LULL1 retargets torsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation

Abigail B. Vander Heyden, Teresa V. Naismith, Erik L. Snapp, Didier Hodzic, Phyllis I. Hanson

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

TorsinA (TorA) is an AAA+ ATPase in the endoplasmic reticulum (ER) lumen that is mutated in early onset DYT1 dystonia. TorA is an essential protein in mice and is thought to function in the nuclear envelope (NE) despite localizing throughout the ER. Here, we report that transient interaction of TorA with the ER membrane protein LULL1 targets TorA to the NE. FRAP and Blue Native PAGE indicate that TorA is a stable, slowly diffusing oligomer in either the absence or presence of LULL1. Increasing LULL1 expression redistributes both wild-type and disease-mutant TorA to the NE, while decreasing LULL1 with shRNAs eliminates intrinsic enrichment of disease-mutant TorA in the NE. When concentrated in the NE, TorA displaces the nuclear membrane proteins Sun2, nesprin-2G, and nesprin-3 while leaving nuclear pores and Sun1 unchanged. Wild-type TorA also induces changes in NE membrane structure. Because SUN proteins interact with nesprins to connect nucleus and cytoskeleton, these effects suggest a new role for TorA in modulating complexes that traverse the NE. Importantly, once concentrated in the NE, disease-mutant TorA displaces Sun2 with reduced efficiency and does not change NE membrane structure. Together, our data suggest that LULL1 regulates the distribution and activity of TorA within the ER and NE lumen and reveal functional defects in the mutant protein responsible for DYT1 dystonia.

Original languageEnglish (US)
Pages (from-to)2661-2672
Number of pages12
JournalMolecular Biology of the Cell
Volume20
Issue number11
DOIs
StatePublished - Jun 1 2009

Fingerprint

Dystonia
Nuclear Envelope
Mutation
Endoplasmic Reticulum
Membrane Proteins
Native Polyacrylamide Gel Electrophoresis
Nuclear Pore
Mutant Proteins
Nuclear Proteins
Cytoskeleton
Adenosine Triphosphatases

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

LULL1 retargets torsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation. / Vander Heyden, Abigail B.; Naismith, Teresa V.; Snapp, Erik L.; Hodzic, Didier; Hanson, Phyllis I.

In: Molecular Biology of the Cell, Vol. 20, No. 11, 01.06.2009, p. 2661-2672.

Research output: Contribution to journalArticle

Vander Heyden, Abigail B. ; Naismith, Teresa V. ; Snapp, Erik L. ; Hodzic, Didier ; Hanson, Phyllis I. / LULL1 retargets torsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation. In: Molecular Biology of the Cell. 2009 ; Vol. 20, No. 11. pp. 2661-2672.
@article{86172a84ef6e4ed184c3acabc4c65e85,
title = "LULL1 retargets torsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation",
abstract = "TorsinA (TorA) is an AAA+ ATPase in the endoplasmic reticulum (ER) lumen that is mutated in early onset DYT1 dystonia. TorA is an essential protein in mice and is thought to function in the nuclear envelope (NE) despite localizing throughout the ER. Here, we report that transient interaction of TorA with the ER membrane protein LULL1 targets TorA to the NE. FRAP and Blue Native PAGE indicate that TorA is a stable, slowly diffusing oligomer in either the absence or presence of LULL1. Increasing LULL1 expression redistributes both wild-type and disease-mutant TorA to the NE, while decreasing LULL1 with shRNAs eliminates intrinsic enrichment of disease-mutant TorA in the NE. When concentrated in the NE, TorA displaces the nuclear membrane proteins Sun2, nesprin-2G, and nesprin-3 while leaving nuclear pores and Sun1 unchanged. Wild-type TorA also induces changes in NE membrane structure. Because SUN proteins interact with nesprins to connect nucleus and cytoskeleton, these effects suggest a new role for TorA in modulating complexes that traverse the NE. Importantly, once concentrated in the NE, disease-mutant TorA displaces Sun2 with reduced efficiency and does not change NE membrane structure. Together, our data suggest that LULL1 regulates the distribution and activity of TorA within the ER and NE lumen and reveal functional defects in the mutant protein responsible for DYT1 dystonia.",
author = "{Vander Heyden}, {Abigail B.} and Naismith, {Teresa V.} and Snapp, {Erik L.} and Didier Hodzic and Hanson, {Phyllis I.}",
year = "2009",
month = "6",
day = "1",
doi = "10.1091/mbc.E09-01-0094",
language = "English (US)",
volume = "20",
pages = "2661--2672",
journal = "Molecular Biology of the Cell",
issn = "1059-1524",
publisher = "American Society for Cell Biology",
number = "11",

