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First published online 30 September 2008
doi: 10.1242/jcs.029454

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TorsinA binds the KASH domain of nesprins and participates in linkage between nuclear envelope and cytoskeleton

Flávia C. Nery¹, Juan Zeng^1,*, Brian P. Niland^1,*, Jeffrey Hewett¹, Jonathan Farley¹, Daniel Irimia², Yuqing Li³, Gerhard Wiche⁴, Arnoud Sonnenberg⁵ and Xandra O. Breakefield^1,

¹ Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, MA 02114, USA
² BioMEMS Resource Center, Department of Surgery and Bioengineering, Massachusetts General Hospital, Boston, MA 02114, USA
³ Department of Neurology and Center for Neurodegeneration and Experimental Therapeutics, University of Alabama, Birmingham, AL 35294, USA
⁴ Department of Molecular Cell Biology, Max F. Perutz Laboratories, University of Vienna, A-1030 Vienna, Austria
⁵ Department of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

Author for correspondence (e-mail: breakefield{at}hms.harvard.edu)

Accepted 21 July 2008

A specific mutation (E) in torsinA underlies most cases of the dominantly inherited movement disorder, early-onset torsion dystonia (DYT1). TorsinA, a member of the AAA+ ATPase superfamily, is located within the lumen of the nuclear envelope (NE) and endoplasmic reticulum (ER). We investigated an association between torsinA and nesprin-3, which spans the outer nuclear membrane (ONM) of the NE and links it to vimentin via plectin in fibroblasts. Mouse nesprin-3 co-immunoprecipitated with torsinA and this involved the C-terminal region of torsinA and the KASH domain of nesprin-3. This association with human nesprin-3 appeared to be stronger for torsinAE than for torsinA. TorsinA also associated with the KASH domains of nesprin-1 and -2 (SYNE1 and 2), which link to actin. In the absence of torsinA, in knockout mouse embryonic fibroblasts (MEFs), nesprin-3 was localized predominantly in the ER. Enrichment of yellow fluorescent protein (YFP)-nesprin-3 in the ER was also seen in the fibroblasts of DYT1 patients, with formation of YFP-positive globular structures enriched in torsinA, vimentin and actin. TorsinA-null MEFs had normal NE structure, but nuclear polarization and cell migration were delayed in a wound-healing assay, as compared with wild-type MEFs. These studies support a role for torsinA in dynamic interactions between the KASH domains of nesprins and their protein partners in the lumen of the NE, with torsinA influencing the localization of nesprins and associated cytoskeletal elements and affecting their role in nuclear and cell movement.

Key words: Nesprin, Dystonia, Cell migration, Nuclear polarization, DYT1, Vimentin, Actin

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