The CYTOLD and ERTOLD pathways for lipid droplet–protein targeting

Olarte, Maria-Jesus; Swanson, Jessica M. J.; Walther, Tobias C.; Farese, Robert V.

doi:10.1016/j.tibs.2021.08.007

Cited by 59 publications

(59 citation statements)

References 114 publications

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“…These lens-like structures accumulate lipids and bud into the cytoplasm to produce nascent cytoplasmic LDs (cLD). cLDs continue to mature or 'ripen' through three mechanisms: 1) seipin-dependent membrane bridges that connect the cLD monolayer with the cytosolic leaflet of the ER, allowing the diffusion of proteins and lipids to the LD (Wang et al, 2016;Salo et al, 2019), 2) targeting of GPAT4, AGPAT4, and DGAT2 to the LD to facilitate in situ TAG synthesis (Wilfling et al, 2013;McFie et al, 2018;Olarte et al, 2022) and 3) coalescence of lipid droplets (Thiam et al, 2013).…”

Section: Mechanisms Of Nuclear Lipid Droplet Biogenesis Nuclear Lipid Droplet Biogenesis On the Inner Nuclear Membranementioning

confidence: 99%

Running ‘LAPS’ Around nLD: Nuclear Lipid Droplet Form and Function

McPhee

Salsman

Foster

et al. 2022

Front. Cell Dev. Biol.

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The nucleus harbours numerous protein subdomains and condensates that regulate chromatin organization, gene expression and genomic stress. A novel nuclear subdomain that is formed following exposure of cells to excess fatty acids is the nuclear lipid droplet (nLD), which is composed of a neutral lipid core surrounded by a phospholipid monolayer and associated regulatory and lipid biosynthetic enzymes. While structurally resembling cytoplasmic LDs, nLDs are formed by distinct but poorly understood mechanisms that involve the emergence of lipid droplets from the lumen of the nucleoplasmic reticulum and de novo lipid synthesis. Luminal lipid droplets that emerge into the nucleoplasm do so at regions of the inner nuclear membrane that become enriched in promyelocytic leukemia (PML) protein. The resulting nLDs that retain PML on their surface are termed lipid-associated PML structures (LAPS), and are distinct from canonical PML nuclear bodies (NB) as they lack key proteins and modifications associated with these NBs. PML is a key regulator of nuclear signaling events and PML NBs are sites of gene regulation and post-translational modification of transcription factors. Therefore, the subfraction of nLDs that form LAPS could regulate lipid stress responses through their recruitment and retention of the PML protein. Both nLDs and LAPS have lipid biosynthetic enzymes on their surface suggesting they are active sites for nuclear phospholipid and triacylglycerol synthesis as well as global lipid regulation. In this review we have summarized the current understanding of nLD and LAPS biogenesis in different cell types, their structure and composition relative to other PML-associated cellular structures, and their role in coordinating a nuclear response to cellular overload of fatty acids.

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Section: Mechanisms Of Nuclear Lipid Droplet Biogenesis Nuclear Lipid Droplet Biogenesis On the Inner Nuclear Membranementioning

confidence: 99%

Running ‘LAPS’ Around nLD: Nuclear Lipid Droplet Form and Function

McPhee

Salsman

Foster

et al. 2022

Front. Cell Dev. Biol.

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“…Although an LD is derived from the ER, its phospholipid composition is quite different from that of the ER [ 5 ]. Proteins associated with LDs are divided into two classes [ 12 , 13 ]. Class I LD proteins, such as caveolin-1 and DGAT2, are transported to LDs from the ER, while Class Ⅱ LD proteins, such as phosphocholine cytidylyltransferase α (CCTα) and Cide-A, can be transferred to LDs from the cytosol [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Sar1 Affects the Localization of Perilipin 2 to Lipid Droplets

