2. Academic Validation
  3. 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

  • Mol Cell. 2017 Sep 21;67(6):974-989.e6. doi: 10.1016/j.molcel.2017.08.005.
Yan G Zhao 1,  Yong Chen 1,  Guangyan Miao 1,  Hongyu Zhao 1,  Wenyan Qu 1,  Dongfang Li 1,  Zheng Wang 1,  Nan Liu 1,  Lin Li 2,  She Chen 2,  Pingsheng Liu 1,  Du Feng 3,  Hong Zhang 4
Affiliations

Affiliations

  • 1 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China.
  • 2 National Institute of Biological Sciences, Beijing 102206, P.R. China.
  • 3 School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, P.R. China.
  • 4 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, P.R. China. Electronic address: [email protected].
PMID: 28890335 DOI: 10.1016/j.molcel.2017.08.005
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.

Keywords

LD; SERCA; VMP1; autophagosome; membrane contact.

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