PMID:19339278

Citation	Vander Heyden, AB, Naismith, TV, Snapp, EL, Hodzic, D and Hanson, PI (2009) LULL1 retargets TorsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation. Mol. Biol. Cell 20:2661-72
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.
Links	PubMed PMC2688546 Online version:10.1091/mbc.E09-01-0094
Keywords	Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Line, Tumor; Dystonia/genetics; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum/metabolism; Green Fluorescent Proteins/genetics; Green Fluorescent Proteins/metabolism; Humans; Immunoblotting; Membrane Proteins/genetics; Membrane Proteins/metabolism; Microscopy, Fluorescence; Molecular Chaperones/chemistry; Molecular Chaperones/genetics; Molecular Chaperones/metabolism; Mutation; Nuclear Envelope/metabolism; Protein Binding; Protein Multimerization; Protein Transport; RNA, Small Interfering/genetics; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Transfection
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:TOIP2		GO:0090435: protein localization to nuclear envelope	ECO:0000314:		P		Figure 1: LULL1 promotes relocalization of TorA to the NE They studied the subcellular localization of TorA with mGFP fused to its C-terminus in transfected U2OS cells	complete CACAO 7168
HUMAN:TOIP2	involved_in	GO:0090435: protein localization to nuclear envelope	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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