Lipid Exchangers: Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism

Lipp, Nicolas-Frédéric; Ikhlef, Souade; Milanini, Julie; Drin, Guillaume

doi:10.3389/fcell.2020.00663

Cited by 42 publications

(30 citation statements)

References 293 publications

(474 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Oxysterol-binding proteins (OSBP)-related proteins (ORPs) compose a large conserved family of lipid-binding proteins in eukaryotes and are implicated in many cellular processes including cell signaling, vesicular trafficking, lipid metabolism, and transport [ 4 ]. Mammals have twelve ORP genes and their gene splicing increases the number of different protein products [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…The long ORPs containing the N-terminal targeting modules seem to transport lipids efficiently at the membrane contacts sites because they diffuse only a short distance between the membranes. Besides the role as LTPs, diverse functions of ORPs have been reported as sterol regulators or sensors that transfer information to a spectrum of different cellular processes [ 4 ]. Human ORP3 localizes to the ER-PM contacts and recruits R-Ras, a small GTPase that controls cell adhesion and migration [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Structure of human ORP3 ORD reveals conservation of a key function and ligand specificity in OSBP-related proteins

Tong

Tan

2021

PLoS ONE

View full text Add to dashboard Cite

Human ORP3 belongs to the oxysterol-binding protein (OSBP) family of lipid transfer proteins and is involved in lipid trafficking and cell signaling. ORP3 localizes to the ER-PM interfaces and is implicated in lipid transport and focal adhesion dynamics. Here, we report the 2.6–2.7 Å structures of the ORD (OSBP-related domain) of human ORP3 in apo-form and in complex with phosphatidylinositol 4-phosphate. The ORP3 ORD displays a helix grip β-barrel fold with a deep hydrophobic pocket which is conserved in the OSBP gene family. ORP3 binds PI(4)P by the residues around tunnel entrance and in the hydrophobic pocket, whereas it lacks sterol binding due to the narrow hydrophobic tunnel. The heterologous expression of the ORDs of human ORP3 or OSBP1 rescued the lethality of seven ORP (yeast OSH1-OSH7) knockout in yeast. In contrast, the PI(4)P-binding site mutant of ORP3 did not complement the OSH knockout cells. The N-terminal PH domain and FFAT motif of ORP3 are involved in protein targeting but are not essential in yeast complementation. This observation suggests that the essential function conserved in the ORPs of yeast and human is mediated by PI(4)P-binding of the ORD domain. This study suggests that the non-vesicular PI(4)P transport is a conserved function of all ORPs in eukaryotes.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure of human ORP3 ORD reveals conservation of a key function and ligand specificity in OSBP-related proteins

Tong

Tan

2021

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…Oxysterol-binding protein-like 2 (OSBPL2/ORP2) is an important ORP that contains an FFAT (diphenylalanine [FF] in an acidic tract [AT]) motif for ER targeting and a functional ORD for lipid binding 6 . Similar to other members of the OSBP/ORPs family, OSBPL2/ORP2 is a lipid transfer protein (LTP) 7 and has a function in lipid transport and regulation of sterol and phospholipid metabolism 6 , 8 – 11 . OSBPL2/ORP2 also regulates the actin cytoskeleton and affects cell adhesion 12 .…”

Section: Introductionmentioning

confidence: 99%

Oxysterol-binding protein-like 2 contributes to the developmental progression of preadipocytes by binding to β-catenin

