime of these transporters or how they are regulated. Using Saccharomyces cerevisiae as a model, we discovered a new pathway intrinsic to homotypic lysosome membrane fusion that is responsible for their degradation. Transporter proteins are selectively sorted by the docking machinery into an area between apposing lysosome membranes, which is internalized and degraded by lumenal hydrolases upon organelle fusion. These proteins have diverse lifetimes that are regulated in response to protein misfolding, changing substrate levels, or TOR activation. Analogous to endocytosis for controlling surface protein levels, the "intralumenal fragment pathway" is critical for lysosome membrane remodeling required for organelle function in the context of cellular protein quality control, ion homeostasis, and metabolism.
authors.affiliation: Department of Biology, Concordia University, 7141 Sherbrooke Street West, SP-501.15, Montréal, QC H4B 1R6, Canada.
authors.forename: Erin Kate
authors.initials: EK
authors.lastname: McNally
authors.affiliation: Department of Biology, Concordia University, 7141 Sherbrooke Street West, SP-501.15, Montréal, QC H4B 1R6, Canada.
authors.forename: Mahmoud Abdul
authors.initials: MA
authors.lastname: Karim
authors.affiliation: Department of Biology, Concordia University, 7141 Sherbrooke Street West, SP-501.15, Montréal, QC H4B 1R6, Canada. Electronic address: christopher.brett@concordia.ca.
authors.forename: Christopher Leonard
authors.initials: CL
authors.lastname: Brett
mesh_terms: D001343:Autophagy / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008561:Membrane Fusion / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D026901:Membrane Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; D049452:Green Fluorescent Proteins; D003513:Cycloheximide; D025262:Vacuolar Proton-Translocating ATPases
keywords: TOR; intralumenal fragment; lysosomal transporter; lysosome biology; membrane fusion; multivesicular body; protein degradation; protein quality control; vacuole