scholarly journals A Unique Junctional Interface at Contact Sites Between the Endoplasmic Reticulum and Lipid Droplets

2021 ◽  
Vol 9 ◽  
Author(s):  
Vineet Choudhary ◽  
Roger Schneiter
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Close Contact ◽  
Lipid Storage ◽  
Metabolic Energy ◽  
Lipid Monolayer ◽  
Storage Diseases ◽  
Contact Sites ◽  
Ordered Assembly

Lipid droplets (LDs) constitute compartments dedicated to the storage of metabolic energy in the form of neutral lipids. LDs originate from the endoplasmic reticulum (ER) with which they maintain close contact throughout their life cycle. These ER–LD junctions facilitate the exchange of both proteins and lipids between these two compartments. In recent years, proteins that are important for the proper formation of LDs and localize to ER–LD junctions have been identified. This junction is unique as it is generally believed to invoke a transition from the ER bilayer membrane to a lipid monolayer that delineates LDs. Proper formation of this junction requires the ordered assembly of proteins and lipids at specialized ER subdomains. Without such a well-ordered assembly of LD biogenesis factors, neutral lipids are synthesized throughout the ER membrane, resulting in the formation of aberrant LDs. Such ectopically formed LDs impact ER and lipid homeostasis, resulting in different types of lipid storage diseases. In response to starvation, the ER–LD junction recruits factors that tether the vacuole to these junctions to facilitate LD degradation. In addition, LDs maintain close contacts with peroxisomes and mitochondria for metabolic channeling of the released fatty acids toward beta-oxidation. In this review, we discuss the function of different components that ensure proper functioning of LD contact sites, their role in lipogenesis and lipolysis, and their relation to lipid storage diseases.

scholarly journals Multiple C2 domain-containing transmembrane proteins promote lipid droplet biogenesis and growth at specialized ER subdomains

2021 ◽  
pp. mbc.E20-09-0590
Author(s):  
Amit S. Joshi ◽  
Joey V. Ragusa ◽  
William A. Prinz ◽  
Sarah Cohen
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Droplets ◽  
Transmembrane Domain ◽  
Neutral Lipids ◽  
Transmembrane Proteins ◽  
C2 Domain ◽  
General Role ◽  
C2 Domains ◽  
Contact Sites ◽  
Er Membrane

Lipid droplets (LDs) are neutral lipid-containing organelles enclosed in a single monolayer of phospholipids. LD formation begins with the accumulation of neutral lipids within the bilayer of the endoplasmic reticulum (ER) membrane. It is not known how the sites of formation of nascent LDs in the ER membrane are determined. Here we show that multiple C2 domain-containing transmembrane proteins, MCTP1 and MCTP2, are at sites of LD formation in specialized ER subdomains. We show that the transmembrane domain (TMD) of these proteins is similar to a reticulon homology domain. Like reticulons, these proteins tubulate the ER membrane and favor highly curved regions of the ER. Our data indicate that the MCTP TMDs promote LD biogenesis, increasing LD number. MCTPs co-localize with seipin, a protein involved in LD biogenesis, but form more stable microdomains in the ER. The MCTP C2 domains bind charged lipids and regulate LD size, likely by mediating ER-LD contact sites. Together, our data indicate that MCTPs form microdomains within ER tubules that regulate LD biogenesis, size, and ER-LD contacts. Interestingly, MCTP punctae colocalized with other organelles as well, suggesting that these proteins may play a more general role in linking tubular ER to organelle contact sites. [Media: see text] [Media: see text]

scholarly journals Human VPS13A is associated with multiple organelles and influences mitochondrial morphology and lipid droplet motility

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Wondwossen M Yeshaw ◽  
Marianne van der Zwaag ◽  
Francesco Pinto ◽  
Liza L Lahaye ◽  
Anita IE Faber ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Droplet ◽  
Mammalian Cells ◽  
Lipid Droplets ◽  
Neurodegenerative Disorder ◽  
Close Contact ◽  
Mitochondrial Morphology ◽  
Published Data ◽  
Membrane Contact Sites ◽  
Contact Sites

