Oxygen-regulated degradation of fission yeast SREBP by Ofd1, a prolyl hydroxylase family member
Oxygen-regulated degradation of fission yeast SREBP by Ofd1, a prolyl hydroxylase family member
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DOI：
10.1038/emboj.2008.83
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发表时间：
2008-05-21
期刊：
影响因子：
11.4
通讯作者：
Espenshade, Peter J.
中科院分区：
文献类型：
--
作者：
Hughes, Bridget T.;Espenshade, Peter J.
Sre 1是裂殖酵母固醇调节元件结合蛋白，是一种内质网膜结合转录因子，其响应氧依赖性固醇合成的变化，作为氧可用性的间接测量。在低氧条件下，Sre 1被蛋白水解裂解，释放的N-末端转录因子（Sre 1 N）激活低氧生长所必需的基因表达。在这里，我们描述了一个氧依赖性的机制，调节SRE 1是独立的甾醇调节的蛋白水解。使用酵母只表达Sre 1 N，我们表明，Sre 1 N营业额是由氧调节。Ofd 1是一种未表征的脯氨酰4-羟化酶样2-酮戊二酸铁（II）双加氧酶，在氧气存在下加速Sre 1 N降解。然而，与调节哺乳动物缺氧诱导因子的脯氨酰4-羟化酶不同，Ofd 1使用多个结构域来调节氧对Sre 1 N的降解; Ofd 1 N-末端双加氧酶结构域是氧传感所需的，Ofd 1 C-末端结构域加速Sre 1 N降解。我们的数据支持一个模型，其中Ofd 1 N-末端双加氧酶结构域是一个氧传感器，调节C-末端降解结构域的活性。
Sre1, the fission yeast sterol regulatory element binding protein, is an endoplasmic reticulum membrane-bound transcription factor that responds to changes in oxygen-dependent sterol synthesis as an indirect measure of oxygen availability. Under low oxygen, Sre1 is proteolytically cleaved and the released N-terminal transcription factor (Sre1N) activates gene expression essential for hypoxic growth. Here, we describe an oxygen-dependent mechanism for regulation of Sre1 that is independent of sterol-regulated proteolysis. Using yeast expressing only Sre1N, we show that Sre1N turnover is regulated by oxygen. Ofd1, an uncharacterized prolyl 4-hydroxylase- like 2-oxoglutarateFe(II) dioxygenase, accelerates Sre1N degradation in the presence of oxygen. However, unlike the prolyl 4-hydroxylases that regulate mammalian hypoxia-inducible factor, Ofd1 uses multiple domains to regulate Sre1N degradation by oxygen; the Ofd1 N-terminal dioxygenase domain is required for oxygen sensing and the Ofd1 C-terminal domain accelerates Sre1N degradation. Our data support a model whereby the Ofd1 N-terminal dioxygenase domain is an oxygen sensor that regulates the activity of the C-terminal degradation domain.