2-Deoxyglucose Impairs Saccharomyces cerevisiae Growth by Stimulating Snf1-Regulated and α-Arrestin-Mediated Trafficking of Hexose Transporters 1 and 3
2-Deoxyglucose Impairs Saccharomyces cerevisiae Growth by Stimulating Snf1-Regulated and α-Arrestin-Mediated Trafficking of Hexose Transporters 1 and 3
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DOI：
10.1128/mcb.01183-14
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发表时间：
2015-03-01
影响因子：
5.3
通讯作者：
Schmidt, Martin C.
中科院分区：
文献类型：
--
作者：
O'Donnell, Allyson F.;McCartney, Rhonda R.;Schmidt, Martin C.
葡萄糖类似物2-脱氧葡萄糖（2DG）抑制酿酒酵母和人肿瘤细胞的生长，但其作用模式尚未完全阐明。缺乏Snf1 （amp活化蛋白激酶）的酵母细胞对2DG过敏。过表达两种低亲和力、高容量葡萄糖转运体Hxt1和Hxt3中的任何一种，都会抑制snf1 Delta细胞的2DG超敏性。2DG的加入或Snf1的缺失会降低HXT1和HXT3的表达水平，并刺激液泡中转运蛋白的内吞和降解。2dg刺激的Hxt1和Hxt3的贩运需要Rod1/Art4和Rog3/Art7，这是α -逮捕贩运适配器家族的两个成员。ROD1和ROG3的突变阻断了与泛素连接酶Rsp5的结合，从而消除了ROD1和ROG3介导的Hxt1和Hxt3的转运。遗传分析表明Snf1负调控Rod1和Rog3，但通过不同的机制。被2DG激活的Snf1使Rod1磷酸化，但不能磷酸化其他已知靶标，如转录抑制因子Mig1。我们提出了2DG诱导毒性的新机制，即2DG刺激α -抑制蛋白的修饰，从而促进葡萄糖转运蛋白的内化和降解，即使细胞处于富含葡萄糖的环境中也会导致葡萄糖饥饿。
The glucose analog 2-deoxyglucose (2DG) inhibits the growth of Saccharomyces cerevisiae and human tumor cells, but its modes of action have not been fully elucidated. Yeast cells lacking Snf1 (AMP-activated protein kinase) are hypersensitive to 2DG. Overexpression of either of two low-affinity, high-capacity glucose transporters, Hxt1 and Hxt3, suppresses the 2DG hypersensitivity of snf1 Delta cells. The addition of 2DG or the loss of Snf1 reduces HXT1 and HXT3 expression levels and stimulates transporter endocytosis and degradation in the vacuole. 2DG-stimulated trafficking of Hxt1 and Hxt3 requires Rod1/Art4 and Rog3/Art7, two members of the alpha-arrestin trafficking adaptor family. Mutations in ROD1 and ROG3 that block binding to the ubiquitin ligase Rsp5 eliminate Rod1- and Rog3-mediated trafficking of Hxt1 and Hxt3. Genetic analysis suggests that Snf1 negatively regulates both Rod1 and Rog3, but via different mechanisms. Snf1 activated by 2DG phosphorylates Rod1 but fails to phosphorylate other known targets, such as the transcriptional repressor Mig1. We propose a novel mechanism for 2DG-induced toxicity whereby 2DG stimulates the modification of alpha-arrestins, which promote glucose transporter internalization and degradation, causing glucose starvation even when cells are in a glucose-rich environment.