VMP1 Establishes ER-Microdomains that Regulate Membrane Contact Sites and Autophagy.

Luis-Carlos Tábara,Ricardo Escalante,Ludger Johannes

doi:10.1371/journal.pone.0166499

Luis-Carlos Tábara, Ricardo Escalante + Show 1 more

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https://doi.org/10.1371/journal.pone.0166499

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Abstract

The endoplasmic reticulum (ER) regulates organelle dynamics through the formation of membrane contact sites (MCS). Here we describe that VMP1, a multispanning ER-resident protein involved in autophagy, is enriched in ER micro-domains that are in close proximity to diverse organelles in HeLa and Cos-7 cells. These VMP1 puncta are highly dynamic, moving in concert with lipid droplets, mitochondria and endosomes. Some of these micro-domains are associated with ER sliding events and also with fission events of mitochondria and endosomes. VMP1-depleted cells display increased ER-mitochondria MCS and altered mitochondria morphology demonstrating a role in the regulation of MCS. Additional defects in ER structure and lipid droplets size and distribution are consistent with a more general function of VMP1 in membrane remodeling and organelle function. We hypothesize that in autophagy VMP1 is required for the correct morphogenesis of the omegasome by regulating MCS at the site of autophagosome formation.

Highlights

The endoplasmic reticulum (ER) is in close proximity with most organelles, establishing membrane contact sites (MCS) that facilitate signaling events and trafficking of lipids and ions [1,2,3]
Using time-lapse confocal microscopy of living cells we found that VMP1 puncta are highly dynamic and frequently associated with ER movements known as sliding events [28,29,30]
Our results show that VMP1 is a surprisingly ubiquitous protein associated with a wide range of events in mammalian cells as it forms micro-domains associated with ER remodeling, ERorganelle contacts and organelle fissions

Summary

Introduction

The endoplasmic reticulum (ER) is in close proximity with most organelles, establishing membrane contact sites (MCS) that facilitate signaling events and trafficking of lipids and ions [1,2,3]. The ER forms a specialized structure, the omegasome that cradles the phagophore ( known as isolation membrane) as it elongates to form a mature double membrane autophagosome. The membrane source that elongates the phagophore may come from the ER itself and from vesicles originating from ERGIC [8], Golgi and recycling endosomes [9, 10], some of them containing Atg and lipidated LC3. Autophagosome formation requires the close proximity of other organelles or ER regions such as lipid droplets (LDs) [12, 13], late endosomes [14] and ER-exit sites

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