}

TY - JOUR

T1 - LULL1 retargets torsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation

AU - Vander Heyden, Abigail B.

AU - Naismith, Teresa V.

AU - Snapp, Erik L.

AU - Hodzic, Didier

AU - Hanson, Phyllis I.

PY - 2009/6/1

Y1 - 2009/6/1

N2 - TorsinA (TorA) is an AAA+ ATPase in the endoplasmic reticulum (ER) lumen that is mutated in early onset DYT1 dystonia. TorA is an essential protein in mice and is thought to function in the nuclear envelope (NE) despite localizing throughout the ER. Here, we report that transient interaction of TorA with the ER membrane protein LULL1 targets TorA to the NE. FRAP and Blue Native PAGE indicate that TorA is a stable, slowly diffusing oligomer in either the absence or presence of LULL1. Increasing LULL1 expression redistributes both wild-type and disease-mutant TorA to the NE, while decreasing LULL1 with shRNAs eliminates intrinsic enrichment of disease-mutant TorA in the NE. When concentrated in the NE, TorA displaces the nuclear membrane proteins Sun2, nesprin-2G, and nesprin-3 while leaving nuclear pores and Sun1 unchanged. Wild-type TorA also induces changes in NE membrane structure. Because SUN proteins interact with nesprins to connect nucleus and cytoskeleton, these effects suggest a new role for TorA in modulating complexes that traverse the NE. Importantly, once concentrated in the NE, disease-mutant TorA displaces Sun2 with reduced efficiency and does not change NE membrane structure. Together, our data suggest that LULL1 regulates the distribution and activity of TorA within the ER and NE lumen and reveal functional defects in the mutant protein responsible for DYT1 dystonia.

AB - TorsinA (TorA) is an AAA+ ATPase in the endoplasmic reticulum (ER) lumen that is mutated in early onset DYT1 dystonia. TorA is an essential protein in mice and is thought to function in the nuclear envelope (NE) despite localizing throughout the ER. Here, we report that transient interaction of TorA with the ER membrane protein LULL1 targets TorA to the NE. FRAP and Blue Native PAGE indicate that TorA is a stable, slowly diffusing oligomer in either the absence or presence of LULL1. Increasing LULL1 expression redistributes both wild-type and disease-mutant TorA to the NE, while decreasing LULL1 with shRNAs eliminates intrinsic enrichment of disease-mutant TorA in the NE. When concentrated in the NE, TorA displaces the nuclear membrane proteins Sun2, nesprin-2G, and nesprin-3 while leaving nuclear pores and Sun1 unchanged. Wild-type TorA also induces changes in NE membrane structure. Because SUN proteins interact with nesprins to connect nucleus and cytoskeleton, these effects suggest a new role for TorA in modulating complexes that traverse the NE. Importantly, once concentrated in the NE, disease-mutant TorA displaces Sun2 with reduced efficiency and does not change NE membrane structure. Together, our data suggest that LULL1 regulates the distribution and activity of TorA within the ER and NE lumen and reveal functional defects in the mutant protein responsible for DYT1 dystonia.

UR - http://www.scopus.com/inward/record.url?scp=66349137319&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66349137319&partnerID=8YFLogxK

U2 - 10.1091/mbc.E09-01-0094

DO - 10.1091/mbc.E09-01-0094

M3 - Article

C2 - 19339278

AN - SCOPUS:66349137319

VL - 20

SP - 2661

EP - 2672

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

SN - 1059-1524

IS - 11

ER -