Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases

Nature Reviews Molecular Cell Biology, Год журнала: 2023, Номер 24(8), С. 576 - 596

Опубликована: Апрель 27, 2023

Язык: Английский

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RBG Motif Bridge-Like Lipid Transport Proteins: Structure, Functions, and Open Questions

Annual Review of Cell and Developmental Biology, Год журнала: 2023, Номер 39(1), С. 409 - 434

Опубликована: Июль 5, 2023

The life of eukaryotic cells requires the transport lipids between membranes, which are separated by aqueous environment cytosol. Vesicle-mediated traffic along secretory and endocytic pathways lipid transfer proteins (LTPs) cooperate in this transport. Until recently, known LTPs were shown to carry one or a few at time thought mediate shuttle-like mechanisms. Over last years, new family has been discovered that is defined repeating β-groove (RBG) rod-like structure with hydrophobic channel running their entire length. This localization these membrane contact sites suggest bridge-like mechanism Mutations some result neurodegenerative developmental disorders. Here we review properties well-established putative physiological roles proteins, highlight many questions remain open about functions.

Язык: Английский

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A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(35)

Опубликована: Авг. 22, 2022

Chorea-acanthocytosis (ChAc) and McLeod syndrome are diseases with shared clinical manifestations caused by mutations in VPS13A XK, respectively. Key features of these conditions the degeneration caudate neurons presence abnormally shaped erythrocytes. XK belongs to a family plasma membrane (PM) lipid scramblases whose action results exposure PtdSer at cell surface. is an endoplasmic reticulum (ER)-anchored transfer protein putative role transport lipids contacts ER other membranes. Recently were reported interact still unknown mechanisms. So far, however, there no evidence for colocalization two proteins PM, where resides, as was shown be localized between either mitochondria or droplets. Here we show that can also localize ER–PM via binding its PH domain cytosolic loop such interaction regulated intramolecular within both highly expressed neurons. Binding competitive intracellular membranes mediate tethering functions VPS13A. Our findings support model according which VPS13A-dependent PM coupled scrambling PM. They raise possibility defective surface may responsible neurodegeneration.

Язык: Английский

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Parallel phospholipid transfer by Vps13 and Atg2 determines autophagosome biogenesis dynamics

The Journal of Cell Biology, Год журнала: 2023, Номер 222(7)

Опубликована: Апрель 28, 2023

During autophagy, rapid membrane assembly expands small phagophores into large double-membrane autophagosomes. Theoretical modeling predicts that the majority of autophagosomal phospholipids are derived from highly efficient non-vesicular phospholipid transfer (PLT) across phagophore-ER contacts (PERCS). Currently, tether Atg2 is only PLT protein known to drive phagophore expansion in vivo. Here, our quantitative live-cell imaging analysis reveals a poor correlation between duration and size forming autophagosomes number molecules at PERCS starving yeast cells. Strikingly, we find Atg2-mediated non-rate limiting for autophagosome biogenesis because Vps13 localizes rim promotes parallel with Atg2. In absence Vps13, determines an apparent vivo rate ∼200 per molecule second. We propose conserved proteins cooperate channeling organelle contact sites non-rate-limiting during biogenesis.

Язык: Английский

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Neuroacanthocytosis Syndromes: The Clinical Perspective

Contact, Год журнала: 2023, Номер 6

Опубликована: Янв. 1, 2023

The two very rare neurodegenerative diseases historically known as the “neuroacanthocytosis syndromes” are due to mutations of either VPS13A or XK. These phenotypically similar disorders that affect primarily basal ganglia and hence result in involuntary abnormal movements well neuropsychiatric cognitive alterations. There other shared features such abnormalities red cell membranes which acanthocytes, whose relationship neurodegeneration is not yet known. Recent insights into functions these proteins suggest dysfunction lipid processing trafficking at subcellular level may provide a mechanism for neuronal death, potentially target therapeutic interventions.

Язык: Английский

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YdbH and YnbE form an intermembrane bridge to maintain lipid homeostasis in the outer membrane of Escherichia coli

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(21)

Опубликована: Май 15, 2024

The outer membrane (OM) of didermic gram-negative bacteria is essential for growth, maintenance cellular integrity, and innate resistance to many antimicrobials. Its asymmetric lipid distribution, with phospholipids in the inner leaflet lipopolysaccharides (LPS) leaflet, required these functions. Lpt proteins form a transenvelope bridge that transports newly synthesized LPS from (IM) OM, but how bulk are transported between membranes poorly understood. Recently, three members AsmA-like protein family, TamB, YhdP, YdbH, were shown be functionally redundant proposed transport IM OM

