A pathway linking oxidative stress and the Ran GTPase system in progeria.
A pathway linking oxidative stress and the Ran GTPase system in progeria.
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DOI：
10.1091/mbc.e13-07-0430
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发表时间：
2014-04
影响因子：
3.3
通讯作者：
Paschal BM
中科院分区：
文献类型：
--
作者：
Datta S;Snow CJ;Paschal BM
在早衰症中，核纤层蛋白 A 的突变形式持续束缚在内核膜上，通过诱导 ROS 破坏 Ran GTPase 系统。然而，ROS 也是由 Ran 系统的破坏引起的。数据表明核纤层和 Ran GTPase 系统是包含正反馈环和负反馈环的途径的一部分。将 Ran GTPase 在细胞核中维持在适当的浓度对于核细胞质运输非常重要。此前，我们发现哈钦森-吉尔福德早衰综合症（HGPS）患者的细胞中 Ran 水平降低，这种疾病是由核纤层蛋白 A（称为早衰蛋白）的突变形式持续附着在核膜上引起的。在这里，我们探讨早老素、Ran GTP 酶和氧化应激之间的关系。早老素与核膜的稳定附着会破坏 Ran 梯度，并导致 Ubc9（一种 Ran 依赖性输入货物）在细胞质中定位。用 H2O2 可以可逆地诱导 Ran 和 Ubc9 破坏。预适应氧化应激的 CHO 细胞可抵抗早老素对 Ran 和 Ubc9 的影响。鉴于 HGPS 患者成纤维细胞显示出升高的 ROS，这些数据表明早老素通过氧化应激抑制核转运。抑制核纤层蛋白 A 前裂解的药物通过破坏 Ran 梯度来模拟早老素的作用，但在 ROS 大幅增加之前观察到对 Ran 的影响。此外，无论早老素如何，降低 Ran 的核浓度都足以诱导 ROS。我们推测早老素引起的氧化应激可能发生在 Ran 的上游或下游，具体取决于细胞类型和生理环境。
In progeria, a mutant form of lamin A constitutively tethered to the inner nuclear membrane causes disruption of the Ran GTPase system by inducing ROS. However, ROS are also induced by disruption of the Ran system. The data suggest that the nuclear lamina and Ran GTPase system are part of a pathway that contains positive and negative feedback loops. Maintaining the Ran GTPase at a proper concentration in the nucleus is important for nucleocytoplasmic transport. Previously we found that nuclear levels of Ran are reduced in cells from patients with Hutchinson–Gilford progeria syndrome (HGPS), a disease caused by constitutive attachment of a mutant form of lamin A (termed progerin) to the nuclear membrane. Here we explore the relationship between progerin, the Ran GTPase, and oxidative stress. Stable attachment of progerin to the nuclear membrane disrupts the Ran gradient and results in cytoplasmic localization of Ubc9, a Ran-dependent import cargo. Ran and Ubc9 disruption can be induced reversibly with H2O2. CHO cells preadapted to oxidative stress resist the effects of progerin on Ran and Ubc9. Given that HGPS-patient fibroblasts display elevated ROS, these data suggest that progerin inhibits nuclear transport via oxidative stress. A drug that inhibits pre–lamin A cleavage mimics the effects of progerin by disrupting the Ran gradient, but the effects on Ran are observed before a substantial ROS increase. Moreover, reducing the nuclear concentration of Ran is sufficient to induce ROS irrespective of progerin. We speculate that oxidative stress caused by progerin may occur upstream or downstream of Ran, depending on the cell type and physiological setting.