TorsinA participates in endoplasmic reticulum-associated degradation

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, Guy A. Caldwell, Wayne I. Lencer, Yihong Ye and Xandra O. Breakefield ()
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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

Nature Communications, 2011, vol. 2, issue 1, 1-10

Abstract: 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.

Date: 2011
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DOI: 10.1038/ncomms1383

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