Nesprin-2 Giant (NUANCE) maintains nuclear envelope architecture and composition in skin
Nesprin-2 Giant (NUANCE) maintains nuclear envelope architecture and composition in skin
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DOI：
10.1242/jcs.019075
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发表时间：
2008-06-01
影响因子：
4
通讯作者：
Noegel, Angelika A.
中科院分区：
文献类型：
--
作者：
Lueke, Yvonne;Zaim, Hafida;Noegel, Angelika A.
由Nesprin-1（Syne 1）和Nesprin-2（Syne 2）编码的巨型异构体是多功能肌动蛋白结合和核被膜相关蛋白，属于血影蛋白超家族。在这里，我们调查的功能Nesprin-2巨人（NUANCE）在皮肤中产生的小鼠缺乏肌动蛋白结合域的Nesprin-2（Nesprin-2 Δ ABD）。这种损失导致轻微但显著的表皮增厚，这是上皮细胞核大小增加的结果。尽管如此，表皮增殖和分化在敲除表皮中表现正常。令人惊讶的是，Nesprin-2的C-末端亚型表达和核膜定位在某些组织中受到影响。原代真皮敲除成纤维细胞和角质形成细胞的细胞核严重畸形，显示出与核纤层蛋白病特征性核变形的惊人相似性。此外，Emerin（与埃默里-德赖富斯肌营养不良症（EDMD）的X连锁形式相关的蛋白质）在突变成纤维细胞中沿着核被膜不均匀分布，通常在变形的核被膜区域形成聚集体。因此，Nesprin-2是一种重要的支架蛋白，参与维持核膜结构。老年敲除成纤维细胞容易产生，通过选择性剪接和选择性翻译起始，异常Nesprin-2 Giant亚型，缺乏ABD，但足以恢复核形状和emerin定位;这表明Nesprin-2 Giant的其他区域，可能包括其血影蛋白重复序列，对这些功能至关重要。
Giant isoforms, encoded by Nesprin-1 (Syne1) and Nesprin-2 (Syne2), are multifunctional actin-binding and nuclear-envelope-associated proteins belonging to the spectrin superfamily. Here, we investigate the function of Nesprin-2 Giant (NUANCE) in skin by generating mice lacking the actin-binding domain of Nesprin-2 (Nesprin-2 Delta ABD). This loss results in a slight but significant thickening of the epidermis, which is a consequence of the increased epithelial nuclear size. Nonetheless, epidermal proliferation and differentiation appear normal in the knockout epidermis. Surprisingly, Nesprin-2 C-terminal-isoform expression and nuclear envelope localization were affected in certain tissues. Nuclei of primary dermal knockout fibroblasts and keratinocytes were heavily misshapen, displaying a striking similarity to nuclear deformations characteristic of laminopathies. Furthermore, emerin, the protein involved in the X-linked form of Emery-Dreifuss muscular dystrophy (EDMD), was unevenly distributed along the nuclear envelope in mutant fibroblasts, often forming aggregates in the deformed nuclear envelope areas. Thus, Nesprin-2 is an important scaffold protein implicated in the maintenance of nuclear envelope architecture. Aged knockout fibroblasts readily generated, by alternative splicing and alternative translation initiation, aberrant Nesprin-2 Giant isoforms that lacked an ABD but that were sufficient to restore nuclear shape and emerin localization; this suggests that other regions of Nesprin-2 Giant, potentially including its spectrin repeats, are crucial for these functions.