The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates SERCA Activity to Control ER-Isolation Membrane Contacts for Autophagosome Formation
The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates SERCA Activity to Control ER-Isolation Membrane Contacts for Autophagosome Formation
复制标题
内质网定位跨膜蛋白 EPG-3/VMP1 调节 SERCA 活性以控制自噬体形成的内质网隔离膜接触
DOI：
10.1016/j.molcel.2017.08.005
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发表时间：
2017-09-21
期刊：
影响因子：
16
通讯作者：
Zhang, Hong
中科院分区：
文献类型：
--
作者：
Zhao, Yan G.;Chen, Yong;Zhang, Hong
在哺乳动物细胞中自噬体形成期间，隔离膜（IM;自噬体前体）动态地接触ER。在这里，我们证明了ER定位的后生动物特异性自噬蛋白EPG-3/VMP 1控制ERIM接触。VMP 1的缺失导致IM与ER的稳定结合，从而阻断自噬体的形成。WIPI 2与ULK 1/FIP 200复合物和PI（3）P的相互作用有助于ER-IM接触的形成，并且这些相互作用通过VMP 1耗尽而增强。VMP 1通过促进SERCA（肌内]浆网钙ATP酶）活性来控制接触形成。VMP 1与SERCA相互作用并阻止SERCA/PLN/SLN抑制复合物的形成。VMP 1还调节ER与脂滴、线粒体和内体的接触。这些ER接触被SERCA抑制剂毒胡萝卜素大大提高。钙调素作为一个传感器/效应器来调节由VMP 1/SERCA介导的ER接触。我们的研究为ER-IM接触的建立和分离提供了机制性的见解，并揭示了VMP 1调节SERCA活性以控制ER接触。
q During autophagosome formation in mammalian cells, isolation membranes (IMs; autophagosome precursors) dynamically contact the ER. Here, we demonstrated that the ER-localized metazoan-specific autophagy protein EPG-3/VMP1 controls ERIM contacts. Loss of VMP1 causes stable association of IMs with the ER, thus blocking autophagosome formation. Interaction of WIPI2 with the ULK1/FIP200 complex and PI(3) P contributes to the formation of ER-IM contacts, and these interactions are enhanced by VMP1 depletion. VMP1 controls contact formation by promoting SERCA (sarcoendo] plasmic reticulum calciumATPase) activity. VMP1 interacts with SERCA and prevents formation of the SERCA/PLN/SLN inhibitory complex. VMP1 also modulates ER contacts with lipid droplets, mitochondria, and endosomes. These ER contacts are greatly elevated by the SERCA inhibitor thapsigargin. Calmodulin acts as a sensor/effector to modulate the ER contacts mediated by VMP1/SERCA. Our study provides mechanistic insights into the establishment and disassociation of ER-IM contacts and reveals that VMP1 modulates SERCA activity to control ER contacts.