scholarly journals Interactions of Lipid Droplets with the Intracellular Transport Machinery

2021 ◽  
Vol 22 (5) ◽  
pp. 2776
Author(s):  
Selma Yilmaz Dejgaard ◽  
John F. Presley
Keyword(s):  
Membrane Trafficking ◽  
Lipid Droplets ◽  
Intracellular Transport ◽  
Neutral Lipids ◽  
Small Gtpases ◽  
Lipid Phase ◽  
Intracellular Organelles ◽  
And Function ◽  
Lipid Phase Separation ◽  
Endocytic Pathways

Historically, studies of intracellular membrane trafficking have focused on the secretory and endocytic pathways and their major organelles. However, these pathways are also directly implicated in the biogenesis and function of other important intracellular organelles, the best studied of which are peroxisomes and lipid droplets. There is a large recent body of work on these organelles, which have resulted in the introduction of new paradigms regarding the roles of membrane trafficking organelles. In this review, we discuss the roles of membrane trafficking in the life cycle of lipid droplets. This includes the complementary roles of lipid phase separation and proteins in the biogenesis of lipid droplets from endoplasmic reticulum (ER) membranes, and the attachment of mature lipid droplets to membranes by lipidic bridges and by more conventional protein tethers. We also discuss the catabolism of neutral lipids, which in part results from the interaction of lipid droplets with cytosolic molecules, but with important roles for both macroautophagy and microautophagy. Finally, we address their eventual demise, which involves interactions with the autophagocytotic machinery. We pay particular attention to the roles of small GTPases, particularly Rab18, in these processes.

Early endocytic Rabs: functional prediction to functional characterization.

2005 ◽  
Vol 72 ◽  
pp. 99-108 ◽  
Author(s):  
Jeremy C Simpson ◽  
Arwyn T Jones
Keyword(s):  
Membrane Trafficking ◽  
Functional Characterization ◽  
Specific Interaction ◽  
Small Gtpases ◽  
Endocytic Pathway ◽  
Functional Prediction ◽  
Final Destination ◽  
Similarities And Differences ◽  
And Function ◽  
Endocytic Pathways

Endocytic pathways are highly dynamic gateways for molecules to enter cells. Functionality and specificity is in part controlled by a number of small GTPases called Rabs. In defined cellular locations, Rabs mediate multiple functions in membrane trafficking via their specific interaction with organelle membranes and a host of affector and effector molecules. On endocytic pathways, Rabs have been shown to control the formation of vesicles on the plasma membrane and the downstream delivery of internalized molecules to a number of cellular locations. As numerous Rabs are located to endocytic pathways, an internalized molecule may traverse a number of Rab specific substations or subdomains en route to its final destination. Rabs 5, 21 and 22 have all been localized to the early endocytic pathway and have been shown to share a number of characteristics to merit their segregation into a single functional endocytic group. In this review, we compare experiments that describe similarities and differences in endosome morphology and function that is mediated by their expression in cells.

Intermolecular hydrogen bonding between lipids: influence on organization and function of lipids in membranes

1980 ◽  
Vol 58 (10) ◽  
pp. 755-770 ◽  
Author(s):  
Joan M. Boggs
Keyword(s):  
Hydrogen Bonding ◽  
Phase Separation ◽  
Dynamic Equilibrium ◽  
Hexagonal Phase ◽  
Intermolecular Forces ◽  
Lipid Phase ◽  
Intermolecular Hydrogen Bonding ◽  
Extracellular Stimuli ◽  
And Function ◽  
Lipid Phase Separation

Biological membranes have unique lipid compositions suggesting a specific role for many lipids. Evidence is reviewed concerning the intermolecular forces between glycero- and sphingolipids and cholesterol, the dependence of many of these interactions on the state of ionization of lipids, pH, ionic strength, and divalent cation concentration. The effect of intermolecular interactions between certain lipids on lipid clustering, interaction with cholesterol, on the conformation of proteins, and on transitions to the hexagonal phase is considered. Other forces which cause lipid phase separation or clustering are discussed. It is concluded that lipids are in dynamic equilibrium with their environment and can act as receptors for certain intra- or extracellular stimuli, which they can translate into a response by undergoing changes in fluidity, phase transitions, or phase separation.

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 Dissecting virus entry via endocytosis

2002 ◽  
Vol 83 (7) ◽  
pp. 1535-1545 ◽  
Author(s):  
Sara B. Sieczkarski ◽  
Gary R. Whittaker
Keyword(s):  
Virus Entry ◽  
Small Gtpases ◽  
Dominant Negative ◽  
Host Cells ◽  
Regulatory Proteins ◽  
Component Structure ◽  
Chemical Inhibitors ◽  
Experimental Approaches ◽  
And Function ◽  
Endocytic Pathways

Numerous virus families utilize endocytosis to infect host cells, mediating virus internalization as well as trafficking to the site of replication. Recent research has demonstrated that viruses employ the full endocytic capabilities of the cell. The endocytic pathways utilized include clathrin-mediated endocytosis, caveolae, macropinocytosis and novel non-clathrin, non-caveolae pathways. The tools to study endocytosis and, consequently, virus entry are becoming more effective and specific as the amount of information on endocytic component structure and function increases. The use of inhibitory drugs, although still quite common, often leads to non-specific disruptions in the cell. Molecular inhibitors in the form of dominant–negative proteins have surpassed the use of chemical inhibitors in terms of specificity to individual pathways. Dominant–negative molecules are derived from both structural proteins of endocytosis, such as dynamin and caveolin, and regulatory proteins, primarily small GTPases and kinases. This review focuses on the experimental approaches taken to examine virus entry and provides both classic examples and recent research on a variety of virus families.

