The Proteasomal and Autophagic Pathways  Converge on Lipid Droplets

Fujimoto, Toyoshi; Ohsaki, Yuki

doi:10.4161/auto.2904

Cited by 38 publications

(38 citation statements)

References 19 publications

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“…Out of many end products of this pathway, ubiquinone is required in the process of ATP formation during oxidative phosphorylation. Interestingly, it was reported that ubiquitinated hydrophobic proteins, which are prone to aggregation, are kept on the surface of lipid droplets (formation of lipid droplets is affected by statins20) and subjected to autophagy as well as proteasomal degradation41.…”

Section: Discussionmentioning

confidence: 99%

Variability in statin-induced changes in gene expression profiles of pancreatic cancer

Gbelcová

Rimpelová

Ruml

et al. 2017

Sci Rep

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Statins, besides being powerful cholesterol-lowering drugs, also exert potent anti-proliferative activities. However, their anti-cancer efficacy differs among the individual statins. Thus, the aim of this study was to identify the biological pathways affected by individual statins in an in vitro model of human pancreatic cancer. The study was performed on a human pancreatic cancer cell line MiaPaCa-2, exposed to all commercially available statins (12 μM, 24 h exposure). DNA microarray analysis was used to determine changes in the gene expression of treated cells. Intracellular concentrations of individual statins were measured by UPLC (ultra performance liquid chromatography)-HRMS (high resolution mass spectrometer). Large differences in the gene transcription profiles of pancreatic cancer cells exposed to various statins were observed; cerivastatin, pitavastatin, and simvastatin being the most efficient modulators of expression of genes involved namely in the mevalonate pathway, cell cycle regulation, DNA replication, apoptosis and cytoskeleton signaling. Marked differences in the intracellular concentrations of individual statins in pancreatic cancer cells were found (>11 times lower concentration of rosuvastatin compared to lovastatin), which may contribute to inter-individual variability in their anti-cancer effects. In conclusion, individual statins exert different gene expression modulating effects in treated pancreatic cancer cells. These effects may be partially caused by large differences in their bioavailability. We report large differences in gene transcription profiles of pancreatic cancer cells exposed to various statins. These data correlate to some extent with the intracellular concentrations of statins, and may explain the inter-individual variability in the anti-cancer effects of statins.

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Section: Discussionmentioning

confidence: 99%

Variability in statin-induced changes in gene expression profiles of pancreatic cancer

Gbelcová

Rimpelová

Ruml

et al. 2017

Sci Rep

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“…Recently, the importance of E3 ligases for LD turnover was reported, but further molecular components or mechanistic details are lacking (54). Apolipoprotein B accumulates in crescent-shaped structures around LDs in hepatocytes after inhibition of the proteasome or autophagy (7,55), suggesting a role of LDs in degradation of excess apolipoproteins. In support of this function of LDs, a recent study (56) demonstrated accumulation of hydroxymethylglutaryl-CoA reductase around LDs under conditions of impaired proteasomal degradation.…”

Section: Discussionmentioning

confidence: 99%

Ancient Ubiquitous Protein 1 (AUP1) Localizes to Lipid Droplets and Binds the E2 Ubiquitin Conjugase G2 (Ube2g2) via Its G2 Binding Region

Spandl

Lohmann

Kuerschner

et al. 2011

Journal of Biological Chemistry

105

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Lipid droplets (LDs), the major intracellular storage sites for neutral lipids, consist of a neutral lipid core surrounded by a phospholipid monolayer membrane. In addition to their function in lipid storage, LDs participate in lipid biosynthesis and recently were implicated in proteasomal protein degradation and autophagy. To identify components of the protein degradation machinery on LDs, we studied several candidates identified in previous LD proteome analyses. Here, we demonstrate that the highly conserved and broadly expressed ancient ubiquitous protein 1 (AUP1) localizes to LDs, where it integrates into the LD surface in a monotopic fashion with both termini facing the cytosol. AUP1 contains a C-terminal domain with strong homology to a domain known as G2BR, which binds E2 ubiquitin conjugases. We show that AUP1, by means of its G2BR domain, binds to Ube2g2. This binding is abolished by deletion or mutation of the G2BR domain, although the LD localization of AUP1 is not affected. The presence of the AUP1-Ube2g2 complex at LDs provides a direct molecular link between LDs and the cellular ubiquitination machinery.

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“…These observations led to the proposal that LDs might serve as an obligatory platform for the turnover of specific proteins [174]. This intermediary LD step may assist the degradation of certain highly hydrophobic proteins that would otherwise form hard-to-clear aggregates in the cytoplasm [175] or it may facilitate the wholesale delivery of a large set of damaged proteins to the lysosome via autophagy [96].…”

Section: 4 Protein Turnovermentioning

confidence: 99%

Lipid droplet functions beyond energy storage

Welte

Gould

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

442

358

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Lipid droplets are cytoplasmic organelles that store neutral lipids and are critically important for energy metabolism. Their function in energy storage is firmly established and increasingly well characterized. However, emerging evidence indicates that lipid droplets also play important and diverse roles in the cellular handling of lipids and proteins that may not be directly related to energy homeostasis. Lipid handling roles of droplets include the storage of hydrophobic vitamin and signaling precursors, and the management of endoplasmic reticulum and oxidative stress. Roles of lipid droplets in protein handling encompass functions in the maturation, storage, and turnover of cellular and viral polypeptides. Other potential roles of lipid droplets may be connected with their intracellular motility and, in some cases, their nuclear localization. This diversity highlights that lipid droplets are very adaptable organelles, performing different functions in different biological contexts.

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The Proteasomal and Autophagic Pathways Converge on Lipid Droplets

Cited by 38 publications

References 19 publications

Variability in statin-induced changes in gene expression profiles of pancreatic cancer

Variability in statin-induced changes in gene expression profiles of pancreatic cancer

Ancient Ubiquitous Protein 1 (AUP1) Localizes to Lipid Droplets and Binds the E2 Ubiquitin Conjugase G2 (Ube2g2) via Its G2 Binding Region

Lipid droplet functions beyond energy storage

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