Instituto de Investigaciones Biomédicas Alberto Sols, C.S.I.C./U.A.M., Madrid, Spain.
Department of Physiology and Biophysics, School of Medicine, University of Washington, Seattle, Washington.
Traffic. 2018 Aug;19(8):624-638. doi: 10.1111/tra.12581. Epub 2018 Jun 10.
The multispanning membrane protein vacuole membrane protein 1 (VMP1) marks and regulates endoplasmic reticulum (ER)-domains associated with diverse ER-organelle membrane contact sites. A proportion of these domains associate with endosomes during their maturation and remodeling. We found that these VMP1 domains are enriched in choline/ethanolamine phosphotransferase and phosphatidylinositol synthase (PIS1), 2 ER enzymes required for the synthesis of various phospholipids. Interestingly, the lack of VMP1 impairs the formation of PIS1-enriched ER domains, suggesting a role in the distribution of phosphoinositides. In fact, depletion of VMP1 alters the distribution of PtdIns4P and proteins involved in the trafficking of PtdIns4P. Consistently, in these conditions, defects were observed in endosome trafficking and maturation as well as in Golgi morphology. We propose that VMP1 regulates the formation of ER domains enriched in lipid synthesizing enzymes. These domains might be necessary for efficient distribution of PtdIns4P and perhaps other lipid species. These findings, along with previous reports that involved VMP1 in regulating PtdIns3P during autophagy, expand the role of VMP1 in lipid trafficking and explain the pleiotropic effects observed in VMP1-deficient mammalian cells and other model systems.
多跨膜蛋白液泡膜蛋白 1（VMP1）标记和调节与各种内质网-细胞器膜接触位点相关的内质网（ER）结构域。这些结构域中有一部分在成熟和重塑过程中与内体相关联。我们发现，这些 VMP1 结构域富含胆碱/乙醇胺磷酸转移酶和磷脂酰肌醇合酶（PIS1），这两种 ER 酶是合成各种磷脂所必需的。有趣的是，缺乏 VMP1 会损害富含 PIS1 的 ER 结构域的形成，这表明 VMP1 在磷酸肌醇的分布中起作用。事实上，VMP1 的耗竭会改变 PtdIns4P 的分布以及参与 PtdIns4P 运输的蛋白质。一致地，在这些条件下，观察到内体运输和成熟以及高尔基体形态的缺陷。我们提出 VMP1 调节富含脂质合成酶的 ER 结构域的形成。这些结构域可能对于 PtdIns4P 和其他脂质物种的有效分布是必需的。这些发现，以及之前的报道表明 VMP1 在自噬过程中调节 PtdIns3P，扩展了 VMP1 在脂质运输中的作用，并解释了在 VMP1 缺陷型哺乳动物细胞和其他模型系统中观察到的多效性效应。
