scholarly journals Syntaxin 17 promotes lipid droplet formation by regulating the distribution of acyl-CoA synthetase 3

2017 ◽  
Author(s):  
Hana Kimura ◽  
Kohei Arasaki ◽  
Yuki Ohsaki ◽  
Toyoshi Fujimoto ◽  
Mitsuo Tagaya
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Raft ◽  
Lipid Droplets ◽  
Time Course ◽  
Neutral Lipids ◽  
Maturation Stage ◽  
Phospholipid Monolayer ◽  
Lipid Droplet Formation ◽  
Initial Stage ◽  
Key Enzyme

AbstractLipid droplets (LDs) are ubiquitous organelles that contain neutral lipids and are surrounded by a phospholipid monolayer. How proteins specifically localize to the phospholipid monolayer of the LD surface has been a matter of extensive investigations. Here we show that syntaxin 17 participates in LD biogenesis by regulating the distribution of acyl-CoA synthetase 3 (ACSL3), a key enzyme for LD biogenesis that redistributes from the endoplasmic reticulum to LDs during LD formation. Time course experiments revealed that syntaxin 17 binds to ACSL3 in the initial stage of LD formation, and that ACSL3 is released as a consequence of competitive binding of SNAP23 to syntaxin 17 in the maturation stage. We propose a model in which ACSL3 redistributes from the endoplasmic reticulum to LDs through association with syntaxin 17 and SNAP23-mediated dissociation from syntaxin 17. We also provide evidence that lipid raft-like structures are important for LD formation and SNAREs-ACSL3 interactions.

scholarly journals Mechanism of lipid droplet formation by the yeast Sei1/Ldb16 Seipin complex

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yoel A. Klug ◽  
Justin C. Deme ◽  
Robin A. Corey ◽  
Mike F. Renne ◽  
Phillip J. Stansfeld ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Molecular Dynamics Simulation ◽  
Membrane Protein ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Dynamics Simulation ◽  
Transmembrane Segments ◽  
Lipid Droplet Formation

AbstractLipid droplets (LDs) are universal lipid storage organelles with a core of neutral lipids, such as triacylglycerols, surrounded by a phospholipid monolayer. This unique architecture is generated during LD biogenesis at endoplasmic reticulum (ER) sites marked by Seipin, a conserved membrane protein mutated in lipodystrophy. Here structural, biochemical and molecular dynamics simulation approaches reveal the mechanism of LD formation by the yeast Seipin Sei1 and its membrane partner Ldb16. We show that Sei1 luminal domain assembles a homooligomeric ring, which, in contrast to other Seipins, is unable to concentrate triacylglycerol. Instead, Sei1 positions Ldb16, which concentrates triacylglycerol within the Sei1 ring through critical hydroxyl residues. Triacylglycerol recruitment to the complex is further promoted by Sei1 transmembrane segments, which also control Ldb16 stability. Thus, we propose that LD assembly by the Sei1/Ldb16 complex, and likely other Seipins, requires sequential triacylglycerol-concentrating steps via distinct elements in the ER membrane and lumen.

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 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 Motility Plays an Important Role in the Lifetime of Mammalian Lipid Droplets

2021 ◽  
Vol 22 (8) ◽  
pp. 3802
Author(s):  
Yi Jin ◽  
Zhuqing Ren ◽  
Yanjie Tan ◽  
Pengxiang Zhao ◽  
Jian Wu
Keyword(s):  
Signal Transduction ◽  
Endoplasmic Reticulum ◽  
Lipid Droplet ◽  
Molecular Basis ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Future Research ◽  
Biological Processes ◽  
Cellular Processes ◽  
Resistance To Stress

The lipid droplet is a kind of organelle that stores neutral lipids in cells. Recent studies have found that in addition to energy storage, lipid droplets also play an important role in biological processes such as resistance to stress, immunity, cell proliferation, apoptosis, and signal transduction. Lipid droplets are formed at the endoplasmic reticulum, and mature lipid droplets participate in various cellular processes. Lipid droplets are decomposed by lipase and lysosomes. In the life of a lipid droplet, the most important thing is to interact with other organelles, including the endoplasmic reticulum, mitochondria, peroxisomes, and autophagic lysosomes. The interaction between lipid droplets and other organelles requires them to be close to each other, which inevitably involves the motility of lipid droplets. In fact, through many microscopic observation techniques, researchers have discovered that lipid droplets are highly dynamic organelles that move quickly. This paper reviews the process of lipid droplet motility, focusing on explaining the molecular basis of lipid droplet motility, the factors that regulate lipid droplet motility, and the influence of motility on the formation and decomposition of lipid droplets. In addition, this paper also proposes several unresolved problems for lipid droplet motility. Finally, this paper makes predictions about the future research of lipid droplet motility.

scholarly journals Seipin forms a flexible cage at lipid droplet formation sites

2021 ◽  
Author(s):  
Henning Arlt ◽  
Xuewu Sui ◽  
Brayden Folger ◽  
Carson Adams ◽  
Xiao Chen ◽  
...  
Keyword(s):  
Phase Separation ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Transmembrane Segments ◽  
Cryo Electron Microscopy ◽  
Open Conformation ◽  
Lipid Droplet Formation ◽  
Switch Regions ◽  
Modeling Data ◽  
Stable Ring

