Multilevel regulation of an α-arrestin by glucose depletion controls hexose transporter endocytosis.
Multilevel regulation of an α-arrestin by glucose depletion controls hexose transporter endocytosis.
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DOI：
10.1083/jcb.201610094
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发表时间：
2017-06-05
期刊：
影响因子：
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通讯作者：
Léon S
中科院分区：
文献类型：
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作者：
Hovsepian J;Defenouillère Q;Albanèse V;Váchová L;Garcia C;Palková Z;Léon S
营养物质可利用性的变化触发了酵母质膜蛋白质组的大规模重排。这项工作表明，arrestin相关蛋白Csr 2/Art 8在多个水平上受葡萄糖信号转导的调节，从而控制葡萄糖耗尽后的己糖转运蛋白泛素化和内吞作用。营养物质的可利用性控制着质膜上营养物质转运蛋白的分布，特别是通过调节它们的泛素化和随后的内吞作用。在酵母中，这涉及Nedd 4泛素连接酶Rsp 5和抑制蛋白相关的运输衔接子（ARTs）。ART是信号通路的靶点，并保证货物泛素化和内吞作用适当地响应营养输入。在这里，我们表明，葡萄糖剥夺调节ART蛋白Csr 2/Art 8在多个水平触发高亲和力葡萄糖转运蛋白的内吞作用。Csr 2在这些条件下通过AMPK直系同源物Snf 1和下游转录抑制因子转录诱导。在合成时，Csr 2通过泛素化被激活。相反，葡萄糖补充诱导CSR 2转录关闭并将Csr 2转换为无活性的去泛素化形式。这种葡萄糖诱导的Csr 2去泛素化与其与14-3-3蛋白的磷酸依赖性结合相关，并涉及蛋白激酶A。因此，两个葡萄糖信号通路会聚到Csr 2上，以通过葡萄糖可用性调节己糖转运蛋白的内吞作用。这些数据说明了营养素调节ART活性和内吞作用的新机制。
Changes in nutrient availability trigger massive rearrangements of the yeast plasma membrane proteome. This work shows that the arrestin-related protein Csr2/Art8 is regulated by glucose signaling at multiple levels, allowing control of hexose transporter ubiquitylation and endocytosis upon glucose depletion. Nutrient availability controls the landscape of nutrient transporters present at the plasma membrane, notably by regulating their ubiquitylation and subsequent endocytosis. In yeast, this involves the Nedd4 ubiquitin ligase Rsp5 and arrestin-related trafficking adaptors (ARTs). ARTs are targeted by signaling pathways and warrant that cargo ubiquitylation and endocytosis appropriately respond to nutritional inputs. Here, we show that glucose deprivation regulates the ART protein Csr2/Art8 at multiple levels to trigger high-affinity glucose transporter endocytosis. Csr2 is transcriptionally induced in these conditions through the AMPK orthologue Snf1 and downstream transcriptional repressors. Upon synthesis, Csr2 becomes activated by ubiquitylation. In contrast, glucose replenishment induces CSR2 transcriptional shutdown and switches Csr2 to an inactive, deubiquitylated form. This glucose-induced deubiquitylation of Csr2 correlates with its phospho-dependent association with 14-3-3 proteins and involves protein kinase A. Thus, two glucose signaling pathways converge onto Csr2 to regulate hexose transporter endocytosis by glucose availability. These data illustrate novel mechanisms by which nutrients modulate ART activity and endocytosis.