scholarly journals ORP5 and ORP8: Sterol Sensors and Phospholipid Transfer Proteins at Membrane Contact Sites?

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 928
Author(s):  
Nina Criado Santos ◽  
Vladimir Girik ◽  
Paula Nunes-Hasler
Keyword(s):  
Structural Similarity ◽  
Lipid Transfer ◽  
Cellular Functions ◽  
Oxysterol Binding Protein ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Phospholipid Transfer ◽  
Membrane Contact ◽  
And Migration ◽  
Phosphatidylinositol 4

Oxysterol binding related proteins 5 and 8 (ORP5 and ORP8) are two close homologs of the larger oxysterol binding protein (OSBP) family of sterol sensors and lipid transfer proteins (LTP). Early studies indicated these transmembrane proteins, anchored to the endoplasmic reticulum (ER), bound and sensed cholesterol and oxysterols. They were identified as important for diverse cellular functions including sterol homeostasis, vesicular trafficking, proliferation and migration. In addition, they were implicated in lipid-related diseases such as atherosclerosis and diabetes, but also cancer, although their mechanisms of action remained poorly understood. Then, alongside the increasing recognition that membrane contact sites (MCS) serve as hubs for non-vesicular lipid transfer, added to their structural similarity to other LTPs, came discoveries showing that ORP5 and 8 were in fact phospholipid transfer proteins that rather sense and exchange phosphatidylserine (PS) for phosphoinositides, including phosphatidylinositol-4-phosphate (PI(4)P) and potentially phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2). Evidence now points to their action at MCS between the ER and various organelles including the plasma membrane, lysosomes, mitochondria, and lipid droplets. Dissecting exactly how this unexpected phospholipid transfer function connects with sterol regulation in health or disease remains a challenge for future studies.

Building lipid ‘PIPelines’ throughout the cell by ORP/Osh proteins

2014 ◽  
Vol 42 (5) ◽  
pp. 1465-1470 ◽  
Author(s):  
Joachim Moser von Filseck ◽  
Bruno Mesmin ◽  
Joëlle Bigay ◽  
Bruno Antonny ◽  
Guillaume Drin
Keyword(s):  
Secretory Pathway ◽  
Eukaryotic Cells ◽  
Transport Mechanisms ◽  
Related Protein ◽  
Oxysterol Binding Protein ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Lipid Species ◽  
Membrane Contact ◽  
Phosphatidylinositol 4

In eukaryotic cells, a sterol gradient exists between the early and late regions of the secretory pathway. This gradient seems to rely on non-vesicular transport mechanisms mediated by specialized carriers. The oxysterol-binding protein-related protein (ORP)/oxysterol-binding homology (Osh) family has been assumed initially to exclusively include proteins acting as sterol sensors/transporters and many efforts have been made to determine their mode of action. Our recent studies have demonstrated that some ORP/Osh proteins are not mere sterol transporters, but sterol/phosphatidylinositol 4-phosphate [PI(4)P] exchangers. They exploit the PI(4)P gradient at the endoplasmic reticulum (ER)/Golgi interface, or at membrane-contact sites between these compartments, to actively create a sterol gradient. Other recent reports have suggested that all ORP/Osh proteins bind PI(4)P and recognize a second lipid that is not necessary sterol. We have thus proposed that ORP/Osh proteins use PI(4)P gradients between organelles to convey various lipid species.

scholarly journals Nanoscale architecture of a VAP-A-OSBP tethering complex at membrane contact sites

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Eugenio de la Mora ◽  
Manuela Dezi ◽  
Aurélie Di Cicco ◽  
Joëlle Bigay ◽  
Romain Gautier ◽  
...  
Keyword(s):  
Lipid Transfer Protein ◽  
Structural Information ◽  
Transmembrane Protein ◽  
Lipid Transfer ◽  
Oxysterol Binding Protein ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
Golgi Network

AbstractMembrane contact sites (MCS) are subcellular regions where two organelles appose their membranes to exchange small molecules, including lipids. Structural information on how proteins form MCS is scarce. We designed an in vitro MCS with two membranes and a pair of tethering proteins suitable for cryo-tomography analysis. It includes VAP-A, an ER transmembrane protein interacting with a myriad of cytosolic proteins, and oxysterol-binding protein (OSBP), a lipid transfer protein that transports cholesterol from the ER to the trans Golgi network. We show that VAP-A is a highly flexible protein, allowing formation of MCS of variable intermembrane distance. The tethering part of OSBP contains a central, dimeric, and helical T-shape region. We propose that the molecular flexibility of VAP-A enables the recruitment of partners of different sizes within MCS of adjustable thickness, whereas the T geometry of the OSBP dimer facilitates the movement of the two lipid-transfer domains between membranes.