Язык: Английский

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Biogenesis of Rab14-positive endosome buds at Golgi–endosome contacts by the RhoBTB3–SHIP164–Vps26B complex

Cell Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Апрель 2, 2024

Abstract Early endosomes (EEs) are crucial in cargo sorting within vesicular trafficking. While cargoes destined for degradation retained EEs and eventually transported to lysosomes, recycled the plasma membrane (PM) or Golgi undergo segregation into specialized structures known as EE buds during sorting. Despite this significance, molecular basis of expansion bud formation has been poorly understood. In study, we identify a protein complex comprising SHIP164, an ATPase RhoBTB3, retromer subunit Vps26B, which promotes at Golgi–EE contacts. Our findings reveal that Vps26B acts novel Rab14 effector, activity regulates association SHIP164 with EEs. Depletion leads enlarged + without buds, phenotype rescued by wild-type but not lipid transfer-defective mutants. Suppression RhoBTB3 mirrors effects depletion. Together, propose transport-dependent pathway mediated RhoBTB3–SHIP164–Vps26B contacts, is essential budding.

Язык: Английский

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Erythroid Differentiation Dependent Interaction of VPS13A with XK at the Plasma Membrane of K562 Cells

Contact, Год журнала: 2023, Номер 6

Опубликована: Янв. 1, 2023

Mutations of the bridge-like lipid transport protein VPS13A and scramblase XK result in Chorea Acanthocytosis (ChAc) McLeod syndrome (MLS), respectively, two similar conditions involving neurodegeneration deformed erythrocytes (acanthocytes). binds XK, suggesting a model which forms bridge between endoplasmic reticulum (ER) plasma membrane (PM), where resides. However, studies HeLa COS7 cells showed that this localizes primarily at contacts ER with mitochondria. Overexpression these redistributed to biosynthetic pool but not PM-localized XK. Colocalization PM was only observed if overexpressed harbored mutations disengaged its VPS13A-binding site from an intramolecular interaction. As acanthocytosis phenotype ChAc MLS suggests role proteins erythroid lineage, we explored their localization K562 cells, differentiate into erythroblasts upon hemin addition. When tagged hemin-treated robust formation ER-PM positive for abolished KO cells. were seldom undifferentiated despite presence concentrations those after differentiation. These findings reveal interaction requires permissive state depends cell type and/or functional cell.

Язык: Английский

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Neurodegenerative and Neurodevelopmental Roles for Bulk Lipid Transporters VPS13A and BLTP2

Movement Disorders, Год журнала: 2025, Номер unknown

Опубликована: Март 28, 2025

Abstract Background Bridge‐like lipid transfer proteins (BLTPs) mediate bulk transport at membrane contact sites. Mutations in BLTPs are linked to both early‐onset neurodevelopmental and later‐onset neurodegenerative diseases, including movement disorders. The tissue specificity temporal requirements of disease pathogenesis remain poorly understood. Objective objective this study was determine tissue‐specific aging‐dependent roles for VPS13A BLTP2 using Drosophila models. Methods We generated knockdowns the ortholog ( Vps13 ) hobbit neurons muscles . analyzed age‐dependent locomotor behavior, neurodegeneration, synapse development function. Results Neuron‐specific loss caused neurodegeneration followed by deficits reduced lifespan, whereas muscle‐specific affected only lifespan. In contrast, neuronal resulted severe defects without muscle impaired synaptogenesis neurotransmission neuromuscular junction. Conclusions maintains survival, orchestrates synaptic development. phenotypic BLTP function provides mechanistic insights into distinct trajectories BLTP‐associated © 2025 Author(s). Movement Disorders published Wiley Periodicals LLC on behalf International Parkinson Disorder Society.

Язык: Английский

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A Possible Role of VPS13B in the Formation of Golgi-Lipid Droplet Contacts Associating with the ER

Contact, Год журнала: 2023, Номер 6

Опубликована: Янв. 1, 2023

While the physical interactions between Golgi apparatus (Golgi) and lipid droplets (LDs) have been suggested through system-level imaging, Golgi-LD membrane contact sites (MCSs) remain largely uncharacterized. Here, we show evidence to support existence of MCSs in HEK293 cells. We further suggest that vacuolar protein sorting-associated 13B (VPS13B) localizes promotes formation contacts upon oleic acid (OA) stimulation using 3D high-resolution microscopy. Depletion VPS13B moderately affects OA treatment addition fragmentation Golgi. Although cellular functions VPS13B-mediated are still elusive, these findings may provide a new insight into related diseases caused by loss-of-function mutations VPS13B.

Язык: Английский

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