title: Torsins Are Essential Regulators of Cellular Lipid Metabolism.
abstract: Torsins are developmentally essential AAA+ proteins, and mutation of human torsinA causes the neurological disease DYT1 dystonia. They localize in the ER membranes, but their cellular function remains unclear. We now show that dTorsin is required in Drosophila adipose tissue, where it suppresses triglyceride levels, promotes cell growth, and elevates membrane lipid content. We also see that human torsinA at the inner nuclear membrane is associated with membrane expansion and elevated cellular lipid content. Furthermore, the key lipid metabolizing enzyme, lipin, is mislocalized in dTorsin-KO cells, and dTorsin increases levels of the lipin substrate, phosphatidate, and reduces the product, diacylglycerol. Finally, genetic suppression of dLipin rescues dTorsin-KO defects, including adipose cell size, animal growth, and survival. These findings identify that torsins are essential regulators of cellular lipid metabolism and implicate disturbed lipid biology in childhood-onset DYT1 dystonia.
authors.affiliation: VIB Centre for the Biology of Disease, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Micheline
authors.initials: M
authors.lastname: Grillet
authors.affiliation: VIB Centre for the Biology of Disease, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Dominguez Gonzalez
authors.affiliation: VIB Centre for the Biology of Disease, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Adria
authors.initials: A
authors.lastname: Sicart
authors.affiliation: VIB Centre for the Biology of Disease, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Pöttler
authors.affiliation: VIB Centre for the Biology of Disease, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Ana
authors.initials: A
authors.lastname: Cascalho
authors.affiliation: VIB Centre for the Biology of Disease, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Karolien
authors.initials: K
authors.lastname: Billion
authors.affiliation: VIB Centre for the Biology of Disease, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Sergio
authors.initials: S
authors.lastname: Hernandez Diaz
authors.affiliation: VIB Centre for the Biology of Disease, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Swerts
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Teresa V
authors.initials: TV
authors.lastname: Naismith
authors.affiliation: VIB Centre for the Biology of Disease, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium; Electron Microscopy Platform, VIB Bio-Imaging Core, Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Gounko
authors.affiliation: VIB Centre for the Biology of Disease, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Phyllis I
authors.initials: PI
authors.lastname: Hanson
authors.affiliation: VIB Centre for the Biology of Disease, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium. Electronic address: rose.goodchild@cme.vib-kuleuven.be.
authors.forename: Rose E
authors.initials: RE
authors.lastname: Goodchild
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism
chemical_list: D004075:Diglycerides; D008563:Membrane Lipids; D018832:Molecular Chaperones; D010743:Phospholipids; C108175:TOR1A protein, human; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase