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TorsinA participates in endoplasmic reticulum-associated degradation

Author

Listed:
  • Flávia C. Nery

    (Neuroscience Center, and Center for Molecular Imaging Research, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School)

  • Ioanna A. Armata

    (Neuroscience Center, and Center for Molecular Imaging Research, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School)

  • Jonathan E. Farley

    (Neuroscience Center, and Center for Molecular Imaging Research, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School)

  • Jin A. Cho

    (Gastrointestinal Cell Biology and The Harvard Digestive Diseases Center, Children's Hospital, Harvard Medical School)

  • Uzma Yaqub

    (Neuroscience Center, and Center for Molecular Imaging Research, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School)

  • Pan Chen

    (Center for Neurodegeneration and Experimental Therapeutics, Birmingham, University of Alabama)

  • Cintia Carla da Hora

    (Neuroscience Center, and Center for Molecular Imaging Research, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School)

  • Qiuyan Wang

    (Laboratory of Molecular Biology, NIDDK, National Institutes of Health)

  • Mitsuo Tagaya

    (School of Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji)

  • Christine Klein

    (University of Lübeck)

  • Bakhos Tannous

    (Neuroscience Center, and Center for Molecular Imaging Research, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School)

  • Kim A. Caldwell

    (Center for Neurodegeneration and Experimental Therapeutics, Birmingham, University of Alabama)

  • Guy A. Caldwell

    (Center for Neurodegeneration and Experimental Therapeutics, Birmingham, University of Alabama)

  • Wayne I. Lencer

    (Gastrointestinal Cell Biology and The Harvard Digestive Diseases Center, Children's Hospital, Harvard Medical School)

  • Yihong Ye

    (Laboratory of Molecular Biology, NIDDK, National Institutes of Health)

  • Xandra O. Breakefield

    (Neuroscience Center, and Center for Molecular Imaging Research, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School)

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.

Suggested Citation

  • Flávia C. Nery & Ioanna A. Armata & Jonathan E. Farley & Jin A. Cho & Uzma Yaqub & Pan Chen & Cintia Carla da Hora & Qiuyan Wang & Mitsuo Tagaya & Christine Klein & Bakhos Tannous & Kim A. Caldwell & , 2011. "TorsinA participates in endoplasmic reticulum-associated degradation," Nature Communications, Nature, vol. 2(1), pages 1-10, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1383
    DOI: 10.1038/ncomms1383
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