Lammerding Jan, Hsiao Janet, Schulze P Christian, Kozlov Serguei, Stewart Colin L, Lee Richard T
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
J Cell Biol. 2005 Aug 29;170(5):781-91. doi: 10.1083/jcb.200502148. Epub 2005 Aug 22.
Emery-Dreifuss muscular dystrophy can be caused by mutations in the nuclear envelope proteins lamin A/C and emerin. We recently demonstrated that A-type lamin-deficient cells have impaired nuclear mechanics and altered mechanotransduction, suggesting two potential disease mechanisms (Lammerding, J., P.C. Schulze, T. Takahashi, S. Kozlov, T. Sullivan, R.D. Kamm, C.L. Stewart, and R.T. Lee. 2004. J. Clin. Invest. 113:370-378). Here, we examined the function of emerin on nuclear mechanics and strain-induced signaling. Emerin-deficient mouse embryo fibroblasts have abnormal nuclear shape, but in contrast to A-type lamin-deficient cells, exhibit nuclear deformations comparable to wild-type cells in cellular strain experiments, and the integrity of emerin-deficient nuclear envelopes appeared normal in a nuclear microinjection assay. Interestingly, expression of mechanosensitive genes in response to mechanical strain was impaired in emerin-deficient cells, and prolonged mechanical stimulation increased apoptosis in emerin-deficient cells. Thus, emerin-deficient mouse embryo fibroblasts have apparently normal nuclear mechanics but impaired expression of mechanosensitive genes in response to strain, suggesting that emerin mutations may act through altered transcriptional regulation and not by increasing nuclear fragility.
埃默里 - 德赖富斯肌营养不良症可由核纤层蛋白A/C和emerin等核被膜蛋白的突变引起。我们最近证明,缺乏A型核纤层蛋白的细胞具有受损的核力学和改变的机械转导,提示了两种潜在的疾病机制(Lammerding, J., P.C. Schulze, T. Takahashi, S. Kozlov, T. Sullivan, R.D. Kamm, C.L. Stewart, and R.T. Lee. 2004. J. Clin. Invest. 113:370 - 378)。在此,我们研究了emerin在核力学和应变诱导信号传导方面的功能。缺乏emerin的小鼠胚胎成纤维细胞具有异常的核形状,但与缺乏A型核纤层蛋白的细胞不同,在细胞应变实验中其核变形与野生型细胞相当,并且在核显微注射试验中,缺乏emerin的核被膜完整性看起来正常。有趣的是,缺乏emerin的细胞中机械应变响应的机械敏感基因表达受损,并且长时间的机械刺激会增加缺乏emerin的细胞中的凋亡。因此,缺乏emerin的小鼠胚胎成纤维细胞显然具有正常的核力学,但对应变的机械敏感基因表达受损,提示emerin突变可能通过改变转录调控起作用,而不是通过增加核脆性起作用。