Central Role of the Oxygen-dependent Degradation Domain of Drosophila HIFα/Sima in Oxygen-dependent Nuclear Export
Central Role of the Oxygen-dependent Degradation Domain of Drosophila HIFα/Sima in Oxygen-dependent Nuclear Export
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DOI：
10.1091/mbc.e09-01-0038
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发表时间：
2009-09-01
影响因子：
3.3
通讯作者：
Wappner, Pablo
中科院分区：
文献类型：
--
作者：
Irisarri, Maximiliano;Lavista-Llanos, Sofia;Wappner, Pablo
果蝇 HIF α 同源物 Sima 在常氧条件下主要定位于细胞质中，并在缺氧时在细胞核中积累。我们表征了 Sima 氧依赖性亚细胞定位的机制，并发现 Sima 在细胞核和细胞质之间连续穿梭。我们之前已经表明，核输入取决于蛋白质 C 末端旁边的非典型二分核定位信号。我们在此表明，核输出部分是由位于氧依赖性降解域 (ODDD) 中的 CRM1 依赖性核输出信号介导的。 CRM1 依赖性核输出需要 ODDD 中特定脯氨酰残基 (Pro850) 的氧依赖性羟基化，以及 von Hippel Lindau 肿瘤抑制因子的活性。在高氧张力下，Sima 的核输出快速发生，而在缺氧条件下，Sima 的核输出很大程度上受到抑制。 HIF α/Sima 核胞质定位是核输入和核输出之间动态平衡的结果，核输出受氧张力调节。
The Drosophila HIF alpha homologue, Sima, is localized mainly in the cytoplasm in normoxia and accumulates in the nucleus upon hypoxic exposure. We have characterized the mechanism governing Sima oxygen-dependent subcellular localization and found that Sima shuttles continuously between the nucleus and the cytoplasm. We have previously shown that nuclear import depends on an atypical bipartite nuclear localization signal mapping next to the C-terminus of the protein. We show here that nuclear export is mediated in part by a CRM1-dependent nuclear export signal localized in the oxygen-dependent degradation domain (ODDD). CRM1-dependent nuclear export requires both oxygen-dependent hydroxylation of a specific prolyl residue (Pro850) in the ODDD, and the activity of the von Hippel Lindau tumor suppressor factor. At high oxygen tension rapid nuclear export of Sima occurs, whereas in hypoxia, Sima nuclear export is largely inhibited. HIF alpha/Sima nucleo-cytoplasmic localization is the result of a dynamic equilibrium between nuclear import and nuclear export, and nuclear export is modulated by oxygen tension.