Transcriptional regulation of sphingolipid metabolism in budding yeast
Transcriptional regulation of sphingolipid metabolism in budding yeast
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芽殖酵母鞘脂代谢的转录调控
DOI：
10.1101/2021.11.05.467429
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Tabuchi Mitsuaki
中科院分区：
文献类型：
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作者：
Komatsu Nao;Ishino Yuko;Shirai Rina;Sakata Ken-taro;Tani Motohiro;Maeda Tatsuya;Tanaka Naotaka;Tabuchi Mitsuaki
构成双层细胞膜的脂质合成的全局控制是由少数被称为主转录调节因子的转录因子控制的，这些转录因子针对编码脂质代谢酶和/或其调节因子的广泛基因。虽然在酵母和哺乳动物中已经发现了甘油磷脂和甾醇的主要转录调节因子，但鞘脂代谢的这方面还不清楚。在本研究中，我们发现c2h2型锌指转录因子Com2是出芽酵母（Saccharomyces cerevisiae）鞘脂代谢的主要转录调节因子。已知雷帕霉素复合物2 （TORC2）激活的蛋白激酶Ypk1的靶标调节鞘脂代谢。激活的Ypk1通过磷酸化和抑制SPT的负调节因子Orm1/2，刺激鞘脂生物合成的第一步酶丝氨酸棕榈酰转移酶（SPT）的活性。SPT活性的调节被认为是鞘脂代谢调节的主要途径。在本研究中，我们发现抑制鞘脂合成可上调Com2的表达，进而导致Ypk1的伴随表达。发现Ypk1表达的上调依赖于Ypk1启动子中一个假定的com2结合位点。我们的研究结果还表明，Com2通过独立于torc2 - ypk1介导的鞘脂感知的途径来感知细胞内鞘脂水平。我们的研究结果揭示了一个额外的机制调节层，它允许细胞维持适当的鞘脂生物合成水平，并在环境压力下迅速诱导这一过程。意义声明生物膜双层脂质代谢的主要调控机制之一是在转录水平上由主控转录调控因子调控，主控转录调控因子控制编码脂质代谢酶和/或其调控因子的基因的转录。在本研究中，我们发现c2h2型锌指转录因子Com2是鞘脂代谢的主要转录调节因子。我们发现Com2通过转录控制Ypk1的表达来调节鞘脂代谢，Ypk1通过磷酸化调节Orm1/2， Orm1/2是鞘脂生物合成的第一步酶丝氨酸棕榈酰转移酶的负调节因子。我们的研究揭示了一个新的调控层，它允许维持适当水平的鞘脂生物合成，以快速响应环境压力。
Global control for the synthesis of lipids constituting a bilayer of cell membranes is known to be with a small number of transcription factors called master transcriptional regulators, which target a wide range of genes encoding lipid metabolism enzymes and/or their regulators. Although master transcriptional regulators of glycerophospholipids and sterols have been identified in both yeast and mammals, this aspect of sphingolipid metabolism is not yet understood. In the present study, we identified the C2H2-type zinc finger transcription factor, Com2, as a master transcriptional regulator of sphingolipid metabolism in the budding yeast,Saccharomyces cerevisiae. The target of rapamycin complex 2 (TORC2)-activated protein kinase Ypk1 is known to regulate sphingolipid metabolism. Activated Ypk1 stimulates the activity of serine palmitoyl transferase (SPT), the first-step enzyme in sphingolipid biosynthesis, by phosphorylating and inhibiting Orm1/2, a negative regulator of SPT. This regulation of SPT activity is thought to be a major pathway in the regulation of sphingolipid metabolism. In the present study, we found that inhibition of sphingolipid synthesis upregulates the expression of Com2, which in turn leads to the concomitant expression of Ypk1. The upregulation of Ypk1 expression was found to be dependent on a putative Com2-binding site in theYPK1promoter. Our results also suggested that Com2 senses intracellular sphingolipid levels through a pathway independent of TORC2-Ypk1-mediated sensing of sphingolipids. Our results revealed an additional layer of mechanistic regulation that allows cells to maintain appropriate levels of sphingolipid biosynthesis and to rapidly induce this process in response to environmental stresses.Significance StatementOne of the major regulatory mechanisms involved in the control of lipid metabolism in bilayers of biological membranes is regulation at the transcriptional level by master transcriptional regulators that control the transcription of genes encoding lipid metabolism enzymes and/or their regulators. In the present study, we identified the C2H2-type zinc finger transcription factor Com2 as a master transcriptional regulator in sphingolipid metabolism. We found that Com2 regulates sphingolipid metabolism by transcriptionally controlling the expression of Ypk1, which regulates Orm1/2, a negative regulator of serine palmitoyl transferase, the first-step enzyme in sphingolipid biosynthesis, through phosphorylation. Our study revealed a new layer of regulation that allows the maintenance of an appropriate level of sphingolipid biosynthesis for a rapid response to environmental stresses.