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Nesprin-3, a novel outer nuclear membrane protein, associates with the cytoskeletal linker protein plectin

Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands

Correspondence to Arnoud Sonnenberg: a.sonnenberg{at}nki.nl

Despite their importance in cell biology, the mechanisms that maintain the nucleus in its proper position in the cell are not well understood. This is primarily the result of an incomplete knowledge of the proteins in the outer nuclear membrane (ONM) that are able to associate with the different cytoskeletal systems. Two related ONM proteins, nuclear envelope spectrin repeat (nesprin)–1 and –2, are known to make direct connections with the actin cytoskeleton through their NH₂-terminal actin-binding domain (ABD). We have now isolated a third member of the nesprin family that lacks an ABD and instead binds to the plakin family member plectin, which can associate with the intermediate filament (IF) system. Overexpression of nesprin-3 results in a dramatic recruitment of plectin to the nuclear perimeter, which is where these two molecules are colocalized with both keratin-6 and -14. Importantly, plectin binds to the integrin 6ß4 at the cell surface and to nesprin-3 at the ONM in keratinocytes, suggesting that there is a continuous connection between the nucleus and the extracellular matrix through the IF cytoskeleton.

Abbreviations used in this paper: ABD, actin-binding domain; BPAG1, bullous pemphigoid antigen-1; cDNA, complementary DNA; EBS-MD, epidermolysis bullosa simplex with muscular dystrophy; FC, focal contact; FNIII, fibronectin type III; IF, intermediate filament; INM, inner nuclear membrane; KASH, Klarsicht/ANC-1/Syne-1 homology; MACF, MT–actin cross-linking factor; MEF, mouse embryonic fibroblast; MT, microtubule; NE, nuclear envelope; nesprin, nuclear envelope spectrin repeat; ONM, outer nuclear membrane; pAb, polyclonal antibody; PA-JEB, pyloric atresia associated with junctional epidermolysis bullosa; RACE, rapid analysis of cDNA ends; mRFP, monomeric red fluorescent protein; RIPA, radioimmunoprecipitation; siRNA, small interfering RNA; SMART, simple modular architecture research tool; SR, spectrin repeat; TM, transmembrane domain; VSV, vesicular stomatitis virus; WCL, whole cell lysate; Y2H, yeast two-hybrid.

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