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The ER-localized transmembrane protein EPG-3/VMP1 regulates SERCA activity to control ER-isolation membrane contacts for autophagosome formation

Author: Update time: 2017-09-26

The ER is intimately connected with other organelles at membrane contact sites (MCSs), including the PM, mitochondria, Golgi and endosomes. The ER contacts mediate Ca2+ exchange and lipid transfer, and also regulate various aspects of organelle dynamics, such as fission, maturation and positioning. Autophagy involves the engulfment of a portion of cytosol in the double-membrane autophagosome and its subsequent delivery to lysosomes for degradation. Autophagosome formation starts with the initiation and nucleation of a crescent-shaped isolation membrane (IM), which further expands and seals. The ER plays a pivotal role in autophagosome formation. Little is known about how the formation, maintenance and disassembly of ER-IM contacts is modulated during autophagosome formation.
Recently, a study led by Prof. Hong Zhang from the institute of Biophysics (IBP) of the Chinese Academy of Sciences (CAS) was reported as a cover story in Molecular Cell on Sep. 21st, 2017, entitled " The ER-localized transmembrane protein EPG-3/VMP1 regulates SERCA activity to control ER-isolation membrane contacts for autophagosome formation".
Metazoan-specific ER-localized transmembrane protein EPG-3/VMP1 (C. elegans homolog/mammalian homolog), previously identified by our genetic screen in C. elegans, regulates the ER contacts with IMs. In VMP1 KO cells, IMs remain stably associated with the ER and fail to form autophagosomes. 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. We further showed that VMP1 depletion also enhances ER contacts with LDs and other membranes. Calmodulin (CaM) acts as a sensor/effector to modulate the ER contacts controlled by VMP1/SERCA. Our study provides mechanistic insights into establishment and disassociation of ER-IM contacts in autophagosome formation and also uncovers VMP1 as a key factor in regulating ER contacts.
This study was supported by the grants from the National Natural Science Foundation of China, the National Basic Research Program of China, and in part by an International Early Career Scientist Grant from the Howard Hughes Medical Institute.

Figure showing that the ER contacts with other organelles dramatically increased in VMP1-depletion cells, just like water droplets sticking to a spider's web after rain as shown in the cover.(Image by IBP)



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