The VPS13A gene is associated with the neurodegenerative disorder Chorea Acanthocytosis. It is unknown what the consequences are of impaired function of VPS13A at the subcellular level. We demonstrate that VPS13A is a peripheral membrane protein, associated with mitochondria, the endoplasmic reticulum and lipid droplets. VPS13A is localized at sites where the endoplasmic reticulum and mitochondria are in close contact. VPS13A interacts with the ER residing protein VAP-A via its FFAT domain. Interaction with mitochondria is mediated via its C-terminal domain. In VPS13A-depleted cells, ER-mitochondria contact sites are decreased, mitochondria are fragmented and mitophagy is decreased. VPS13A also localizes to lipid droplets and affects lipid droplet motility. In VPS13A-depleted mammalian cells lipid droplet numbers are increased. Our data, together with recently published data from others, indicate that VPS13A is required for establishing membrane contact sites between various organelles to enable lipid transfer required for mitochondria and lipid droplet related processes.

scholarly journals ORP5 AND ORP8 ORCHESTRATE LIPID DROPLET BIOGENESIS AND MAINTENANCE AT ER-MITOCHONDRIA CONTACT SITES

2021 ◽  
Author(s):  
Valentin Guyard ◽  
Vera F Monteiro-Cardoso ◽  
Mohyeddine Omrane ◽  
Cecile Sauvanet ◽  
Audrey Houcine ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Phosphatidic Acid ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Nucleation And Growth ◽  
Lipid Transfer ◽  
Lipid Transfer Proteins ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact

Lipid droplets (LDs) are the primary organelles of lipid storage, buffering energy fluctuations of the cell. They store neutral lipids in their core that is surrounded by a protein-decorated phospholipid monolayer. LDs arise from the Endoplasmic Reticulum (ER). The ER-protein seipin, localizing at ER-LD junctions, controls LD nucleation and growth. However, how LD biogenesis is spatially and temporally coordinated remains elusive. Here, we show that the lipid transfer proteins ORP5 and ORP8 control LD biogenesis at Mitochondria-Associated ER Membrane (MAM) subdomains, enriched in phosphatidic acid. We found that ORP5/8 regulate seipin recruitment to these MAM-LD contacts, and their loss impairs LD biogenesis. Importantly, the integrity of ER-mitochondria contact sites is crucial for the ORP5/8 function in regulating seipin-mediated LD biogenesis. Our study uncovers an unprecedented ORP5/8 role in orchestrating LD biogenesis at MAMs and brings novel insights into the metabolic crosstalk between mitochondria, ER, and LDs at membrane contact sites.

scholarly journals In Close Proximity: The Lipid Droplet Proteome and Crosstalk With the Endoplasmic Reticulum

Contact ◽  
2018 ◽  
Vol 1 ◽  
pp. 251525641876899 ◽  
Author(s):  
Kirill Bersuker ◽  
James A. Olzmann
Keyword(s):  
Mass Spectrometry ◽  
Endoplasmic Reticulum ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
26S Proteasome ◽  
High Confidence ◽  
Close Proximity ◽  
Bona Fide ◽  
A Site ◽  
High Degree

Lipid droplets (LDs) are conserved, endoplasmic reticulum (ER)-derived organelles that act as a dynamic cellular repository for neutral lipids. Numerous studies have examined the composition of LD proteomes by using mass spectrometry to identify proteins present in biochemically isolated buoyant fractions that are enriched in LDs. Although many bona fide LD proteins were identified, high levels of non-LD proteins that contaminate buoyant fractions complicate the detection of true LD proteins. To overcome this problem, we recently developed a proximity-labeling proteomic method to define high-confidence LD proteomes. Moreover, employing this approach, we discovered that ER-associated degradation impacts the composition of LD proteomes by targeting select LD proteins for clearance by the 26S proteasome as they transit between the ER and LDs. These findings implicate the ER as a site of LD protein degradation and underscore the high degree of crosstalk between ER and LDs.

