Sphingolipids Function as Downstream Effectors of a Fungal PAQR
Sphingolipids Function as Downstream Effectors of a Fungal PAQR
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DOI：
10.1124/mol.108.049809
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发表时间：
2009-04-01
影响因子：
3.6
通讯作者：
Lyons, Thomas J.
中科院分区：
文献类型：
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作者：
Villa, Nancy Y.;Kupchak, Brian R.;Lyons, Thomas J.
酿酒酵母的Izh2p蛋白属于新发现的孕激素和脂肪q受体（PAQR）超家族，其信号转导机制尚不清楚。Izh2p是植物PR-5防御渗透素的受体，在细胞生化中具有多效性。这种多效性的一个例子是izhbp依赖性的fe3的抑制，这是一种参与铁摄取的基因。尽管Izh2p抑制FET3的生理目的尚不明确，但它为探索这类新型受体的信号转导机制提供了一个报告因子。PAQR家族中的受体与参与神经酰胺代谢的酶具有序列相似性，这导致鞘脂参与izhbp依赖性信号传导的假设。在本研究中，我们发现影响鞘脂代谢的药物，如d - red - mapp和肉豆蔻素，抑制Izh2p对FET3的作用。我们还表明Izh2p导致稳态水平的增加。此外，我们发现与Izh2p无关的鞘碱基的增加再现了Izh2p对fe3的影响。最后，我们的数据表明Pkh2p和Pkh2p鞘基传感激酶是izh2p依赖性信号通路的重要组成部分。总之，我们的数据表明Izh2p产生鞘碱，这些生物活性脂质可能是Izh2p对FET3影响的第二信使。
The Izh2p protein from Saccharomyces cerevisiae belongs to the newly characterized progestin and adipoQ receptor (PAQR) superfamily of receptors whose mechanism of signal transduction is still unknown. Izh2p functions as a receptor for the plant PR-5 defensin osmotin and has pleiotropic effects on cellular biochemistry. One example of this pleiotropy is the Izh2p-dependent repression of FET3, a gene involved in iron-uptake. Although the physiological purpose of FET3 repression by Izh2p is a matter of speculation, it provides a reporter with which to probe the mechanism of signal transduction by this novel class of receptor. Receptors in the PAQR family share sequence similarity with enzymes involved in ceramide metabolism, which led to the hypothesis that sphingolipids are involved in Izh2p-dependent signaling. In this study, we demonstrate that drugs affecting sphingolipid metabolism, such as D-erythro-MAPP and myriocin, inhibit the effect of Izh2p on FET3. We also show that Izh2p causes an increase in steady-state levels of sphingoid base. Moreover, we show that Izh2p-independent increases in sphingoid bases recapitulate the effect of Izh2p on FET3. Finally, our data indicate that the Pkh1p and Pkh2p sphingoid base-sensing kinases are essential components of the Izh2p-dependent signaling pathway. In conclusion, our data indicate that Izh2p produces sphingoid bases and that these bioactive lipids probably function as the second messenger responsible for the effect of Izh2p on FET3.