Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System

Zhao, Kexin; Ridgway, Neale D.

doi:10.1016/j.celrep.2017.05.028

Cited by 125 publications

(137 citation statements)

References 39 publications

(52 reference statements)

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“…Compared to the short (2 h) OSW-1 treatment, the long (72 h) exposure of cells to siRNA against OSBP is more likely to favor compensatory effects preventing toxic cholesterol accumulation at the ER. In this respect, we noted that cholesterol transfer proteins acting between the ER and late endosomal compartments have been very recently identified (Wilhelm et al, 2017;Zhao & Ridgway, 2017).…”

Section: Inhibition Of Endogenous Osbp Affects Intracellular Sterol Dmentioning

confidence: 96%

Sterol transfer, PI 4P consumption, and control of membrane lipid order by endogenous OSBP

et al. 2017

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The network of proteins that orchestrate the distribution of cholesterol among cellular organelles is not fully characterized. We previously proposed that oxysterol-binding protein (OSBP) drives cholesterol/PI4P exchange at contact sites between the endoplasmic reticulum (ER) and the -Golgi network (TGN). Using the inhibitor OSW-1, we report here that the sole activity of endogenous OSBP makes a major contribution to cholesterol distribution, lipid order, and PI4P turnover in living cells. Blocking OSBP causes accumulation of sterols at ER/lipid droplets at the expense of TGN, thereby reducing the gradient of lipid order along the secretory pathway. OSBP consumes about half of the total cellular pool of PI4P, a consumption that depends on the amount of cholesterol to be transported. Inhibiting the spatially restricted PI4-kinase PI4KIIIβ triggers large periodic traveling waves of PI4P across the TGN These waves are cadenced by long-range PI4P production by PI4KIIα and PI4P consumption by OSBP Collectively, these data indicate a massive spatiotemporal coupling between cholesterol transport and PI4P turnover via OSBP and PI4-kinases to control the lipid composition of subcellular membranes.

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Section: Inhibition Of Endogenous Osbp Affects Intracellular Sterol Dmentioning

confidence: 96%

Sterol transfer, PI 4P consumption, and control of membrane lipid order by endogenous OSBP

et al. 2017

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“…As a result of this newly formed membrane contact sites, the lysosome is tethered to the ER and the dynein‐dynactin motor is displaced from RILP. Within the ER contact sites formed by ORP1L/VAP interaction between the two compartments, cholesterol is transferred from lysosomes to the ER . Overall, ORP1L‐regulated endosomal motility is responsible for interacting with the ER protein VAP that then determines clustering of lysosomes in cholesterol‐rich conditions and their immobilization in a scattered state when cholesterol is depleted.…”

Section: Lysosomal Positioning Regulated By Other Organellesmentioning

confidence: 99%

Mechanisms of lysosomal positioning and movement

Cabukusta

Neefjes

2018

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Lysosomes are highly dynamic organelles that can move rapidly throughout the cell. They distribute in a rather immobile pool located around the microtubule‐organizing center in a “cloud,” and a highly dynamic pool in the cell periphery. Their spatiotemporal characteristics allow them to carry out multiple biological functions, such as cargo degradation, antigen presentation and plasma membrane repair. Therefore, it is not surprising that lysosomal dysfunction underlies various diseases, including cancer, neurodegenerative and autoimmune diseases. In most of these biological events, the involvement of lysosomes is dependent on their ability to move throughout the cytoplasm, to find and fuse to the correct compartments to receive and deliver substrates for further handling. These dynamics are orchestrated by motor proteins moving along cytoskeletal components. The complexity of the mechanisms responsible for controlling lysosomal transport has recently been appreciated and has yielded novel insights into interorganellar communication, as well as lipid‐protein interplay. In this review, we discuss the current understanding of the mechanisms of lysosomal transport and the molecular machineries that control this mobility.

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“…Cholesterol accumulation in lysosomes of cells lacking ORP5, suggests that ORP5 may be an acceptor for cholesterol mobilized by the NPC2-NPC1 system (Du et al, 2011). The OSBP-related protein 1L (ORP1L), which was previously implicated in lysosomal positioning in response to cholesterol levels (Rocha et al, 2009), was recently found to mediate transport of cholesterol from LE/LY to the ER in a VAPA/B dependent manner (Zhao and Ridgway, 2017). Cells lacking ORP1L showed significant accumulation of cholesterol at the lysosomal limiting membrane, with concomitant reduction of cholesterol esterification in the ER, suggesting blockage of an important route for cholesterol delivery to the ER.…”

Section: Mechanisms Of Lipid Export From the Lysosome (Le/ly)mentioning

confidence: 99%

Emerging Roles for the Lysosome in Lipid Metabolism

Thelen

Zoncu

2017

Trends in Cell Biology

199

156

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Precise regulation of lipid biosynthesis, transport, and storage is key to the homeostasis of cells and organisms. Cells rely on a sophisticated but poorly understood network of vesicular and non-vesicular transport mechanisms to ensure efficient delivery of lipids to target organelles. The lysosome stands at the crossroads of this network due to its ability to process and sort exogenous and endogenous lipids. The lipid sorting function of the lysosome is intimately connected to its recently discovered role as a metabolic command-and-control center, which relays multiple nutrient cues to the master growth regulator, mechanistic Target of Rapamycin Complex 1 (mTORC1) kinase. In turn, mTORC1 potently drives anabolic processes, including de novo lipid synthesis, while inhibiting lipid catabolism. Here we describe the dual role of the lysosome in lipid transport and biogenesis, and we discuss how integration of these two processes may play important roles both in normal physiology and in disease.

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Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System

Cited by 125 publications

References 39 publications

Sterol transfer, PI 4P consumption, and control of membrane lipid order by endogenous OSBP

Sterol transfer, PI 4P consumption, and control of membrane lipid order by endogenous OSBP

Mechanisms of lysosomal positioning and movement

Emerging Roles for the Lysosome in Lipid Metabolism

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