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

• Published in: Molecular cell Vol. 67; no. 6; pp. 974 - 989.e6
• Main Authors: Zhao, Yan G., Chen, Yong, Miao, Guangyan, Zhao, Hongyu, Qu, Wenyan, Li, Dongfang, Wang, Zheng, Liu, Nan, Li, Lin, Chen, She, Liu, Pingsheng, Feng, Du, Zhang, Hong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.09.2017
• Subjects: Animals; Animals, Genetically Modified; autophagosome; Autophagosomes - enzymology; autophagy; Autophagy-Related Protein-1 Homolog - genetics; Autophagy-Related Protein-1 Homolog - metabolism; Ca2-transporting ATPase; Caenorhabditis elegans - enzymology; Caenorhabditis elegans - genetics; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Calcium-Binding Proteins - metabolism; calmodulin; Cercopithecus aethiops; COS Cells; CRISPR-Cas Systems; droplets; Endoplasmic Reticulum - enzymology; endosomes; Genotype; HEK293 Cells; HeLa Cells; Humans; Intracellular Membranes - enzymology; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Lipid Droplets - metabolism; lipids; mammals; membrane contact; Membrane Proteins - genetics; Membrane Proteins - metabolism; mitochondria; Muscle Proteins - metabolism; Phenotype; Phosphatidylinositol Phosphates - metabolism; Proteolipids - metabolism; reticulum; RNA Interference; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; SERCA; Transfection; transmembrane proteins; VMP1; VMP1; LD; membrane contact; SERCA; autophagosome
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2017.08.005

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. [Display omitted] •The ER-localized autophagy protein VMP1 modulates ER contact maintenance/disassembly•WIPI2 interacts with the ULK1/FIP200 complex and PI(3)P for ER-IM contact formation•VMP1 controls membrane contact disassembly by promoting SERCA activity•VMP1 prevents formation of the SERCA/PLN/SLN inhibitory complex 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.