scholarly journals The yeast lipin orthologue Pah1p is important for biogenesis of lipid droplets

2011 ◽  
Vol 192 (6) ◽  
pp. 1043-1055 ◽  
Author(s):  
Oludotun Adeyo ◽  
Patrick J. Horn ◽  
SungKyung Lee ◽  
Derk D. Binns ◽  
Anita Chandrahas ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neutral Lipid ◽  
Strong Evidence ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Glucose Medium ◽  
Wild Type ◽  
Lipid Levels ◽  
Total Neutral Lipid ◽  
A Site

Lipins are phosphatidate phosphatases that generate diacylglycerol (DAG). In this study, we report that yeast lipin, Pah1p, controls the formation of cytosolic lipid droplets. Disruption of PAH1 resulted in a 63% decrease in droplet number, although total neutral lipid levels did not change. This was accompanied by an accumulation of neutral lipids in the endoplasmic reticulum (ER). The droplet biogenesis defect was not a result of alterations in neutral lipid ratios. No droplets were visible in the absence of both PAH1 and steryl acyltransferases when grown in glucose medium, even though the strain produces as much triacylglycerol as wild type. The requirement of PAH1 for normal droplet formation can be bypassed by a knockout of DGK1. Nem1p, the activator of Pah1p, localizes to a single punctum per cell on the ER that is usually next to a droplet, suggesting that it is a site of droplet assembly. Overall, this study provides strong evidence that DAG generated by Pah1p is important for droplet biogenesis.

scholarly journals The seipin complex Fld1/Ldb16 stabilizes ER–lipid droplet contact sites

2015 ◽  
Vol 211 (4) ◽  
pp. 829-844 ◽  
Author(s):  
Alexandra Grippa ◽  
Laura Buxó ◽  
Gabriel Mora ◽  
Charlotta Funaya ◽  
Fatima-Zahra Idrissi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Protein ◽  
Neutral Lipid ◽  
Diffusion Barrier ◽  
Lipid Droplets ◽  
Lipid Binding ◽  
Contact Sites ◽  
Packing Defects ◽  
Specific Proteins ◽  
Lipid Binding Proteins

Lipid droplets (LDs) are storage organelles consisting of a neutral lipid core surrounded by a phospholipid monolayer and a set of LD-specific proteins. Most LD components are synthesized in the endoplasmic reticulum (ER), an organelle that is often physically connected with LDs. How LD identity is established while maintaining biochemical and physical connections with the ER is not known. Here, we show that the yeast seipin Fld1, in complex with the ER membrane protein Ldb16, prevents equilibration of ER and LD surface components by stabilizing the contact sites between the two organelles. In the absence of the Fld1/Ldb16 complex, assembly of LDs results in phospholipid packing defects leading to aberrant distribution of lipid-binding proteins and abnormal LDs. We propose that the Fld1/Ldb16 complex facilitates the establishment of LD identity by acting as a diffusion barrier at the ER–LD contact sites.

scholarly journals Arf1/COPI machinery acts directly on lipid droplets and enables their connection to the ER for protein targeting

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Florian Wilfling ◽  
Abdou Rachid Thiam ◽  
Maria-Jesus Olarte ◽  
Jing Wang ◽  
Rainer Beck ◽  
...  
Keyword(s):  
Surface Tension ◽  
Lipid Droplets ◽  
Protein Targeting ◽  
Neutral Lipids ◽  
Vesicle Trafficking ◽  
Metabolic Energy ◽  
Key Enzymes ◽  
Specific Proteins ◽  
Oil Water