Makiyama

Obama

Watanabe

et al. 2022

IJMS

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Lipid droplets (LDs) are intracellular organelles that are ubiquitous in many types of cells. The LD core consists of triacylglycerols (TGs) surrounded by a phospholipid monolayer and surface proteins such as perilipin 2 (PLIN2). Although TGs accumulate in the phospholipid bilayer of the endoplasmic reticulum (ER) and subsequently nascent LDs buds from ER, the mechanism by which LD proteins are transported to LD particles is not fully understood. Sar1 is a GTPase known as a regulator of coat protein complex Ⅱ (COPⅡ) vesicle budding, and its role in LD formation was investigated in this study. HuH7 human hepatoma cells were infected with adenoviral particles containing genes coding GFP fused with wild-type Sar1 (Sar1 WT) or a GTPase mutant form (Sar1 H79G). When HuH7 cells were treated with oleic acid, Sar1 WT formed a ring-like structure around the LDs. The transient expression of Sar1 did not significantly alter the levels of TG and PLIN2 in the cells. However, the localization of PLIN2 to the LDs decreased in the cells expressing Sar1 H79G. Furthermore, the effects of Sar1 on PLIN2 localization to the LDs were verified by the suppression of endogenous Sar1 using the short hairpin RNA technique. In conclusion, it was found that Sar1 has some roles in the intracellular distribution of PLIN2 to LDs in liver cells.

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“…Class II (CYTOLD) proteins target the LD monolayer from the cytosol typically via amphipathic helices that interact with the LD monolayer. 2 Some of these proteins can bind to either LD monolayers or ER bilayers, as both membranes generally share the same PL composition. However, proteins can preferentially target one or the other contingent on the metabolic state of the cell and the lifecycle stage of the LD, such as an expanding LD under growth conditions.…”

Section: Introductionmentioning

confidence: 99%

“…Acting as the hubs of lipid metabolism, they not only store and dispense neutral lipids for energy and membrane building, but also harbor metabolic enzymes that participate in lipolysis and lipogenesis. [1][2][3] Additionally, LDs can interact with transcription factors and proteins involved in the innate immune system, expanding their significance to other facets of the cellular lifecycle. 4,5 Malfunctioning of LD metabolic pathways or alteration of LD proteomes can lead to an onslaught of diseases due to lipid imbalances.…”

Section: Introductionmentioning

confidence: 99%

“…However, proteins can preferentially target one or the other contingent on the metabolic state of the cell and the lifecycle stage of the LD, such as an expanding LD under growth conditions. 2,7 Identifying how proteins dynamically target LDs to regulate lipid trafficking and metabolism is an emerging area of research. It is somewhat challenging as LDs do not utilize the dedicated protein-targeting machinery or biochemical landmarks used by other organelles, such as those found in peroxisomes, the ER, or mitochondria.…”

Section: Introductionmentioning

confidence: 99%

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Capturing the liquid-crystalline phase transformation: Implications for protein targeting to sterol ester-rich lipid droplets

Braun

Swanson

2022

Preprint

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Lipid droplets are essential organelles that store and traffic neutral lipids. The phospholipid monolayer surrounding their neutral lipid core engages with a highly dynamic proteome that changes according to cellular and metabolic conditions. Recent work has demonstrated that when the abundance of sterol esters increases above a critical concentration, such as under conditions of starvation or high LDL exposure, the lipid droplet core can undergo an amorphous to liquid-crystalline phase transformation. Herein we study the consequences of this transformation on the physical properties of lipid droplets that are thought to regulate protein association. Using simulations of different sterol-ester concentrations we have captured the liquid-crystalline phase transformation at the molecular level, highlighting the alignment of sterol esters in alternating orientations to form concentric layers. We demonstrate how ordering in the core permeates into the neutral lipid/phospholipid interface, changing the magnitude and nature of neutral lipid intercalation and inducing ordering in the phospholipid monolayer. Increased phospholipid packing is concomitate with altered surface properties, including smaller area per phospholipid and substantially reduced packing defects. Additionally, the ordering of sterol esters in the core causes less hydration in more ordered regions. We discuss these findings in the context of their expected consequences for preferential protein recruitment to lipid droplets under different metabolic conditions.

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The CYTOLD and ERTOLD pathways for lipid droplet–protein targeting

Cited by 59 publications

References 114 publications

Running ‘LAPS’ Around nLD: Nuclear Lipid Droplet Form and Function

Running ‘LAPS’ Around nLD: Nuclear Lipid Droplet Form and Function

Sar1 Affects the Localization of Perilipin 2 to Lipid Droplets

Capturing the liquid-crystalline phase transformation: Implications for protein targeting to sterol ester-rich lipid droplets

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