title: VAPs and ACBD5 tether peroxisomes to the ER for peroxisome maintenance and lipid homeostasis.
abstract: Lipid exchange between the endoplasmic reticulum (ER) and peroxisomes is necessary for the synthesis and catabolism of lipids, the trafficking of cholesterol, and peroxisome biogenesis in mammalian cells. However, how lipids are exchanged between these two organelles is not understood. In this study, we report that the ER-resident VAMP-associated proteins A and B (VAPA and VAPB) interact with the peroxisomal membrane protein acyl-CoA binding domain containing 5 (ACBD5) and that this interaction is required to tether the two organelles together, thereby facilitating the lipid exchange between them. Depletion of either ACBD5 or VAP expression results in increased peroxisome mobility, suggesting that VAP-ACBD5 complex acts as the primary ER-peroxisome tether. We also demonstrate that tethering of peroxisomes to the ER is necessary for peroxisome growth, the synthesis of plasmalogen phospholipids, and the maintenance of cellular cholesterol levels. Collectively, our data highlight the importance of VAP-ACBD5-mediated contact between the ER and peroxisomes for organelle maintenance and lipid homeostasis.
authors.affiliation: Cell Biology Program, Hospital for Sick Children, Toronto, Ontario M5G0A4, Canada.|Department of Biochemistry, University of Toronto, Toronto, Ontario M5S1A8, Canada.
authors.forename: Rong
authors.initials: R
authors.lastname: Hua
authors.affiliation: Cell Biology Program, Hospital for Sick Children, Toronto, Ontario M5G0A4, Canada.|Department of Biochemistry, University of Toronto, Toronto, Ontario M5S1A8, Canada.
authors.forename: Derrick
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G1L7, Canada.
authors.forename: Étienne
authors.identifier: 0000-0002-5893-4557
authors.initials: É
authors.lastname: Coyaud
authors.affiliation: Cell Biology Program, Hospital for Sick Children, Toronto, Ontario M5G0A4, Canada.
authors.forename: Spencer
authors.initials: S
authors.lastname: Freeman
authors.affiliation: Department of Pediatrics and Human Genetics, Research Institute of the McGill University Health Center and McGill University, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Erminia
authors.initials: E
authors.lastname: Di Pietro
authors.affiliation: Cell Biology Program, Hospital for Sick Children, Toronto, Ontario M5G0A4, Canada.|Department of Biochemistry, University of Toronto, Toronto, Ontario M5S1A8, Canada.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Cell Biology Program, Hospital for Sick Children, Toronto, Ontario M5G0A4, Canada.|Department of Biochemistry, University of Toronto, Toronto, Ontario M5S1A8, Canada.|Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5S3E1, Canada.
authors.forename: Adriano
authors.initials: A
authors.lastname: Vissa
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario M5S1A8, Canada.|Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5S3E1, Canada.
authors.forename: Christopher M
authors.identifier: 0000-0003-4507-556X
authors.initials: CM
authors.lastname: Yip
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario M5S1A8, Canada.
authors.forename: Gregory D
authors.identifier: 0000-0001-6508-168X
authors.initials: GD
authors.lastname: Fairn
authors.affiliation: Department of Pediatrics and Human Genetics, Research Institute of the McGill University Health Center and McGill University, Montreal, Quebec H4A 3J1, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Braverman
authors.affiliation: Cell Biology Program, Hospital for Sick Children, Toronto, Ontario M5G0A4, Canada.|SickKids Inflammatory Bowel Disease Centre, Hospital for Sick Children, Toronto, Ontario M5G0A4, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario M5S1A8, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G1L7, Canada.
authors.forename: John H
authors.initials: JH
authors.lastname: Brumell
authors.affiliation: Cell Biology Program, Hospital for Sick Children, Toronto, Ontario M5G0A4, Canada.|Department of Biochemistry, University of Toronto, Toronto, Ontario M5S1A8, Canada.
authors.forename: William S
authors.initials: WS
authors.lastname: Trimble
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G1L7, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G1L7, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Raught
authors.affiliation: Cell Biology Program, Hospital for Sick Children, Toronto, Ontario M5G0A4, Canada pkim@sickkids.ca.|Department of Biochemistry, University of Toronto, Toronto, Ontario M5S1A8, Canada.
authors.forename: Peter K
authors.identifier: 0000-0001-6626-0575
authors.initials: PK
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D020675:Peroxisomes / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C548478:ACBD5 protein, human; D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; C486345:PEX16 protein, human; D010743:Phospholipids; C114051:VAPA protein, human; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; D002784:Cholesterol