title: TorsinA participates in endoplasmic reticulum-associated degradation.
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.
authors.affiliation: 1] Neuroscience Center, Department of Neurology, and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02114, USA. [2].
authors.forename: Flávia C
authors.initials: FC
authors.lastname: Nery
authors.forename: Ioanna A
authors.initials: IA
authors.lastname: Armata
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Farley
authors.forename: Jin A
authors.initials: JA
authors.lastname: Cho
authors.forename: Uzma
authors.initials: U
authors.lastname: Yaqub
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.forename: Cintia Carla
authors.initials: CC
authors.lastname: da Hora
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: Wang
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Tagaya
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Bakhos
authors.initials: B
authors.lastname: Tannous
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.forename: Wayne I
authors.initials: WI
authors.lastname: Lencer
authors.forename: Yihong
authors.initials: Y
authors.lastname: Ye
authors.forename: Xandra O
authors.initials: XO
authors.lastname: Breakefield
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D002772:Cholera Toxin / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004422:Dystonia Musculorum Deformans / Q000235:genetics / Q000503:physiopathology*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005347:Fibroblasts; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000502:physiology*
chemical_list: D018832:Molecular Chaperones; C108175:TOR1A protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002772:Cholera Toxin; D046988:Proteasome Endopeptidase Complex