Access of torsinA to the inner nuclear membrane is activity dependent and regulated in the endoplasmic reticulum

Rose E. Goodchild, Abigail L. Buchwalter, Teresa V. Naismith, Kristen Holbrook, Karolien Billion, William T. Dauer, Chun Chi Liang, Mary Lynn Dear, Phyllis I. Hanson

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2854-2865
Number of pages12
JournalJournal of cell science
Volume128
Issue number15
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • AAA+ protein
  • Dystonia
  • Endoplasmic reticulum
  • Inner nuclear membrane
  • Torsin

ASJC Scopus subject areas

  • Cell Biology

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