The Yeast ER-Intramembrane Protease Ypf1 Refines Nutrient Sensing by Regulating Transporter Abundance
The Yeast ER-Intramembrane Protease Ypf1 Refines Nutrient Sensing by Regulating Transporter Abundance
复制标题
DOI：
10.1016/j.molcel.2014.10.012
复制
发表时间：
2014-12-04
期刊：
影响因子：
16
通讯作者：
Lemberg, Marius K.
中科院分区：
文献类型：
--
作者：
Avci, Doenem;Fuchs, Shai;Lemberg, Marius K.
蛋白水解的乙酰化膜内蛋白酶，如早老素和信号肽肽酶（SPP）的基础上许多细胞过程中的健康和疾病。酿酒酵母编码一个同源物，我们命名为酵母早老素折叠1（Ypf 1），我们验证是一个SPP型蛋白酶，定位于内质网（ER）。我们的工作表明，Ypf 1功能相互作用与ER相关的降解（ERAD）因子Dfm 1和Doa 10调节丰富的营养转运蛋白的降解。我们证明了ERAD通路的这个非经典分支，我们称之为“ERAD调节”（ERAD-R），如何响应配体介导的传感作为触发器。更一般地说，我们表明，Ypf 1介导的质膜转运蛋白的翻译后调节是必不可少的早期传感和适应营养耗竭。结合系统分析的机制细节揭示了膜内蛋白水解在调节分泌组动力学中的广泛作用。
Proteolysis by aspartyl intramembrane proteases such as presenilin and signal peptide peptidase (SPP) underlies many cellular processes in health and disease. Saccharomyces cerevisiae encodes a homolog that we named yeast presenilin fold 1 (Ypf1), which we verify to be an SPP-type protease that localizes to the endoplasmic reticulum (ER). Our work shows that Ypf1 functionally interacts with the ER-associated degradation (ERAD) factors Dfm1 and Doa10 to regulate the abundance of nutrient transporters by degradation. We demonstrate how this noncanonical branch of the ERAD pathway, which we termed "ERAD regulatory'' (ERAD-R), responds to ligand-mediated sensing as a trigger. More generally, we show that Ypf1-mediated posttranslational regulation of plasma membrane transporters is indispensible for early sensing and adaptation to nutrient depletion. The combination of systematic analysis alongside mechanistic details uncovers a broad role of intramembrane proteolysis in regulating secretome dynamics.