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首页> 外文期刊>Molecular and Cellular Biology >Cancer-Causing Mutations in a Novel Transcription-Dependent Nuclear Export Motif of VHL Abrogate Oxygen-Dependent Degradation of Hypoxia-Inducible Factor
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Cancer-Causing Mutations in a Novel Transcription-Dependent Nuclear Export Motif of VHL Abrogate Oxygen-Dependent Degradation of Hypoxia-Inducible Factor

机译：VHL的新型转录依赖性核出口基序中的致癌突变消除了缺氧诱导因子的氧依赖性降解。

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It is thought that degradation of nuclear proteins by the ubiquitylation system requires nuclear-cytoplasmic trafficking of E3 ubiquitin ligases. The von Hippel-Lindau (VHL) tumor suppressor protein is the substrate recognition component of a Cullin-2-containing E3 ubiquitin ligase that recruits hypoxia-inducible factor (HIF) for oxygen-dependent degradation. We demonstrated that VHL engages in nuclear-cytoplasmic trafficking that requires ongoing transcription to promote efficient HIF degradation. Here, we report the identification of a discreet motif, DXGX2DX2L, that directs transcription-dependent nuclear export of VHL and which is targeted by naturally occurring mutations associated with renal carcinoma and polycythemia in humans. The DXGX2DX2L motif is also found in other proteins, including poly(A)-binding protein 1, to direct its transcription-dependent nuclear export. We define DXGX2DX2L as TD-NEM (transcription-dependent nuclear export motif), since inhibition of transcription by actinomycin D or 5,6-dichlorobenzimidazole abrogates its nuclear export activity. Disease-causing mutations of key residues of TD-NEM restrain the ability of VHL to efficiently mediate oxygen-dependent degradation of HIF by altering its nuclear export dynamics without affecting interaction with its substrate. These results identify a novel nuclear export motif, further highlight the role of nuclear-cytoplasmic shuttling of E3 ligases in degradation of nuclear substrates, and provide evidence that disease-causing mutations can target subcellular trafficking.
机译：认为通过泛素化系统降解核蛋白需要E3泛素连接酶的核质转移。 von Hippel-Lindau（VHL）肿瘤抑制蛋白是含Cullin-2的E3泛素连接酶的底物识别成分，该酶募集缺氧诱导因子（HIF）进行氧依赖性降解。我们证明，VHL参与需要持续转录以促进有效HIF降解的核质运输。在这里，我们报告鉴定了一个谨慎的基序DXGX 2 DX 2 L，该基序指导VHL的转录依赖性核输出，并以与之相关的天然突变为目标肾癌和人类红细胞增多症。 DXGX 2 DX 2 L基序也出现在其他蛋白质中，包括与poly（A）结合的蛋白质1，以指导其转录依赖性核输出。我们将DXGX 2 DX 2 L定义为TD-NEM（ t ranscription- d enden n < / em> uclear e xport m otif），因为放线菌素D或5,6-二氯苯并咪唑对转录的抑制作用消除了其核输出活性。 TD-NEM关键残基的致病突变通过改变VIF的核输出动力学而不会影响其与底物的相互作用，从而抑制VHL有效介导HIF的氧依赖性降解的能力。这些结果确定了一个新颖的核输出基序，进一步突出了E3连接酶的核质穿梭作用在核底物降解中的作用，并提供了致病突变可以靶向亚细胞贩运的证据。

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