Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes
Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes
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DOI：
10.1073/pnas.0505767102
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发表时间：
2005-09-06
影响因子：
11.1
通讯作者：
Fong, LG
中科院分区：
文献类型：
--
作者：
Toth, JI;Yang, SH;Fong, LG
由其法尼化前体--前层素A生物合成的缺陷会导致前层素A在核膜上积聚，导致核畸形，并导致孕激素综合征。ZMPSTE24是一种参与前粘连蛋白A加工的蛋白酶，它的缺失会导致前粘连蛋白A堆积，缺乏成熟层粘连蛋白A，核畸形，以及一种致命的围产期程序性综合征：限制性皮肤病(RD)。Hutchinson-Gilford早衰症(HGPS)是由突变的前层蛋白A不能被加工成层蛋白A引起的。RD和HGPS的显著细胞异常是细胞核畸形。我们推测，在RD和HGPS中，前层蛋白A的法尼化对于其靶向核膜是重要的，阻断法尼化将改善核形状异常。事实上，当用法尼基转移酶抑制剂处理RD成纤维细胞时，前层蛋白A部分错位地远离核膜，核形状异常的频率减少(P<；0.0001)。在Zmpste24基因缺陷的小鼠胚胎成纤维细胞(P<；0.0001)中，FTI还错误地定位了前层蛋白A并改善了核形状(P<；0.0001)，在人类hGPS成纤维细胞中也改善了核形状(P<；0.0001)。最值得注意的是，在没有前层蛋白A积聚的情况下，层蛋白A错义突变的非典型早衰症患者的两个成纤维细胞系的细胞核形状显著改善(P=0.0003和P<；0.0001)。这些发现为改善层蛋白相关的孕激素综合征中最明显的细胞病理建立了一个范例，并提出了治疗这些疾病的潜在策略。
Defects in the biogenesis of lamin A from its farnesylated precursor, prelamin A, lead to the accumulation of prelamin A at the nuclear envelope, cause misshapen nuclei, and result in progeroid syndromes. A deficiency in ZMPSTE24, a protease involved in prelamin A processing, leads to prelamin A accumulation, an absence of mature lamin A, misshapen nuclei, and a lethal perinatal progeroid syndrome: restrictive dermopathy (RD). Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutant prelamin A that cannot be processed to lamin A. The hallmark cellular abnormality in RD and HGPS is misshapen nuclei. We hypothesized that the farnesylation of prelamin A is important for its targeting to the nuclear envelope in RD and HGPS and that blocking farnesylation would ameliorate the nuclear shape abnormalities. Indeed, when RD fibroblasts were treated with a farnesyltransferase inhibitor (FTI), prelamin A was partially mislocalized away from the nuclear envelope, and the frequency of nuclear shape abnormalities was reduced (P < 0.0001). A FTI also mislocalized prelamin A and improved nuclear shape in Zmpste24-deficient mouse embryonic fibroblasts (P < 0.0001) and improved nuclear shape in human HGPS fibroblasts (P < 0.0001). Most remarkably, a FTI significantly improved nuclear shape in two fibroblast cell lines from atypical progeria patients with lamin A missense mutations in the absence of prelamin A accumulation (P = 0.0003 and P < 0.0001). These findings establish a paradigm for ameliorating the most obvious cellular pathology in lamin-related progeroid syndromes and suggest a potential strategy for treating these diseases.