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

Tábara, Luis-Carlos; Escalante, Ricardo

doi:10.1371/journal.pone.0166499

Cited by 71 publications

(106 citation statements)

References 44 publications

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“…The tethering function of E-Syt2 and 3 (namely the C2C domain) was required for the proper autophagosome biogenesis on contact sites. Interestingly, VMP1 protein was recently shown to participate in a certain number of ER-driven contact sites (Tábara & Escalante, 2016). Interestingly, VMP1 protein was recently shown to participate in a certain number of ER-driven contact sites (Tábara & Escalante, 2016).…”

Section: Discussionmentioning

confidence: 99%

ER –plasma membrane contact sites contribute to autophagosome biogenesis by regulation of local PI 3P synthesis

et al. 2017

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The double-membrane-bound autophagosome is formed by the closure of a structure called the phagophore, origin of which is still unclear. The endoplasmic reticulum (ER) is clearly implicated in autophagosome biogenesis due to the presence of the omegasome subdomain positive for DFCP1, a phosphatidyl-inositol-3-phosphate (PI3P) binding protein. Contribution of other membrane sources, like the plasma membrane (PM), is still difficult to integrate in a global picture. Here we show that ER-plasma membrane contact sites are mobilized for autophagosome biogenesis, by direct implication of the tethering extended synaptotagmins (E-Syts) proteins. Imaging data revealed that early autophagic markers are recruited to E-Syt-containing domains during autophagy and that inhibition of E-Syts expression leads to a reduction in autophagosome biogenesis. Furthermore, we demonstrate that E-Syts are essential for autophagy-associated PI3P synthesis at the cortical ER membrane via the recruitment of VMP1, the stabilizing ER partner of the PI3KC3 complex. These results highlight the contribution of ER-plasma membrane tethers to autophagosome biogenesis regulation and support the importance of membrane contact sites in autophagy.

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Section: Discussionmentioning

confidence: 99%

ER –plasma membrane contact sites contribute to autophagosome biogenesis by regulation of local PI 3P synthesis

et al. 2017

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“…To confirm that overexpression of TMEM41B does not perturb its intracellular localization, we tagged the endogenous TMEM41B locus with a C-terminal Myc epitope by CRISPR and validated the knock-in (KI) by immunoblot and genomic PCR (Fig 5B-D). Furthermore, VMP1 KO cells have also been shown to accumulate electron-dense structures, believed to be immature autophagosomes [34,35]. TMEM41B has a predicted "SNARE-associated Golgi protein" domain, which shares homology to bacterial DedA proteins [30], yeast TVP38, and mammalian TMEM41A, TMEM64, and VMP1 (IPR032816, [31]).…”

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confidence: 99%

TMEM 41B is a novel regulator of autophagy and lipid mobilization

et al. 2018

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Autophagy maintains cellular homeostasis by targeting damaged organelles, pathogens, or misfolded protein aggregates for lysosomal degradation. The autophagic process is initiated by the formation of autophagosomes, which can selectively enclose cargo via autophagy cargo receptors. A machinery of well-characterized autophagy-related proteins orchestrates the biogenesis of autophagosomes; however, the origin of the required membranes is incompletely understood. Here, we have applied sensitized pooled CRISPR screens and identify the uncharacterized transmembrane protein TMEM41B as a novel regulator of autophagy. In the absence of TMEM41B, autophagosome biogenesis is stalled, LC3 accumulates at WIPI2- and DFCP1-positive isolation membranes, and lysosomal flux of autophagy cargo receptors and intracellular bacteria is impaired. In addition to defective autophagy, TMEM41B knockout cells display significantly enlarged lipid droplets and reduced mobilization and β-oxidation of fatty acids. Immunostaining and interaction proteomics data suggest that TMEM41B localizes to the endoplasmic reticulum (ER). Taken together, we propose that TMEM41B is a novel ER-localized regulator of autophagosome biogenesis and lipid mobilization.

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“…Vacuole membrane protein 1 (VMP1) is an ER‐resident multispanning protein first identified for its role in autophagy . Recently, we proposed a more general role for VMP1 in regulating MCSs . We found that VMP1 forms ER microdomains in close contact with other organelles such as mitochondria, peroxisomes, lipid droplets, autophagosomes and endosomes.…”

Section: Introductionmentioning

confidence: 94%

“…We found that VMP1 forms ER microdomains in close contact with other organelles such as mitochondria, peroxisomes, lipid droplets, autophagosomes and endosomes. The lack of VMP1 leads to aberrant mitochondrial morphology and larger contact sites between ER and mitochondria, as well as defects in lipid droplets distribution and a blockade in autophagic flux . We hypothesized that VMP1 regulates the size and/or the function of multiple MCSs, but further studies were needed to characterize the nature and properties of these VMP1‐enriched ER subdomains.…”

Section: Introductionmentioning

confidence: 99%

Vacuole membrane protein 1 marks endoplasmic reticulum subdomains enriched in phospholipid synthesizing enzymes and is required for phosphoinositide distribution

Tábara

Vicente

Biazik

et al. 2018

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The multispanning membrane protein vacuole membrane protein 1 (VMP1) marks and regulates endoplasmic reticulum (ER)-domains associated with diverse ER-organelle membrane contact sites. A proportion of these domains associate with endosomes during their maturation and remodeling. We found that these VMP1 domains are enriched in choline/ethanolamine phosphotransferase and phosphatidylinositol synthase (PIS1), 2 ER enzymes required for the synthesis of various phospholipids. Interestingly, the lack of VMP1 impairs the formation of PIS1-enriched ER domains, suggesting a role in the distribution of phosphoinositides. In fact, depletion of VMP1 alters the distribution of PtdIns4P and proteins involved in the trafficking of PtdIns4P. Consistently, in these conditions, defects were observed in endosome trafficking and maturation as well as in Golgi morphology. We propose that VMP1 regulates the formation of ER domains enriched in lipid synthesizing enzymes. These domains might be necessary for efficient distribution of PtdIns4P and perhaps other lipid species. These findings, along with previous reports that involved VMP1 in regulating PtdIns3P during autophagy, expand the role of VMP1 in lipid trafficking and explain the pleiotropic effects observed in VMP1-deficient mammalian cells and other model systems.

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

Cited by 71 publications

References 44 publications

ER –plasma membrane contact sites contribute to autophagosome biogenesis by regulation of local PI 3P synthesis

ER –plasma membrane contact sites contribute to autophagosome biogenesis by regulation of local PI 3P synthesis

TMEM 41B is a novel regulator of autophagy and lipid mobilization

Vacuole membrane protein 1 marks endoplasmic reticulum subdomains enriched in phospholipid synthesizing enzymes and is required for phosphoinositide distribution

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