Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies
Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies
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DOI：
10.1093/hmg/ddr344
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发表时间：
2011-11-01
影响因子：
3.5
通讯作者：
Broers, Jos L. V.
中科院分区：
文献类型：
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作者：
De Vos, Winnok H.;Houben, Frederik;Broers, Jos L. V.
核纤层为核提供结构支持，并在核组织和基因调控中发挥核心作用。其组分核纤层蛋白的缺陷导致一类统称为核纤层蛋白病的遗传疾病。使用活细胞成像，我们观察到发生间歇性，非致命性的核被膜破裂的真皮成纤维细胞培养的患者与不同突变的核纤层蛋白A/C。这些破裂在正常成纤维细胞中不存在，可以通过选择性敲除以及敲除LMNA来模拟，并且伴随着细胞区室化的丧失。细胞质转录因子RelA和调节蛋白Cyclin B1流入细胞核，核转录因子OCT 1和含有早幼粒细胞白血病（PML）肿瘤抑制蛋白的核结构流出细胞质，证明了这一点。虽然细胞核中增强的黄色荧光蛋白标记的核定位信号的恢复证明了核膜完整性的恢复，但部分移动的PML结构永久性易位至细胞质。这些卫星PML结构缺乏典型的PML体成分，如DAXX，SP100或SUMO 1。我们的数据表明，核破裂和区室化的损失可能会增加各种核纤层蛋白病的细胞功能障碍和疾病发展。
The nuclear lamina provides structural support to the nucleus and has a central role in nuclear organization and gene regulation. Defects in its constituents, the lamins, lead to a class of genetic diseases collectively referred to as laminopathies. Using live cell imaging, we observed the occurrence of intermittent, non-lethal ruptures of the nuclear envelope in dermal fibroblast cultures of patients with different mutations of lamin A/C. These ruptures, which were absent in normal fibroblasts, could be mimicked by selective knockdown as well as knockout of LMNA and were accompanied by the loss of cellular compartmentalization. This was demonstrated by the influx of cytoplasmic transcription factor RelA and regulatory protein Cyclin B1 into the nucleus, and efflux of nuclear transcription factor OCT1 and nuclear structures containing the promyelocytic leukemia (PML) tumour suppressor protein to the cytoplasm. While recovery of enhanced yellow fluorescent protein-tagged nuclear localization signal in the nucleus demonstrated restoration of nuclear membrane integrity, part of the mobile PML structures became permanently translocated to the cytoplasm. These satellite PML structures were devoid of the typical PML body components, such as DAXX, SP100 or SUMO1. Our data suggest that nuclear rupture and loss of compartmentalization may add to cellular dysfunction and disease development in various laminopathies.