PI4P/PS countertransport by ORP10 at ER–endosome membrane contact sites regulates endosome fission

2021 ◽  
Vol 221 (1) ◽  
Author(s):  
Asami Kawasaki ◽  
Akiko Sakai ◽  
Hiroki Nakanishi ◽  
Junya Hasegawa ◽  
Tomohiko Taguchi ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Binding Protein ◽  
Dependent Manner ◽  
Oxysterol Binding Protein ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Lipid Exchange ◽  
Membrane Contact ◽  
Phosphatidylinositol 4

Membrane contact sites (MCSs) serve as a zone for nonvesicular lipid transport by oxysterol-binding protein (OSBP)-related proteins (ORPs). ORPs mediate lipid countertransport, in which two distinct lipids are transported counterdirectionally. How such lipid countertransport controls specific biological functions, however, remains elusive. We report that lipid countertransport by ORP10 at ER–endosome MCSs regulates retrograde membrane trafficking. ORP10, together with ORP9 and VAP, formed ER–endosome MCSs in a phosphatidylinositol 4-phosphate (PI4P)-dependent manner. ORP10 exhibited a lipid exchange activity toward its ligands, PI4P and phosphatidylserine (PS), between liposomes in vitro, and between the ER and endosomes in situ. Cell biological analysis demonstrated that ORP10 supplies a pool of PS from the ER, in exchange for PI4P, to endosomes where the PS-binding protein EHD1 is recruited to facilitate endosome fission. Our study highlights a novel lipid exchange at ER–endosome MCSs as a nonenzymatic PI4P-to-PS conversion mechanism that organizes membrane remodeling during retrograde membrane trafficking.

scholarly journals The ER cholesterol sensor SCAP promotes CARTS biogenesis at ER–Golgi membrane contact sites

2020 ◽  
Vol 220 (1) ◽  
Author(s):  
Yuichi Wakana ◽  
Kaito Hayashi ◽  
Takumi Nemoto ◽  
Chiaki Watanabe ◽  
Masato Taoka ◽  
...  
Keyword(s):  
Lipid Transfer ◽  
Golgi Membrane ◽  
Proteolytic Activation ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Defective Mutant ◽  
Transport Defect ◽  
Membrane Contact ◽  
Phosphatidylinositol 4 ◽  
Golgi Network

In response to cholesterol deprivation, SCAP escorts SREBP transcription factors from the endoplasmic reticulum to the Golgi complex for their proteolytic activation, leading to gene expression for cholesterol synthesis and uptake. Here, we show that in cholesterol-fed cells, ER-localized SCAP interacts through Sac1 phosphatidylinositol 4-phosphate (PI4P) phosphatase with a VAP–OSBP complex, which mediates counter-transport of ER cholesterol and Golgi PI4P at ER–Golgi membrane contact sites (MCSs). SCAP knockdown inhibited the turnover of PI4P, perhaps due to a cholesterol transport defect, and altered the subcellular distribution of the VAP–OSBP complex. As in the case of perturbation of lipid transfer complexes at ER–Golgi MCSs, SCAP knockdown inhibited the biogenesis of the trans-Golgi network–derived transport carriers CARTS, which was reversed by expression of wild-type SCAP or a Golgi transport–defective mutant, but not of cholesterol sensing–defective mutants. Altogether, our findings reveal a new role for SCAP under cholesterol-fed conditions in the facilitation of CARTS biogenesis via ER–Golgi MCSs, depending on the ER cholesterol.

scholarly journals Functions of Oxysterol-Binding Proteins at Membrane Contact Sites and Their Control by Phosphoinositide Metabolism

