Vps13 is required for the packaging of the ER into autophagosomes during ER-phagy
Vps13 is required for the packaging of the ER into autophagosomes during ER-phagy
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DOI：
10.1073/pnas.2008923117
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发表时间：
2020-08-04
影响因子：
11.1
通讯作者：
Ferro-Novick, Susan
中科院分区：
文献类型：
--
作者：
Chen, Shuliang;Mari, Muriel;Ferro-Novick, Susan
内质网 (ER) 巨自噬（以下称为 ER-自噬）利用自噬受体选择性降解 ER 结构域，以响应饥饿或易于聚集的蛋白质的积累。自噬受体通过与泛素样酵母蛋白 Atg8（哺乳动物中的 LC3）结合，将 ER 包装到自噬体中，而 Atg8 是自噬体形成所必需的。在芽殖酵母中，皮质和细胞质内质网自噬需要自噬受体 Atg40。虽然已经鉴定出不同的内质网自噬受体，但人们对内质网自噬机制的其他组成部分知之甚少。为了鉴定这些成分，我们筛选了活酵母缺失突变体的全基因组文库，以发现用雷帕霉素（一种模拟饥饿的药物）治疗后皮质 ER 降解的缺陷。我们鉴定出的突变体是 vps131。酵母有一种编码磷脂转运蛋白 VPS13 的基因，而人类有四种液泡蛋白分选 (VPS) 蛋白 13 亚型。所有四种人类亚型的突变都与不同的神经系统疾病有关，包括帕金森病。我们的研究结果表明，Vps13 在 Atg40 参与自噬机制后发挥作用。 Vps13 位于 ER 和多种细胞器（包括晚期内体）之间的接触位点。在缺乏 Vps13 的情况下，皮质 ER 标记物 Rtn1 在晚期内涵体处积累，并且观察到 ER 包装成自噬体的情况急剧减少。总之，这些研究表明 Vps13 在将 ER 隔离到晚期内涵体的自噬体中发挥作用。这些观察结果可能对理解帕金森病和其他神经系统疾病具有重要意义。
Endoplasmic reticulum (ER) macroautophagy (hereafter called ER-phagy) uses autophagy receptors to selectively degrade ER domains in response to starvation or the accumulation of aggregation-prone proteins. Autophagy receptors package the ER into autophagosomes by binding to the ubiquitin-like yeast protein Atg8 (LC3 in mammals), which is needed for autophago-some formation. In budding yeast, cortical and cytoplasmic ER-phagy requires the autophagy receptor Atg40. While different ER autophagy receptors have been identified, little is known about other components of the ER-phagy machinery. In an effort to identify these components, we screened the genome-wide library of viable yeast deletion mutants for defects in the degradation of cortical ER following treatment with rapamycin, a drug that mimics starvation. Among the mutants we identified was vps131. While yeast has one gene that encodes the phospholipid transporter VPS13, humans have four vacuolar protein-sorting (VPS) protein 13 isoforms. Mutations in all four human isoforms have been linked to different neurological disorders, including Parkinson's disease. Our findings have shown that Vps13 acts after Atg40 engages the autophagy machinery. Vps13 resides at contact sites between the ER and several organelles, including late endosomes. In the absence of Vps13, the cortical ER marker Rtn1 accumulated at late endosomes, and a dramatic decrease in ER packaging into autophagosomes was observed. Together, these studies suggest a role for Vps13 in the sequestration of the ER into autophagosomes at late endosomes. These observations may have important implications for understanding Parkinson's and other neurological diseases.