School of Biological and Biomedical Sciences, University of Durham, Durham, UK.
Cell Mol Life Sci. 2012 Oct;69(20):3493-509. doi: 10.1007/s00018-012-1034-1. Epub 2012 Jun 1.
Nesprins-1/-2/-3/-4 are nuclear envelope proteins, which connect nuclei to the cytoskeleton. The largest nesprin-1/-2 isoforms (termed giant) tether F-actin through their N-terminal actin binding domain (ABD). Nesprin-3, however, lacks an ABD and associates instead to plectin, which binds intermediate filaments. Nesprins are integrated into the outer nuclear membrane via their C-terminal KASH-domain. Here, we show that nesprin-1/-2 ABDs physically and functionally interact with nesprin-3. Thus, both ends of nesprin-1/-2 giant are integrated at the nuclear surface: via the C-terminal KASH-domain and the N-terminal ABD-nesprin-3 association. Interestingly, nesprin-2 ABD or KASH-domain overexpression leads to increased nuclear areas. Conversely, nesprin-2 mini (contains the ABD and KASH-domain but lacks the massive nesprin-2 giant rod segment) expression yields smaller nuclei. Nuclear shrinkage is further enhanced upon nesprin-3 co-expression or microfilament depolymerization. Our findings suggest that multivariate intermolecular nesprin interactions with the cytoskeleton form a lattice-like filamentous network covering the outer nuclear membrane, which determines nuclear size.
Nesprins-1/-2/-3/-4 是核膜蛋白，它们将细胞核与细胞骨架连接起来。最大的 nesprin-1/-2 异构体（称为巨）通过其 N 端肌动蛋白结合结构域（ABD）将 F-肌动蛋白固定。然而，nesprin-3 缺乏 ABD，而是与连接中间丝的细丝蛋白（plectin）结合。nesprins 通过其 C 端 KASH 结构域整合到核外膜中。在这里，我们表明 nesprin-1/-2 ABD 与 nesprin-3 物理和功能相互作用。因此，nesprin-1/-2 巨的两端都整合到核表面：通过 C 端 KASH 结构域和 N 端 ABD-nesprin-3 结合。有趣的是，nesprin-2 ABD 或 KASH 结构域的过表达会导致核面积增加。相反，nesprin-2 小体（包含 ABD 和 KASH 结构域，但缺乏巨大的 nesprin-2 棒状结构域）的表达会导致核体积变小。nesprin-3 共表达或微丝解聚会进一步增强核收缩。我们的发现表明，与细胞骨架的多变量分子内 nesprin 相互作用形成覆盖核外膜的类似晶格的丝状网络，从而决定核的大小。