2021 ◽  
Vol 9 ◽  
Author(s):  
Fubito Nakatsu ◽  
Asami Kawasaki
Keyword(s):  
Lipid Transport ◽  
Phosphoinositide Metabolism ◽  
Lipid Transfer ◽  
Cellular Functions ◽  
Characteristic Functional ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Tightly Coupled ◽  
Membrane Contact ◽  
The Right

Lipids must be correctly transported within the cell to the right place at the right time in order to be fully functional. Non-vesicular lipid transport is mediated by so-called lipid transfer proteins (LTPs), which contain a hydrophobic cavity that sequesters lipid molecules. Oxysterol-binding protein (OSBP)-related proteins (ORPs) are a family of LTPs known to harbor lipid ligands, such as cholesterol and phospholipids. ORPs act as a sensor or transporter of those lipid ligands at membrane contact sites (MCSs) where two different cellular membranes are closely apposed. In particular, a characteristic functional property of ORPs is their role as a lipid exchanger. ORPs mediate counter-directional transport of two different lipid ligands at MCSs. Several, but not all, ORPs transport their lipid ligand from the endoplasmic reticulum (ER) in exchange for phosphatidylinositol 4-phosphate (PI4P), the other ligand, on apposed membranes. This ORP-mediated lipid “countertransport” is driven by the concentration gradient of PI4P between membranes, which is generated by its kinases and phosphatases. In this review, we will discuss how ORP function is tightly coupled to metabolism of phosphoinositides such as PI4P. Recent progress on the role of ORP-mediated lipid transport/countertransport at multiple MCSs in cellular functions will be also discussed.

scholarly journals RdgBα reciprocally transfers PA and PI at ER–PM contact sites to maintain PI(4,5)P2 homoeostasis during phospholipase C signalling in Drosophila photoreceptors

2016 ◽  
Vol 44 (1) ◽  
pp. 286-292 ◽  
Author(s):  
Shamshad Cockcroft ◽  
Kathryn Garner ◽  
Shweta Yadav ◽  
Evelyn Gomez-Espinoza ◽  
Padinjat Raghu
Keyword(s):  
Lipid Transfer ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Hydrophobic Cavity ◽  
Dual Specificity ◽  
Lipid Kinases ◽  
Membrane Contact ◽  
Phosphatidylinositol 4 ◽  
G Protein Coupled ◽  
Hydrolysis Of

Phosphatidylinositol (PI) is the precursor lipid for the synthesis of PI 4,5-bisphosphate [PI(4,5)P2] at the plasma membrane (PM) and is sequentially phosphorylated by the lipid kinases, PI 4-kinase and phosphatidylinositol 4-phosphate (PI4P)-5-kinase. Receptor-mediated hydrolysis of PI(4,5)P2 takes place at the PM but PI resynthesis occurs at the endoplasmic reticulum (ER). Thus PI(4,5)P2 resynthesis requires the reciprocal transport of two key intermediates, phosphatidic acid (PA) and PI between the ER and the PM. PI transfer proteins (PITPs), defined by the presence of the PITP domain, can facilitate lipid transfer between membranes; the PITP domain comprises a hydrophobic cavity with dual specificity but accommodates a single phospholipid molecule. The class II PITP, retinal degeneration type B (RdgB)α is a multi-domain protein and its PITP domain can bind and transfer PI and PA. In Drosophila photoreceptors, a well-defined G-protein-coupled phospholipase Cβ (PLCβ) signalling pathway, phototransduction defects resulting from loss of RdgBα can be rescued by expression of the PITP domain provided it is competent for both PI and PA transfer. We propose that RdgBα proteins maintain PI(4,5)P2 homoeostasis after PLC activation by facilitating the reciprocal transport of PA and PI at ER–PM membrane contact sites.

scholarly journals The Hob Proteins: Putative, Novel Lipid Transfer Proteins at ER-PM Contact Sites

Contact ◽  
2021 ◽  
Vol 4 ◽  
pp. 251525642110523
Author(s):  
Sarah D. Neuman ◽  
Amy T. Cavanagh ◽  
Arash Bashirullah
Keyword(s):  
Structural Models ◽  
Model Systems ◽  
Lipid Transfer ◽  
Lipid Transfer Proteins ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Bona Fide ◽  
Membrane Contact ◽  
Mutant Cells ◽  
Critical Process

