scholarly journals A role for oxysterol-binding protein–related protein 5 in endosomal cholesterol trafficking

2011 ◽  
Vol 192 (1) ◽  
pp. 121-135 ◽  
Author(s):  
Ximing Du ◽  
Jaspal Kumar ◽  
Charles Ferguson ◽  
Timothy A. Schulz ◽  
Yan Shan Ong ◽  
...  
Keyword(s):  
Binding Protein ◽  
Lipid Binding ◽  
Cholesterol Trafficking ◽  
Cholesterol Accumulation ◽  
Oxysterol Binding Protein ◽  
Late Endosomes ◽  
Evolutionarily Conserved ◽  
Niemann Pick ◽  
Related Proteins ◽  
Lipid Binding Proteins

Oxysterol-binding protein (OSBP) and its related proteins (ORPs) constitute a large and evolutionarily conserved family of lipid-binding proteins that target organelle membranes to mediate sterol signaling and/or transport. Here we characterize ORP5, a tail-anchored ORP protein that localizes to the endoplasmic reticulum. Knocking down ORP5 causes cholesterol accumulation in late endosomes and lysosomes, which is reminiscent of the cholesterol trafficking defect in Niemann Pick C (NPC) fibroblasts. Cholesterol appears to accumulate in the limiting membranes of endosomal compartments in ORP5-depleted cells, whereas depletion of NPC1 or both ORP5 and NPC1 results in luminal accumulation of cholesterol. Moreover, trans-Golgi resident proteins mislocalize to endosomal compartments upon ORP5 depletion, which depends on a functional NPC1. Our results establish the first link between NPC1 and a cytoplasmic sterol carrier, and suggest that ORP5 may cooperate with NPC1 to mediate the exit of cholesterol from endosomes/lysosomes.

scholarly journals Nonvesicular sterol movement from plasma membrane to ER requires oxysterol-binding protein–related proteins and phosphoinositides

2006 ◽  
Vol 173 (1) ◽  
pp. 107-119 ◽  
Author(s):  
Sumana Raychaudhuri ◽  
Young Jun Im ◽  
James H. Hurley ◽  
William A. Prinz
Keyword(s):  
Plasma Membrane ◽  
Binding Protein ◽  
Large Family ◽  
Lipid Binding ◽  
Oxysterol Binding Protein ◽  
Sterol Transport ◽  
Cellular Compartments ◽  
Related Proteins ◽  
Lipid Binding Proteins

Sterols are moved between cellular membranes by nonvesicular pathways whose functions are poorly understood. In yeast, one such pathway transfers sterols from the plasma membrane (PM) to the endoplasmic reticulum (ER). We show that this transport requires oxysterol-binding protein (OSBP)–related proteins (ORPs), which are a large family of conserved lipid-binding proteins. We demonstrate that a representative member of this family, Osh4p/Kes1p, specifically facilitates the nonvesicular transfer of cholesterol and ergosterol between membranes in vitro. In addition, Osh4p transfers sterols more rapidly between membranes containing phosphoinositides (PIPs), suggesting that PIPs regulate sterol transport by ORPs. We confirmed this by showing that PM to ER sterol transport slows dramatically in mutants with conditional defects in PIP biosynthesis. Our findings argue that ORPs move sterols among cellular compartments and that sterol transport and intracellular distribution are regulated by PIPs.

scholarly journals Lipid-regulated sterol transfer between closely apposed membranes by oxysterol-binding protein homologues

2009 ◽  
Vol 187 (6) ◽  
pp. 889-903 ◽  
Author(s):  
Timothy A. Schulz ◽  
Mal-Gi Choi ◽  
Sumana Raychaudhuri ◽  
Jason A. Mears ◽  
Rodolfo Ghirlando ◽  
...  
Keyword(s):  
Binding Protein ◽  
Binding Pocket ◽  
Lipid Binding ◽  
Dependent Manner ◽  
Oxysterol Binding Protein ◽  
The Core ◽  
Contact Sites ◽  
Core Lipid ◽  
Related Proteins ◽  
Distal Site

Sterols are transferred between cellular membranes by vesicular and poorly understood nonvesicular pathways. Oxysterol-binding protein–related proteins (ORPs) have been implicated in sterol sensing and nonvesicular transport. In this study, we show that yeast ORPs use a novel mechanism that allows regulated sterol transfer between closely apposed membranes, such as organelle contact sites. We find that the core lipid-binding domain found in all ORPs can simultaneously bind two membranes. Using Osh4p/Kes1p as a representative ORP, we show that ORPs have at least two membrane-binding surfaces; one near the mouth of the sterol-binding pocket and a distal site that can bind a second membrane. The distal site is required for the protein to function in cells and, remarkably, regulates the rate at which Osh4p extracts and delivers sterols in a phosphoinositide-dependent manner. Together, these findings suggest a new model of how ORPs could sense and regulate the lipid composition of adjacent membranes.

