title: Cholesterol-binding molecules MLN64 and ORP1L mark distinct late endosomes with transporters ABCA3 and NPC1.
abstract: Cholesterol is an essential lipid in eukaryotic cells and is present in membranes of all intracellular compartments. A major source for cellular cholesterol is internalized lipoprotein particles that are transported toward acidic late endosomes (LE) and lysosomes. Here the lipoprotein particles are hydrolyzed, and free cholesterol is redistributed to other organelles. The LE can contain over half of the cellular cholesterol and, as a major sorting station, can contain many cholesterol-binding proteins from the ABCA, STARD, and ORP families. Here, we show that metastatic lymph node 64 (MLN64, STARD3) and oxysterol-binding protein-related protein 1L (ORP1L) define two subpopulations of LE. MLN64 is present on a LE containing the cholesterol transporter ABCA3, whereas ORP1L localizes to another population of LE containing Niemann Pick type C1 (NPC1), a cholesterol exporter. Endocytosed cargo passes through MLN64/ABCA3-positive compartments before it reaches ORP1L/NPC1-positive LE. The MLN64/ABCA3 compartments cycle between LE and plasma membrane and frequently contact "later" ORP1L/NPC1-containing LE. We propose two stages of cholesterol handling in late endosomal compartments: first, cholesterol enters MLN64/ABCA3-positive compartments from where it can be recycled to the plasma membrane, and later, cholesterol enters ORP1L/NPC1 endosomes that mediate cholesterol export to the endoplasmic reticulum.
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Rik
authors.initials: R
authors.lastname: van der Kant
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Ilse
authors.initials: I
authors.lastname: Zondervan
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Lennert
authors.initials: L
authors.lastname: Janssen
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, Netherlands. Electronic address: j.neefjes@nki.nl.
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D000077296:Niemann-Pick C1 Protein; D011987:Receptors, Steroid / Q000378:metabolism*; D000098825:Oxysterol Binding Proteins
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D011987:Receptors, Steroid; C105684:STARD3 protein, human; D000098825:Oxysterol Binding Proteins; D002784:Cholesterol
keywords: ATP binding cassette transporter A3; Niemann Pick disease type C1; STARD3; lysosome; metastatic lymph node 64; oxysterol-binding protein-related protein 1L