Oxygen-dependent binding of Nro1 to the prolyl hydroxylase Ofd1 regulates SREBP degradation in yeast
Oxygen-dependent binding of Nro1 to the prolyl hydroxylase Ofd1 regulates SREBP degradation in yeast
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DOI：
10.1038/emboj.2008.271
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发表时间：
2009-01-21
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：
Lee, Chih-Yung S.;Stewart, Emerson V.;Espenshade, Peter J.
Sre1是一种分裂酵母类固醇调节元件结合蛋白，是一种内质网膜结合转录因子，控制对低氧生长的适应。在低氧条件下，Sre1被蛋白降解，N端转录因子结构域(Sre1N)从膜上释放并进入细胞核，激活低氧基因的表达。Ofd1是一种类似于Pro-羟基酶的2-氧戊二酸双加氧酶，控制着Sre1N的氧依赖稳定性。在氧气存在的情况下，Ofd1加速Sre1N的降解，但在低氧条件下，Ofd1受到抑制，Sre1N积累。为了确定Sre1N的调控因子，我们对增加Sre1N转录活性的基因进行了基于质粒的筛选。在这里，我们确定Nro1(SPCC4B3.07)是Sre1N稳定性的正向调节因子和Ofd1的直接抑制因子。在无氧条件下，Nro1与Ofd1的C末端降解结构域结合，抑制Sre1N的降解。在氧气存在的情况下，Nro1与Ofd1的结合被破坏，导致Sre1N的快速降解。我们得出结论，Ofd1双加氧酶结构域作为氧感受器调节Nro1与Ofd1的结合，从而控制氧依赖的Sre1N的稳定性。
Sre1, the fission yeast sterol regulatory element-binding protein, is an ER membrane-bound transcription factor that controls adaptation to low oxygen growth. Under low oxygen, Sre1 is proteolytically cleaved and the N-terminal transcription factor domain (Sre1N) is released from the membrane and enters the nucleus to activate hypoxic gene expression. Ofd1, a prolyl 4-hydroxylase-like 2-oxoglutarate dioxygenase, controls the oxygen-dependent stability of Sre1N. In the presence of oxygen, Ofd1 accelerates the degradation of Sre1N, but under low oxygen Ofd1 is inhibited and Sre1N accumulates. To identify the regulators of Sre1N, we performed a plasmid-based screen for genes that increased Sre1N transcriptional activity. Here, we identify Nro1 (SPCC4B3.07) as a positive regulator of Sre1N stability and a direct inhibitor of Ofd1. In the absence of oxygen, Nro1 binds to the Ofd1 C-terminal degradation domain and inhibits Sre1N degradation. In the presence of oxygen, Nro1 binding to Ofd1 is disrupted, leading to rapid degradation of Sre1N. We conclude that the Ofd1 dioxygenase domain functions as an oxygen sensor that regulates binding of Nro1 to Ofd1 to control oxygen-dependent Sre1N stability.