Lipid droplets (LDs) form in the endoplasmic reticulum by phase separation of neutral lipids. This process is facilitated by the seipin protein complex, which consists of a ring of seipin monomers, with yet unclear function. Here, we report a structure of yeast seipin based on cryo-electron microscopy and structural modeling data. Seipin forms a decameric, cage-like structure with the lumenal domains forming a stable ring at the cage floor and transmembrane segments forming the cage sides and top. The transmembrane segments interact with adjacent monomers in two distinct, alternating conformations. These conformations result from changes in switch regions, located between the lumenal domains and the transmembrane segments, that are required for seipin function. Our data suggest a model for LD formation in which a closed seipin cage enables TG phase separation and subsequently switches to an open conformation to allow LD growth and budding.

scholarly journals Seipin accumulates and traps diacylglycerols and triglycerides in its ring-like structure

2020 ◽  
Author(s):  
Valeria Zoni ◽  
Wataru Shinoda ◽  
Stefano Vanni
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Molecular Dynamics Simulations ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Health Concern ◽  
Intracellular Organelles ◽  
Dynamics Simulations ◽  
Precise Role

AbstractLipid droplets (LD) are intracellular organelles responsible for lipid storage, and they emerge from the endoplasmic reticulum (ER) upon the accumulation of neutral lipids, mostly triglycerides (TG), between the two leaflets of the ER membrane. LD biogenesis takes place at ER sites that are marked by the protein seipin, which subsequently recruits additional proteins to catalyse LD formation. Deletion of seipin, however, does not abolish LD biogenesis, and its precise role in controlling LD assembly remains unclear. Here we use molecular dynamics simulations to investigate the molecular mechanism through which seipin promotes LD formation. We find that seipin clusters TG molecules inside its unconventional ring-like oligomeric structure, and that both its luminal and transmembrane regions contribute to this process. Diacylglycerol, the precursor of TG, also clusters inside the seipin oligomer, in turn promoting TG accumulation. Our results suggest that seipin remodels the membrane of specific ER sites to prime them for LD biogenesis.Significance statementMetabolic disorders related to aberrant fat accumulation, including lipodystrophy and obesity, are a particularly serious health concern. In cells, fat accumulates in intracellular organelles, named lipid droplets (LDs). LDs form in the endoplasmic reticulum, where triglycerides, the most abundant form of fat, is produced. The Bernardinelli-Seip congenital lipodystrophy type 2 protein, seipin, has been identified as a key regulator of LD formation, but its mechanism of action remains debated and its molecular details mostly obscure. Here, we use molecular dynamics simulations to investigate the mechanism of seipin. We find that seipin can cluster and trap both triglycerides and its precursor, diacylglycerol. Our results suggest that seipin organizes the lipid composition of specific ER sites to prime them for LD biogenesis.

scholarly journals Pre-existing bilayer stresses modulate triglyceride accumulation in the ER versus lipid droplets

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Valeria Zoni ◽  
Rasha Khaddaj ◽  
Pablo Campomanes ◽  
Abdou Rachid Thiam ◽  
Roger Schneiter ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Fluorescence Microscopy ◽  
Conceptual Understanding ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Yeast Genetics ◽  
Triglyceride Accumulation ◽  
Acyl Chains ◽  
And Function ◽  
Er Homeostasis

Cells store energy in the form of neutral lipids (NLs) packaged into micrometer-sized organelles named lipid droplets (LDs). These structures emerge from the endoplasmic reticulum (ER) at sites marked by the protein seipin, but the mechanisms regulating their biogenesis remain poorly understood. Using a combination of molecular simulations, yeast genetics, and fluorescence microscopy, we show that interactions between lipids’ acyl-chains modulate the propensity of NLs to be stored in LDs, in turn preventing or promoting their accumulation in the ER membrane. Our data suggest that diacylglycerol, which is enriched at sites of LD formation, promotes the packaging of NLs into LDs, together with ER-abundant lipids, such as phosphatidylethanolamine. On the opposite end, short and saturated acyl-chains antagonize fat storage in LDs and promote accumulation of NLs in the ER. Our results provide a new conceptual understanding of LD biogenesis in the context of ER homeostasis and function.

scholarly journals Lipid droplets form a network interconnected by the endoplasmic reticulum through which they equilibrate their proteins

2021 ◽  
Author(s):  
Stéphanie Cottier ◽  
Roger Schneiter
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Yeast Cells ◽  
Zygote Formation ◽  
Protein Transfer ◽  
Mating Partner ◽  
Functional Connection ◽  
Yeast Mating ◽  
Er Membrane

Lipid droplets (LDs) are globular intracellular structures dedicated to the storage of neutral lipids. They are closely associated with the endoplasmic reticulum (ER) and are delineated by a monolayer of phospholipids that is continuous with the cytoplasmic leaflet of the ER membrane. LDs contain a specific set of proteins, but how these proteins are targeted to the LD surface is not fully understood. Here we devised a yeast mating-based microscopic readout to monitor the transfer of LD proteins upon zygote formation. The results of this analysis indicate that ER fusion between mating partners is required for transfer of LD proteins and that this transfer is continuous, bidirectional and affects most LDs simultaneously. These observations suggest that LDs do not fuse upon mating of yeast cells, but that they form a network that is interconnected through the ER membrane. Consistent with this, ER-localized LD proteins rapidly move onto LDs of a mating partner and this protein transfer is affected by seipin, a protein important for proper LD biogenesis and the functional connection of LDs with the ER membrane.

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