Lipid droplets (LDs) are ubiquitous organelles that store neutral lipids, such as triacylglycerol (TG), as reservoirs of metabolic energy and membrane precursors. The Arf1/COPI protein machinery, known for its role in vesicle trafficking, regulates LD morphology, targeting of specific proteins to LDs and lipolysis through unclear mechanisms. Recent evidence shows that Arf1/COPI can bud nano-LDs (∼60 nm diameter) from phospholipid-covered oil/water interfaces in vitro. We show that Arf1/COPI proteins localize to cellular LDs, are sufficient to bud nano-LDs from cellular LDs, and are required for targeting specific TG-synthesis enzymes to LD surfaces. Cells lacking Arf1/COPI function have increased amounts of phospholipids on LDs, resulting in decreased LD surface tension and impairment to form bridges to the ER. Our findings uncover a function for Arf1/COPI proteins at LDs and suggest a model in which Arf1/COPI machinery acts to control ER-LD connections for localization of key enzymes of TG storage and catabolism.

scholarly journals Endoplasmic Reticulum-Vacuole Contact Sites “Bloom” With Stress-Induced Lipid Droplets

Contact ◽  
2018 ◽  
Vol 1 ◽  
pp. 251525641875611 ◽  
Author(s):  
W. Mike Henne ◽  
Hanaa Hariri
Keyword(s):  
Endoplasmic Reticulum ◽  
Recent Work ◽  
Nutrient Availability ◽  
Lipid Droplets ◽  
Nutrient Sources ◽  
Contact Sites ◽  
Long Term Storage ◽  
Specific Proteins ◽  
Term Storage

Lipid droplets (LDs) serve as specialized cytoplasmic organelles that harbor energy-rich lipids for long-term storage and may be mobilized as nutrient sources during extended starvation. How cells coordinate LD biogenesis and utilization in response to fluctuations in nutrient availability remains poorly understood. Here, we discuss our recent work revealing how yeast spatially organize LD budding at organelle contacts formed between the endoplasmic reticulum and yeast vacuole/lysosome (sites known as nucleus-vacuole junctions [NVJs]). During times of imminent nutrient exhaustion, we observe blooms of stress-induced LDs surrounding the NVJ and find that this LD clustering is regulated by NVJ-resident protein Mdm1. We also discuss several emerging studies revealing specific proteins that demarcate a subpopulation of NVJ-associated LDs. Collectively, these studies reveal a previously unappreciated role for the spatial compartmentalization of LDs at organelle contacts and highlight an important role for interorganellar cross talk in LD dynamics under times of nutritional stress.

Intracellular communication between lipid droplets and peroxisomes: the Janus face of PEX19

2018 ◽  
Vol 399 (7) ◽  
pp. 741-749 ◽  
Author(s):  
Bianca Schrul ◽  
Wolfgang Schliebs
Keyword(s):  
Metabolic Pathways ◽  
Lipid Droplets ◽  
Environmental Changes ◽  
Neutral Lipids ◽  
Nutrient Supply ◽  
Metabolic Energy ◽  
Central Question ◽  
And Function ◽  
Metabolic Output

Abstract In order to adapt to environmental changes, such as nutrient availability, cells have to orchestrate multiple metabolic pathways, which are catalyzed in distinct specialized organelles. Lipid droplets (LDs) and peroxisomes are both endoplasmic reticulum (ER)-derived organelles that fulfill complementary functions in lipid metabolism: Upon nutrient supply, LDs store metabolic energy in the form of neutral lipids and, when energy is needed, supply fatty acids for oxidation in peroxisomes and mitochondria. How these organelles communicate with each other for a concerted metabolic output remains a central question. Here, we summarize recent insights into the biogenesis and function of LDs and peroxisomes with emphasis on the role of PEX19 in these processes.

scholarly journals Novel contact sites between lipid droplets, early endosomes, and the endoplasmic reticulum

2020 ◽  
Vol 61 (11) ◽  
pp. 1364-1364
Author(s):  
Robert G. Parton ◽  
Marta Bosch ◽  
Bernhard Steiner ◽  
Albert Pol
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Droplets ◽  
Contact Sites ◽  
Early Endosomes
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