et al. 2021

View full text Add to dashboard Cite

Oxysterol-binding protein-like 2 (OSBPL2), also known as oxysterol-binding protein-related protein (ORP) 2, is a member of lipid transfer protein well-known for its role in regulating cholesterol homeostasis. A recent study reported that OSBPL2/ORP2 localizes to lipid droplets (LDs) and is associated with energy metabolism and obesity. However, the function of OSBPL2/ORP2 in adipocyte differentiation is poorly understood. Here, we report that OSBPL2/ORP2 contributes to the developmental progression of preadipocytes. We found that OSBPL2/ORP2 binds to β-catenin, a key effector in the Wnt signaling pathway that inhibits adipogenesis. This complex plays a role in regulating the protein level of β-catenin only in preadipocytes, not in mature adipocytes. Our data further indicated that OSBPL2/ORP2 mediates the transport of β-catenin into the nucleus and thus regulates target genes related to adipocyte differentiation. Deletion of OSBPL2/ORP2 markedly reduces β-catenin both in the cytoplasm and in the nucleus, promotes preadipocytes maturation, and ultimately leads to obesity-related characteristics. Altogether, we provide novel insight into the function of OSBPL2/ORP2 in the developmental progression of preadipocytes and suggest OSBPL2/ORP2 may be a potential therapeutic target for the treatment of obesity-related diseases.

show abstract

“…Vesicular lipid transport involves budding and fission of vesicles from source membranes followed by trafficking and fusion with destination membranes. Nonvesicular lipid transport occurs via lipid transfer proteins (LTPs) that acquire and release their specific lipid cargoes during transient interaction with source and destination membranes ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ). Variations in LTP transfer mechanisms include: i) shuttling of the amphitropic LTP back and forth through the aqueous milieu between membranes or ii) pendulum-like swinging of membrane-associated protein containing an LTP domain between closely apposed membranes.…”

mentioning

confidence: 99%

Ceramide-1-phosphate transfer protein (CPTP) regulation by phosphoinositides

Gao

Zhai

Болдырев

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

Ceramide-1-phosphate transfer proteins (CPTPs) are members of the glycolipid transfer protein (GLTP) superfamily that shuttle ceramide-1-phosphate (C1P) between membranes. CPTPs regulate cellular sphingolipid homeostasis in ways that impact programmed cell death and inflammation. CPTP downregulation specifically alters C1P levels in the plasma and trans -Golgi membranes, stimulating proinflammatory eicosanoid production and autophagy-dependent inflammasome-mediated cytokine release. However, the mechanisms used by CPTP to target the trans -Golgi and plasma membrane are not well understood. Here, we monitored C1P intervesicular transfer using fluorescence energy transfer (FRET) and showed that certain phosphoinositides (phosphatidylinositol 4,5 bisphosphate (PI-(4,5)P 2 ) and phosphatidylinositol 4-phosphate (PI-4P)) increased CPTP transfer activity, whereas others (phosphatidylinositol 3-phosphate (PI-3P) and PI) did not. PIPs that stimulated CPTP did not stimulate GLTP, another superfamily member. Short-chain PI-(4,5)P 2, which is soluble and does not remain membrane-embedded, failed to activate CPTP. CPTP stimulation by physiologically relevant PI-(4,5)P 2 levels surpassed that of phosphatidylserine (PS), the only known non-PIP stimulator of CPTP, despite PI-(4,5)P 2 increasing membrane equilibrium binding affinity less effectively than PS. Functional mapping of mutations that led to altered FRET lipid transfer and assessment of CPTP membrane interaction by surface plasmon resonance indicated that di-arginine motifs located in the α-6 helix and the α3-α4 helix regulatory loop of the membrane-interaction region serve as PI-(4,5)P 2 headgroup-specific interaction sites. Haddock modeling revealed specific interactions involving the PI-(4,5)P 2 headgroup that left the acyl chains oriented favorably for membrane embedding. We propose that PI-(4,5)P 2 interaction sites enhance CPTP activity by serving as preferred membrane targeting/docking sites that favorably orient the protein for function.

show abstract

Lipid Exchangers: Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism

Cited by 42 publications

References 293 publications

Structure of human ORP3 ORD reveals conservation of a key function and ligand specificity in OSBP-related proteins

Structure of human ORP3 ORD reveals conservation of a key function and ligand specificity in OSBP-related proteins

Oxysterol-binding protein-like 2 contributes to the developmental progression of preadipocytes by binding to β-catenin

Ceramide-1-phosphate transfer protein (CPTP) regulation by phosphoinositides

Contact Info

Product

Resources

About