Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
Mol Cell. 2014 Dec 4;56(5):630-40. doi: 10.1016/j.molcel.2014.10.012. Epub 2014 Nov 13.
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.
天冬氨酰基膜内蛋白酶（如早老素和信号肽肽酶（SPP））的蛋白水解作用是健康和疾病中许多细胞过程的基础。酿酒酵母编码了一种同源物，我们将其命名为酵母早老素折叠 1（Ypf1），我们验证它是一种定位于内质网（ER）的 SPP 型蛋白酶。我们的工作表明，Ypf1 与 ER 相关降解（ERAD）因子 Dfm1 和 Doa10 具有功能相互作用，通过降解来调节营养物质转运蛋白的丰度。我们展示了这种 ERAD 途径的非典型分支，我们称之为“ERAD 调节”（ERAD-R），如何作为触发因素对配体介导的感应做出响应。更普遍地说，我们表明，Ypf1 介导的质膜转运蛋白的翻译后调节对于早期感应和适应营养物质耗竭是必不可少的。系统分析与机制细节的结合揭示了膜内蛋白水解在调节分泌组动力学中的广泛作用。