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

2021 ◽  
Vol 118 (10) ◽  
pp. e2017205118
Author(s):  
Valeria Zoni ◽  
Rasha Khaddaj ◽  
Ivan Lukmantara ◽  
Wataru Shinoda ◽  
Hongyuan Yang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Oligomeric Structure ◽  
Hydrophobic Residues ◽  
Intracellular Organelles ◽  
Transmembrane Regions ◽  
Dynamics Simulations ◽  
Precise Role

Lipid droplets (LDs) 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 catalyze 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, as well as its precursor diacylglycerol, inside its unconventional ring-like oligomeric structure and that both its luminal and transmembrane regions contribute to this process. This mechanism is abolished upon mutations of polar residues involved in protein–TG interactions into hydrophobic residues. Our results suggest that seipin remodels the membrane of specific ER sites to prime them for LD biogenesis.

scholarly journals Rab GTPases: Switching to Human Diseases

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 909 ◽  
Author(s):  
Noemi Antonella Guadagno ◽  
Cinzia Progida
Keyword(s):  
Membrane Trafficking ◽  
Intracellular Transport ◽  
Small Gtpases ◽  
Regulatory Proteins ◽  
Human Diseases ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Intracellular Membrane ◽  
And Migration ◽  
And Control

Rab proteins compose the largest family of small GTPases and control the different steps of intracellular membrane traffic. More recently, they have been shown to also regulate cell signaling, division, survival, and migration. The regulation of these processes generally occurs through recruitment of effectors and regulatory proteins, which control the association of Rab proteins to membranes and their activation state. Alterations in Rab proteins and their effectors are associated with multiple human diseases, including neurodegeneration, cancer, and infections. This review provides an overview of how the dysregulation of Rab-mediated functions and membrane trafficking contributes to these disorders. Understanding the altered dynamics of Rabs and intracellular transport defects might thus shed new light on potential therapeutic strategies.

scholarly journals Lipid Droplet-Associated Factors, PNPLA3, TM6SF2, and HSD17B Proteins in Hepatopancreatobiliary Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4391
Author(s):  
Yoshiaki Sunami ◽  
Artur Rebelo ◽  
Jörg Kleeff
Keyword(s):  
Liver Cancer ◽  
Lipid Droplet ◽  
Associated Factors ◽  
Lipid Droplets ◽  
Cancer Metabolism ◽  
Neutral Lipids ◽  
Cancer Type ◽  
Hepatic Diseases ◽  
Cell Type Specific ◽  
Intracellular Organelles

Pancreatic and liver cancer are leading causes of cancer deaths, and by 2030, they are projected to become the second and the third deadliest cancer respectively. Cancer metabolism, especially lipid metabolism, plays an important role in progression and metastasis of many types of cancer, including pancreatic and liver cancer. Lipid droplets are intracellular organelles that store neutral lipids, but also act as molecular messengers, and signaling factors. It is becoming increasingly evident that alterations in the regulation of lipid droplets and their associated factors influence the risk of developing not only metabolic disease but also fibrosis and cancer. In the current review article, we summarized recent findings concerning the roles of lipid droplet-associated factors, patatin-like phospholipase domain-containing 3, Transmembrane 6 superfamily member 2, and 17β-hydroxysteroid dehydrogenase 11 and 13 as well as genetic variants in pancreatic and hepatic diseases. A better understanding of cancer type- and cell type-specific roles of lipid droplet-associated factors is important for establishing new therapeutic options in the future.

TBC Proteins: Miraculous Regulators of Rabs GTPase Molecular Switches

2021 ◽  
Author(s):  
Jun Yan ◽  
Yingcheng Zheng ◽  
Song Han ◽  
Jun Yin ◽  
Yinping Li ◽  
...  
Keyword(s):  
Amino Acids ◽  
Intracellular Transport ◽  
Molecular Switches ◽  
Small Gtpases ◽  
Structure And Function ◽  
Rab Gtpase ◽  
Cellular Functions ◽  
Eukaryotic Proteins ◽  
And Function ◽  
Hydrolysis Of

TBC proteins are classified as a group because they contain a common conserved structure TBC domain. TBC domain consists of approximately 200 amino acids and presents in many eukaryotic proteins. It is reported that TBC proteins have been shown to function as a GAP for Rab GTPase. TBC proteins catalyze the hydrolysis of GTP and promote the conversion of Rab-GTP to Rab-GDP, thus participating in the specific intracellular transport. Many TBC proteins play important roles in cellular functions in mammals, and their deletions or mutations are closely related to many diseases. It is important to systematically sort out these findings and functions of the TBC family and illuminate the significance of TBC proteins in different physiological conditions. Here we reviewed the structure and function of TBC proteins, especially the function related to to Rab small GTPases.

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