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.
Pubmed ID: 28890335 RIS Download
Mesh terms: Animals | Animals, Genetically Modified | Autophagosomes | Autophagy-Related Protein-1 Homolog | COS Cells | CRISPR-Cas Systems | Caenorhabditis elegans | Caenorhabditis elegans Proteins | Calcium-Binding Proteins | Cercopithecus aethiops | Endoplasmic Reticulum | Genotype | HEK293 Cells | HeLa Cells | Humans | Intracellular Membranes | Intracellular Signaling Peptides and Proteins | Lipid Droplets | Membrane Proteins | Muscle Proteins | Phenotype | Phosphatidylinositol Phosphates | Proteolipids | RNA Interference | Sarcoplasmic Reticulum Calcium-Transporting ATPases | Transfection
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