Multiple mechanisms promote the inhibition of classical nuclear import upon exposure to severe oxidative stress
Multiple mechanisms promote the inhibition of classical nuclear import upon exposure to severe oxidative stress
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DOI：
10.1038/sj.cdd.4401432
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发表时间：
2004-08-01
影响因子：
12.4
通讯作者：
Stochaj, U
中科院分区：
文献类型：
--
作者：
Kodiha, M;Chu, A;Stochaj, U
在生长的HeLa细胞中，由氧化剂过氧化氢引起的严重应激抑制了经典的核输入。氧化处理使核细胞质Ran浓度梯度崩溃，从而提高细胞质GTPase水平。Ran梯度随着应力诱导的RanGTP耗竭和Ran核进口效率的降低而消散。此外，氧化应激诱导核孔蛋白Nup153和核载体importin-beta的重新定位，减少了importin-alpha/beta/cargo复合物在核包膜上的对接。此外，Ran、importin- β和Nup153在氧化应激下发生蛋白水解。半胱天冬酶和蛋白酶体降解Ran和importin- β；然而，没有观察到这些转运因子的泛素化。在应激细胞中抑制caspase可以减轻importin- β的错误定位，但不能恢复Ran的浓度梯度或经典进口。总之，过氧化氢对经典核进口的抑制是由多种机制的组合引起的，这些机制针对转运装置的不同组成部分。
In growing HeLa cells, severe stress elicited by the oxidant hydrogen peroxide inhibits classical nuclear import. Oxidant treatment collapses the nucleocytoplasmic Ran concentration gradient, thereby elevating cytoplasmic GTPase levels. The Ran gradient dissipates in response to a stress-induced depletion of RanGTP and a decreased efficiency of Ran nuclear import. In addition, oxidative stress induces a relocation of the nucleoporin Nup153 as well as the nuclear carrier importin-beta, and docking of the importin-alpha/beta/cargo complex at the nuclear envelope is reduced. Moreover, Ran, importin-beta and Nup153 undergo proteolysis upon oxidative stress. Caspases and the proteasome degrade Ran and importin-beta; however, ubiquitination of these transport factors is not observed. Inhibition of caspases in stressed cells alleviates the mislocalization of importin-beta, but does not restore the Ran concentration gradient or classical import. In summary, inhibition of classical nuclear import by hydrogen peroxide is caused by a combination of multiple mechanisms that target different components of the transport apparatus.