The roles of the human lipid-binding proteins ORP9S and ORP10S in vesicular transport

2005 ◽  
Vol 83 (5) ◽  
pp. 631-636 ◽  
Author(s):  
Gregory D Fairn ◽  
Christopher R McMaster
Keyword(s):  
Binding Protein ◽  
Vesicular Transport ◽  
Lipid Binding ◽  
Yeast Cells ◽  
Phospholipid Transfer Protein ◽  
Related Protein ◽  
Oxysterol Binding Protein ◽  
Transfer Protein ◽  
Phospholipid Transfer ◽  
Lipid Binding Proteins

Inactivation of the yeast oxysterol binding protein related protein (ORP) family member Kes1p allows yeast cells to survive in the absence of Sec14p, a phospholipid transfer protein required for cell viability because of the role it plays in transporting vesicles from the Golgi. We expressed human ORP9S and ORP10S in yeast lacking Sec14p and Kes1p function, and found that ORP9S completely complemented Kes1p function, whereas ORP10S possessed only a weak ability to replace Kes1p function. Purified ORP9S protein bound several phosphoinositides, whereas ORP10 bound specifically to phosphatidylinositol 3-phosphate. The combined evidence demonstrates that only a subset of human ORP proteins can function as negative regulators of Golgi-derived vesicular transport.Key words: phospholipid, Saccharomyces cerevisiae, Golgi, vesicular transport, oxysterol binding protein related protein.

scholarly journals Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells

2019 ◽  
Vol 77 (14) ◽  
pp. 2839-2857 ◽  
Author(s):  
Elsa Meneses-Salas ◽  
Ana García-Melero ◽  
Kristiina Kanerva ◽  
Patricia Blanco-Muñoz ◽  
Frederic Morales-Paytuvi ◽  
...  
Keyword(s):  
Late Endosome ◽  
Dependent Manner ◽  
Lipid Transfer ◽  
Cholesterol Accumulation ◽  
Membrane Contact Sites ◽  
Late Endosomes ◽  
Membrane Contact ◽  
Domain 3 ◽  
Niemann Pick ◽  
Mutant Cells

Abstract Cholesterol accumulation in late endosomes is a prevailing phenotype of Niemann-Pick type C1 (NPC1) mutant cells. Likewise, annexin A6 (AnxA6) overexpression induces a phenotype reminiscent of NPC1 mutant cells. Here, we demonstrate that this cellular cholesterol imbalance is due to AnxA6 promoting Rab7 inactivation via TBC1D15, a Rab7-GAP. In NPC1 mutant cells, AnxA6 depletion and eventual Rab7 activation was associated with peripheral distribution and increased mobility of late endosomes. This was accompanied by an enhanced lipid accumulation in lipid droplets in an acyl-CoA:cholesterol acyltransferase (ACAT)-dependent manner. Moreover, in AnxA6-deficient NPC1 mutant cells, Rab7-mediated rescue of late endosome-cholesterol export required the StAR-related lipid transfer domain-3 (StARD3) protein. Electron microscopy revealed a significant increase of membrane contact sites (MCS) between late endosomes and ER in NPC1 mutant cells lacking AnxA6, suggesting late endosome-cholesterol transfer to the ER via Rab7 and StARD3-dependent MCS formation. This study identifies AnxA6 as a novel gatekeeper that controls cellular distribution of late endosome-cholesterol via regulation of a Rab7-GAP and MCS formation.

scholarly journals Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7–RILP–p150Glued and late endosome positioning

2009 ◽  
Vol 185 (7) ◽  
pp. 1209-1225 ◽  
Author(s):  
Nuno Rocha ◽  
Coenraad Kuijl ◽  
Rik van der Kant ◽  
Lennert Janssen ◽  
Diane Houben ◽  
...  
Keyword(s):  
Motor Proteins ◽  
Oxysterol Binding Protein ◽  
Membrane Contact Sites ◽  
Cholesterol Levels ◽  
Dynein Motor ◽  
Late Endosomes ◽  
In Trans ◽  
Membrane Contact ◽  
Cholesterol Control ◽  
Niemann Pick

