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8.A.97.  The EPG-3/VMP1 (EPG/VPM) Family

During autophagosome formation in mammalian cells, isolated membranes (IM) (autophagosome precursors) dynamically contact the ER. Zhao et al. 2017 demonstrated that the ER-localized metazoan-specific autophagy protein EPG-3/VMP1 controls ER-IM contacts. Loss of VMP1 causes stable association of the IM with the ER, thus blocking autophagosome formation. Interaction of WIPI2 with the ULK1/FIP200 complex and PI3P 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 elevated by the SERCA inhibitor thapsigargin. Calmodulin acts as a sensor/effector to modulate the ER contacts mediated by VMP1/SERCA. Zhao et al. 2017 thus reveals that VMP1 modulates SERCA activity to control ER contacts.

Human VMP1 is a stress-induced protein that, when overexpressed, promotes formation of intracellular vacuoles followed by cell death. It may be involved in the cytoplasmic vacuolization of acinar cells during the early stage of acute pancreatitis, and it plays a role in the initial stages of the autophagic process through its interaction with BECN1. It may also be involved in cell-cell adhesion and plays an essential role in formation of cell junctions (Sauermann et al. 2008). The ectopic P-granules protein, EPG-3, of C. elegans is also thought to act in autophagasome and omegasome formation (Tian et al. 2010). These proteins appear to contain a DedA domain.

References associated with 8.A.97 family:

Kirk, L.M., S.W. Ti, H.I. Bishop, M. Orozco-Llamas, M. Pham, J.S. Trimmer, and E. Díaz. (2016). Distribution of the SynDIG4/proline-rich transmembrane protein 1 in rat brain. J Comp Neurol 524: 2266-2280. 26660156
Manil-Ségalen, M., C. Lefebvre, C. Jenzer, M. Trichet, C. Boulogne, B. Satiat-Jeunemaitre, and R. Legouis. (2014). The C. elegans LC3 acts downstream of GABARAP to degrade autophagosomes by interacting with the HOPS subunit VPS39. Dev Cell 28: 43-55. 24374177
Sauermann, M., O. Sahin, H. Sültmann, F. Hahne, S. Blaszkiewicz, M. Majety, K. Zatloukal, L. Füzesi, A. Poustka, S. Wiemann, and D. Arlt. (2008). Reduced expression of vacuole membrane protein 1 affects the invasion capacity of tumor cells. Oncogene 27: 1320-1326. 17724469
Tian, Y., Z. Li, W. Hu, H. Ren, E. Tian, Y. Zhao, Q. Lu, X. Huang, P. Yang, X. Li, X. Wang, A.L. Kovács, L. Yu, and H. Zhang. (2010). C. elegans screen identifies autophagy genes specific to multicellular organisms. Cell 141: 1042-1055. 20550938
Zhao, Y.G., Y. Chen, G. Miao, H. Zhao, W. Qu, D. Li, Z. Wang, N. Liu, L. Li, S. Chen, P. Liu, D. Feng, and H. Zhang. (2017). The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates SERCA Activity to Control ER-Isolation Membrane Contacts for Autophagosome Formation. Mol. Cell 67: 974-989.e6. 28890335