National Institute of Biological Sciences, 102206 Beijing, China.
College of Life Sciences, Beijing Normal University, 100875 Beijing, China; National Institute of Biological Sciences, 102206 Beijing, China.
Mol Cell. 2020 Sep 17;79(6):963-977.e3. doi: 10.1016/j.molcel.2020.07.019. Epub 2020 Jul 30.
Autophagic degradation of the endoplasmic reticulum (ER-phagy) is triggered by ER stress in diverse organisms. However, molecular mechanisms governing ER stress-induced ER-phagy remain insufficiently understood. Here we report that ER stress-induced ER-phagy in the fission yeast Schizosaccharomyces pombe requires Epr1, a soluble Atg8-interacting ER-phagy receptor. Epr1 localizes to the ER through interacting with integral ER membrane proteins VAPs. Bridging an Atg8-VAP association is the main ER-phagy role of Epr1, as it can be bypassed by an artificial Atg8-VAP tether. VAPs contribute to ER-phagy not only by tethering Atg8 to the ER membrane, but also by maintaining the ER-plasma membrane contact. Epr1 is upregulated during ER stress by the unfolded protein response (UPR) regulator Ire1. Loss of Epr1 reduces survival against ER stress. Conversely, increasing Epr1 expression suppresses the ER-phagy defect and ER stress sensitivity of cells lacking Ire1. Our findings expand and deepen the molecular understanding of ER-phagy.
内质网自噬（ER-phagy）是由多种生物体中的内质网应激触发的。然而，调控内质网应激诱导的 ER 自噬的分子机制仍了解不足。在这里，我们报告称，裂殖酵母 Schizosaccharomyces pombe 中的内质网应激诱导的 ER 自噬需要 Epr1，一种可溶性 Atg8 相互作用的 ER 自噬受体。Epr1 通过与完整的内质网膜蛋白 VAPs 相互作用定位于内质网。桥接 Atg8-VAP 关联是 Epr1 的主要 ER 自噬作用，因为它可以通过人工 Atg8-VAP 系绳绕过。VAPs 不仅通过将 Atg8 锚定在内质网膜上来促进 ER 自噬，还通过维持内质网-质膜接触来促进 ER 自噬。Epr1 在未折叠蛋白反应 (UPR) 调节剂 Ire1 的作用下，在内质网应激期间上调。Epr1 的缺失会降低细胞对内质网应激的存活能力。相反，增加 Epr1 的表达可抑制缺乏 Ire1 的细胞的 ER 自噬缺陷和内质网应激敏感性。我们的发现扩展并深化了对内质网自噬的分子理解。
