Torsins Are Essential Regulators of Cellular Lipid Metabolism

Dev Cell. 2016 Aug 8;38(3):235-47. doi: 10.1016/j.devcel.2016.06.017. Epub 2016 Jul 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Cells, Cultured
  • Diglycerides / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development*
  • Drosophila melanogaster / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Female
  • Humans
  • Lipid Metabolism*
  • Male
  • Membrane Lipids / metabolism
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Nuclear Envelope / metabolism*
  • Phosphatidate Phosphatase / metabolism*
  • Phospholipids / metabolism

Substances

  • Diglycerides
  • Membrane Lipids
  • Molecular Chaperones
  • Phospholipids
  • TOR1A protein, human
  • LPIN1 protein, human
  • Phosphatidate Phosphatase