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Vol. 16, Issue 7, 3411-3424, July 2005
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* Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany;
Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, 50931 Cologne, Germany;
Institute of Human Genetics, Ernst-Moritz-Arndt-University, 17487 Greifswald, Germany;
School of Biological and Biomedical Sciences, University of Durham, Durham, DH1 3LE United Kingdom; and
|| M. E. Mueller Institute, Biozentrum, University of Basel, CH-4056 Basel, Switzerland
Submitted November 17, 2004;
Revised April 1, 2005;
Accepted April 12, 2005
Monitoring Editor: Orna Cohen-Fix
The vertebrate proteins Nesprin-1 and Nesprin-2 (also referred to as Enaptin and NUANCE) together with ANC-1 of Caenorhabditis elegans and MSP-300 of Drosophila melanogaster belong to a novel family of 
-actinin type actin-binding proteins residing at the nuclear membrane. Using biochemical techniques, we demonstrate that Nesprin-2 binds directly to emerin and the C-terminal common region of lamin A/C. Selective disruption of the lamin A/C network in COS7 cells, using a dominant negative lamin B mutant, resulted in the redistribution of Nesprin-2. Furthermore, using lamin A/C knockout fibroblasts we show that lamin A/C is necessary for the nuclear envelope localization of Nesprin-2. In normal skin where lamin A/C is differentially expressed, strong Nesprin-2 expression was found in all epidermal layers, including the basal layer where only lamin C is present. This indicates that lamin C is sufficient for proper Nesprin-2 localization at the nuclear envelope. Expression of dominant negative Nesprin-2 constructs and knockdown studies in COS7 cells revealed that the presence of Nesprin-2 at the nuclear envelope is necessary for the proper localization of emerin. Our data imply a scaffolding function of Nesprin-2 at the nuclear membrane and suggest a potential involvement of this multi-isomeric protein in human disease.
Abbreviations used: aa, amino acids; ABD, actin-binding domain; Co-IP, coimmunoprecipitation; DAPI, 4,6-diamidino-2-phenylindole; GFP, green fluorescent protein; GST, glutathione S-transferase; NUANCE, nucleus and actin connnecting element; Nesprins, nuclear envelope spectrin repeat proteins; siRNA, small interference RNA; X-EDMD, X-linked Emery-Dreifuss muscular dystrophy.
Note added in proof. While this paper was under review, Zhang et al. (2005) published an article demonstrating the existence of various Nesprin-2 isoforms within the nucleus, the outer nuclear membrane, and various cytoplasmic compartments. These data suggest that nesprin-2 isoforms may link various membranous compartments including the nucleus to the actin cytoskeleton. The authors showed that the smaller Nesprin-2 isoforms colocalize and bind to lamin A/C and emerin at the inner nuclear membrane and require lamin A/C for proper localization in SW-13 cells. Those associations allowed the authors to suggest that a Nesprin-based mechanism may explain how disruption/s of NE constituents leads to muscle dysfunction.
Address correspondence to: Angelika A. Noegel (noegel{at}uni-koeln.de).
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