TorsinA participates in endoplasmic reticulum-associated degradation

Nat Commun. 2011 Jul 12:2:393. doi: 10.1038/ncomms1383.

Abstract

TorsinA is an AAA+ ATPase located within the lumen of the endoplasmic reticulum and nuclear envelope, with a mutant form causing early onset torsion dystonia (DYT1). Here we report a new function for torsinA in endoplasmic reticulum-associated degradation (ERAD). Retro-translocation and proteosomal degradation of a mutant cystic fibrosis transmembrane conductance regulator (CFTRΔF508) was inhibited by downregulation of torsinA or overexpression of mutant torsinA, and facilitated by increased torsinA. Retro-translocation of cholera toxin was also decreased by downregulation of torsinA. TorsinA associates with proteins implicated in ERAD, including Derlin-1, VIMP and p97. Further, torsinA reduces endoplasmic reticulum stress in nematodes overexpressing CFTRΔF508, and fibroblasts from DYT1 dystonia patients are more sensitive than controls to endoplasmic reticulum stress and less able to degrade mutant CFTR. Therefore, compromised ERAD function in the cells of DYT1 patients may increase sensitivity to endoplasmic reticulum stress with consequent alterations in neuronal function contributing to the disease state.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Blotting, Western
  • COS Cells
  • Chlorocebus aethiops
  • Cholera Toxin / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Dystonia Musculorum Deformans / genetics
  • Dystonia Musculorum Deformans / physiopathology*
  • Endoplasmic Reticulum / physiology*
  • Fibroblasts
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Mice
  • Mice, Inbred C57BL
  • Molecular Chaperones / metabolism*
  • Proteasome Endopeptidase Complex / physiology*
  • Protein Processing, Post-Translational / physiology*

Substances

  • Molecular Chaperones
  • TOR1A protein, human
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Cholera Toxin
  • Proteasome Endopeptidase Complex