The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates SERCA Activity to Control ER-Isolation Membrane Contacts for Autophagosome Formation

Yan G. Zhao, Yong Chen, Guangyan Miao, Hongyu Zhao, Wenyan Qu, Dongfang Li, Zheng Wang, Nan Liu, Lin Li, She Chen, Pingsheng Liu, Du Feng, Hong Zhang

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

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 ER-IM 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 (sarco[endo]plasmic reticulum calcium ATPase) 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. Zhao et al. demonstrate that the ER-localized metazoan-specific autophagy protein VMP1 controls ER contacts with IMs and other organelles. VMP1 controls contact maintenance by modulating SERCA activity. VMP1 interacts with SERCA and prevents formation of the SERCA/PLN/SLN inhibitory complex.

Original languageEnglish (US)
Pages (from-to)974-989.e6
JournalMolecular Cell
Volume67
Issue number6
DOIs
StatePublished - Sep 21 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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