title: Access of torsinA to the inner nuclear membrane is activity dependent and regulated in the endoplasmic reticulum.
abstract: TorsinA (also known as torsin-1A) is a membrane-embedded AAA+ ATPase that has an important role in the nuclear envelope lumen. However, most torsinA is localized in the peripheral endoplasmic reticulum (ER) lumen where it has a slow mobility that is incompatible with free equilibration between ER subdomains. We now find that nuclear-envelope-localized torsinA is present on the inner nuclear membrane (INM) and ask how torsinA reaches this subdomain. The ER system contains two transmembrane proteins, LAP1 and LULL1 (also known as TOR1AIP1 and TOR1AIP2, respectively), that reversibly co-assemble with and activate torsinA. Whereas LAP1 localizes on the INM, we show that LULL1 is in the peripheral ER and does not enter the INM. Paradoxically, interaction between torsinA and LULL1 in the ER targets torsinA to the INM. Native gel electrophoresis reveals torsinA oligomeric complexes that are destabilized by LULL1. Mutations in torsinA or LULL1 that inhibit ATPase activity reduce the access of torsinA to the INM. Furthermore, although LULL1 binds torsinA in the ER lumen, its effect on torsinA localization requires cytosolic-domain-mediated oligomerization. These data suggest that LULL1 oligomerizes to engage and transiently disassemble torsinA oligomers, and is thereby positioned to transduce cytoplasmic signals to the INM through torsinA.
authors.affiliation: VIB Centre for the Biology of Disease and KU Leuven, Department of Human Genetics, Campus Gasthuisberg, Leuven 3000, Belgium rose.goodchild@cme.vib-kuleuven.be phanson22@wustl.edu.
authors.forename: Rose E
authors.initials: RE
authors.lastname: Goodchild
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63130, USA.
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Buchwalter
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63130, USA.
authors.forename: Teresa V
authors.initials: TV
authors.lastname: Naismith
authors.affiliation: Department of Biochemistry, Cell and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Holbrook
authors.affiliation: VIB Centre for the Biology of Disease and KU Leuven, Department of Human Genetics, Campus Gasthuisberg, Leuven 3000, Belgium.
authors.forename: Karolien
authors.initials: K
authors.lastname: Billion
authors.affiliation: Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Dauer
authors.affiliation: Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Liang
authors.affiliation: Department of Biochemistry, Cell and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Dear
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63130, USA rose.goodchild@cme.vib-kuleuven.be phanson22@wustl.edu.
authors.forename: Phyllis I
authors.initials: PI
authors.lastname: Hanson
mesh_terms: D016475:3T3 Cells; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics; D009685:Nuclear Envelope / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding
chemical_list: D002352:Carrier Proteins; C491548:Dyt1 protein, mouse; C000608254:LAP1 protein, mouse; C000608255:LULL1 protein, mouse; D008565:Membrane Proteins; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases
keywords: AAA+ protein; Dystonia; Endoplasmic reticulum; Inner nuclear membrane; Torsin