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
  • 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.