Nonvesicular transfer of lipids at membrane contact sites (MCS) has recently emerged as a critical process for cellular function. Lipid transfer proteins (LTPs) mediate this unique transport mechanism, and although several LTPs are known, the cellular complement of these proteins continues to expand. Our recent work has revealed the highly conserved but poorly characterized Hobbit/Hob proteins as novel, putative LTPs at endoplasmic reticulum-plasma membrane (ER-PM) contact sites. Using both S. cerevisiae and D. melanogaster model systems, we demonstrated that the Hob proteins localize to ER-PM contact sites via an N-terminal ER membrane anchor and conserved C-terminal sequences. These conserved C-terminal sequences bind to phosphoinositides (PIPs), and the distribution of PIPs is disrupted in hobbit mutant cells. Recently released structural models of the Hob proteins exhibit remarkable similarity to other bona fide LTPs, like VPS13A and ATG2, that function at MCS. Hobbit is required for viability in Drosophila, suggesting that the Hob proteins are essential genes that may mediate lipid transfer at MCS.

scholarly journals Synaptotagmins Maintain Diacylglycerol Homeostasis at Endoplasmic Reticulum-Plasma Membrane Contact Sites during Abiotic Stress

2020 ◽  
Author(s):  
Noemi Ruiz-Lopez ◽  
Jessica Pérez-Sancho ◽  
Alicia Esteban del Valle ◽  
Richard P. Haslam ◽  
Steffen Vanneste ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
Abiotic Stress ◽  
Mechanical Damage ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
Phosphatidylinositol 4 ◽  
Polar Glycerolipids

SUMMARYEndoplasmic Reticulum-Plasma Membrane contact sites (ER-PM CS) play fundamental roles in all eukaryotic cells. Arabidopsis mutants lacking the ER-PM protein tether synaptotagmin1 (SYT1) exhibit decreased plasma membrane (PM) integrity under multiple abiotic stresses such as freezing, high salt, osmotic stress and mechanical damage. Here, we show that, together with SYT1, the stress-induced SYT3 is an ER-PM tether that also functions in maintaining PM integrity. The ER-PM CS localization of SYT1 and SYT3 is dependent on PM phosphatidylinositol-4-phosphate and is regulated by abiotic stress. Lipidomic analysis revealed that cold stress increased the accumulation of diacylglycerol at the PM in a syt1/3 double mutant relative to WT while the levels of most glycerolipid species remain unchanged. Additionally, SYT1-GFP preferentially binds diacylglycerol in vivo with little affinity for polar glycerolipids. Our work uncovers a crucial SYT-dependent mechanism of stress adaptation counteracting the detrimental accumulation of diacylglycerol at the PM produced during episodes of abiotic stress.

scholarly journals The Vacuole and Mitochondria Patch (vCLAMP) Protein Mcp1 Is Involved in Maintenance of Mitochondrial Function and Mitophagy in Candida albicans

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaolong Mao ◽  
Li Yang ◽  
Yiming Fan ◽  
Jiazhen Wang ◽  
Dongkai Cui ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Carbon Sources ◽  
Cellular Functions ◽  
Core Component ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Mitochondrial Functions ◽  
Abnormal Accumulation ◽  
Membrane Contact

The vacuole and mitochondria patches (vCLAMPs) are novel membrane contact sites in yeast. However, their role in autophagy has not been elucidated so far. In this article, the role of Mcp1, one core component of vCLAMP, in mitophagy of Candida albicans was investigated. Deletion of MCP1 led to abnormal accumulation of enlarged mitochondria and attenuated stability of mitochondrial DNA (mtDNA) in C. albicans when cultured in non-fermentable carbon sources. Furthermore, the mcp1Δ/Δ mutant exhibited defective growth and degradation of Csp37-GFP. These results indicate that Mcp1 plays a crucial role in mitophagy and maintenance of mitochondrial functions under the non-fermentable condition. Interestingly, this deletion had no impact on degradation of Atg8 (the macroautophagy reporter) and Lap41 (the cytoplasm-to-vacuole targeting pathway marker) under SD-N medium. Moreover, deletion of MCP1 inhibited filamentous growth and impaired virulence of the pathogen. This study provides an insight to vCLAMPs in cellular functions and pathogenicity in C. albicans.

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