Late endosomes (LEs) have characteristic intracellular distributions determined by their interactions with various motor proteins. Motor proteins associated to the dynactin subunit p150Glued bind to LEs via the Rab7 effector Rab7-interacting lysosomal protein (RILP) in association with the oxysterol-binding protein ORP1L. We found that cholesterol levels in LEs are sensed by ORP1L and are lower in peripheral vesicles. Under low cholesterol conditions, ORP1L conformation induces the formation of endoplasmic reticulum (ER)–LE membrane contact sites. At these sites, the ER protein VAP (VAMP [vesicle-associated membrane protein]-associated ER protein) can interact in trans with the Rab7–RILP complex to remove p150Glued and associated motors. LEs then move to the microtubule plus end. Under high cholesterol conditions, as in Niemann-Pick type C disease, this process is prevented, and LEs accumulate at the microtubule minus end as the result of dynein motor activity. These data explain how the ER and cholesterol control the association of LEs with motor proteins and their positioning in cells.

scholarly journals Identification and evaluation of metastasis-related proteins, oxysterol binding protein-like 5 and calumenin, in lung tumors

2015 ◽  
Vol 47 (1) ◽  
pp. 195-205 ◽  
Author(s):  
KAZUYA NAGANO ◽  
SUNAO IMAI ◽  
XILULI ZHAO ◽  
TAKUYA YAMASHITA ◽  
YASUO YOSHIOKA ◽  
...  
Keyword(s):  
Binding Protein ◽  
Lung Tumors ◽  
Oxysterol Binding Protein ◽  
Related Proteins

scholarly journals Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation

2020 ◽  
Vol 295 (27) ◽  
pp. 9121-9133 ◽  
Author(s):  
Jason Newton ◽  
Elisa N. D. Palladino ◽  
Cynthia Weigel ◽  
Michael Maceyka ◽  
Markus H. Gräler ◽  
...  
Keyword(s):  
Specific Inhibitor ◽  
Sphingosine Kinase ◽  
Autophagic Flux ◽  
Sphingosine Kinase 1 ◽  
Cholesterol Trafficking ◽  
Cholesterol Accumulation ◽  
Cellular Models ◽  
Ester Formation ◽  
Type C ◽  
Niemann Pick

Niemann–Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. In this work, we examined the cause for sphingosine and sphingolipid accumulation in multiple cellular models of NPC disease and observed that the activity of sphingosine kinase 1 (SphK1), one of the two isoenzymes that phosphorylate sphingoid bases, was markedly reduced in both NPC1 mutant and NPC1 knockout cells. Conversely, SphK1 inhibition with the isotype-specific inhibitor SK1-I in WT cells induced accumulation of cholesterol and reduced cholesterol esterification. Of note, a novel SphK1 activator (SK1-A) that we have characterized decreased sphingoid base and complex sphingolipid accumulation and ameliorated autophagic defects in both NPC1 mutant and NPC1 knockout cells. Remarkably, in these cells, SK1-A also reduced cholesterol accumulation and increased cholesterol ester formation. Our results indicate that a SphK1 activator rescues aberrant cholesterol and sphingolipid storage and trafficking in NPC1 mutant cells. These observations highlight a previously unknown link between SphK1 activity, NPC1, and cholesterol trafficking and metabolism.

scholarly journals ORP1L, ORP1S, and ORP2: Lipid Sensors and Transporters

Contact ◽  
2020 ◽  
Vol 3 ◽  
pp. 251525642095681
Author(s):  
Yvette C. Aw ◽  
Andrew J. Brown ◽  
Jia-Wei Wu ◽  
Hongyuan Yang
Keyword(s):  
Plasma Membrane ◽  
Cholesterol Homeostasis ◽  
Cholesterol Transport ◽  
Lipid Transfer ◽  
Cholesterol Trafficking ◽  
Lipid Transfer Proteins ◽  
Oxysterol Binding Protein ◽  
Membrane Contact ◽  
Related Proteins ◽  
Lipid Sensors

Lipid transfer proteins are crucial for intracellular cholesterol trafficking at sites of membrane contact. In the OSBP/ORPs (oxysterol binding protein and OSBP-related proteins) family of lipid transfer proteins, ORP1L, ORP1S and ORP2 play important roles in cholesterol transport. ORP1L is an endosome/lysosome-anchored cholesterol sensor which may also move cholesterol bidirectionally at the interface between the endoplasmic reticulum and the endosome/lysosome. ORP2 delivers cholesterol to the plasma membrane, driven by PI(4,5)P2 hydrolysis. ORP1S may also transport cholesterol to the plasma membrane, although it is unclear if phosphoinositides are involved. The source of cholesterol delivered to the plasma membrane by ORP1S and ORP2 remains unclear. This review summarises the roles of these proteins in maintaining cellular cholesterol homeostasis and in human disease.

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