Who’s in control? Principles of Rab GTPase activation in endolysosomal membrane trafficking and beyond

The Journal of Cell Biology, Год журнала: 2021, Номер 220(9)

Опубликована: Авг. 12, 2021

The eukaryotic endomembrane system consists of multiple interconnected organelles. Rab GTPases are organelle-specific markers that give identity to these membranes by recruiting transport and trafficking proteins. During processes or along organelle maturation, one is replaced another, a process termed cascade, which requires at its center Rab-specific guanine nucleotide exchange factor (GEF). endolysosomal serves here as prime example for cascade. Along with endosomal the Rab5 recruits activates Rab7-specific GEF Mon1-Ccz1, resulting in Rab7 activation on endosomes subsequent fusion lysosomes. In this review, we focus current idea Mon1-Ccz1 recruitment autophagic pathway. We compare identified principles other GTPase cascades endomembranes, highlight importance regulation, evaluate context strength relevance recent developments vitro analyses understand underlying foundation biogenesis maturation.

Язык: Английский

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In situ architecture of the ER–mitochondria encounter structure

Nature, Год журнала: 2023, Номер 618(7963), С. 188 - 192

Опубликована: Май 10, 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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Insights into VPS13 properties and function reveal a new mechanism of eukaryotic lipid transport

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Год журнала: 2021, Номер 1866(10), С. 159003 - 159003

Опубликована: Июль 1, 2021

The occurrence of protein mediated lipid transfer between intracellular membranes has been known since the late 1960's. Since these early discoveries, numerous proteins responsible for such transport, which often act at membrane contact sites, have identified. Typically, they comprise a harboring module thought to shuttle back and forth two adjacent bilayers. Recently, however, studies chorein domain family, includes VPS13 ATG2, led identification novel mechanism transport organelles in eukaryotic cells by rod-like bridge with hydrophobic groove through lipids can slide. This is ideally suited bulk bilayer promote growth. Here we describe how discovery this new mechanism, summarize properties roles proteins, discuss their dysfunction may lead disease.

Язык: Английский

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ER as master regulator of membrane trafficking and organelle function

The Journal of Cell Biology, Год журнала: 2022, Номер 221(10)

Опубликована: Авг. 23, 2022

The endoplasmic reticulum (ER), which occupies a large portion of the cytoplasm, is cell’s main site for biosynthesis lipids and carbohydrate conjugates, it essential folding, assembly, biosynthetic transport secreted proteins integral membrane proteins. discovery abundant contact sites (MCSs) between ER other compartments has revealed that, in addition to its secretory functions, plays key roles regulation organelle dynamics functions. In this review, we will discuss how regulates endosomes, lysosomes, autophagosomes, mitochondria, peroxisomes, Golgi apparatus via MCSs. Such occurs lipid Ca2+ transfer also control trans dephosphorylation reactions motility, positioning, fusion, fission. diverse controls organelles MCSs manifest as master regulator biology.

Язык: Английский

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In situ architecture of the lipid transport protein VPS13C at ER–lysosome membrane contacts

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(29)

Опубликована: Июль 13, 2022

VPS13 is a eukaryotic lipid transport protein localized at membrane contact sites. Previous studies suggested that it may transfer lipids between adjacent bilayers by bridge-like mechanism. Direct evidence for this hypothesis from full-length structure and electron microscopy (EM) in situ still missing, however. Here, we have capitalized on AlphaFold predictions to complement the structural information already available about generate model of human VPS13C, Parkinson's disease-linked paralog contacts endoplasmic reticulum (ER) endo/lysosomes. Such predicts an ∼30-nm rod with hydrophobic groove extends throughout its length. We further investigated whether such can be observed ER-endo/lysosome contacts. To aim, combined genetic approaches cryo-focused ion beam (cryo-FIB) milling cryo-electron tomography (cryo-ET) examine HeLa cells overexpressing (either full length or internal truncation) along VAP, anchoring binding partner ER. Using these methods, identified rod-like densities span space separating two membranes match predicted structures either VPS13C shorter truncated mutant, thus providing bridge transport.

Язык: Английский

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

Frontiers in Cell and Developmental Biology, Год журнала: 2021, Номер 9

Опубликована: Июнь 24, 2021

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

Язык: Английский

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A possible role for VPS13-family proteins in bulk lipid transfer, membrane expansion and organelle biogenesis

Journal of Cell Science, Год журнала: 2022, Номер 135(5)

Опубликована: Март 1, 2022

At organelle-organelle contact sites, proteins have long been known to facilitate the rapid movement of lipids. Classically, this lipid transport involves extraction single lipids into a hydrophobic pocket on protein. Recently, new class transporter has described with physical characteristics that suggest these are likely function differently. They possess tracts can bind many at once and physically span entire gulf between membranes suggesting they may act as bridges bulk flow. Here, we review what learned regarding structure transporters, whose best characterized members VPS13 ATG2 proteins, their apparent coordination other lipid-mobilizing organelle membranes. We also discuss prevailing hypothesis in field, type membrane expansion through delivery lipids, well emerging hypotheses questions surrounding novel proteins.

Язык: Английский

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Vps13-like proteins provide phosphatidylethanolamine for GPI anchor synthesis in the ER

The Journal of Cell Biology, Год журнала: 2022, Номер 221(3)

Опубликована: Янв. 11, 2022

Glycosylphosphatidylinositol (GPI) is a glycolipid membrane anchor found on surface proteins in all eukaryotes. It synthesized the ER membrane. Each GPI requires three molecules of ethanolamine phosphate (P-Etn), which are derived from phosphatidylethanolamine (PE). We that efficient synthesis Saccharomyces cerevisiae Csf1; cells lacking Csf1 accumulate precursors P-Etn. Structure predictions suggest tube-forming lipid transport protein like Vps13. at contact sites between and other organelles. interacts with Mcd4, an enzyme adds P-Etn to nascent anchors, suggesting channels PE Mcd4 support biosynthesis. CSF1 has orthologues Caenorhabditis elegans (lpd-3) humans (KIAA1109/TWEEK); mutations KIAA1109 cause autosomal recessive neurodevelopmental disorder Alkuraya-Kučinskas syndrome. Knockout lpd-3 knockdown reduced GPI-anchored cells, human

Язык: Английский

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Glycerolipid Synthesis and Lipid Droplet Formation in the Endoplasmic Reticulum

Cold Spring Harbor Perspectives in Biology, Год журнала: 2022, Номер 15(5), С. a041246 - a041246

Опубликована: Сен. 12, 2022

Robert V. Farese Jr.1,2,3,4 and Tobias C. Walther1,2,3,4,5 1Department of Molecular Metabolism, Harvard T. H. Chan School Public Health, Boston, Massachusetts 02115, USA 2Department Cell Biology, Medical School, 3Broad Institute MIT, Cambridge, 02142, 4Center for Causes Prevention Cardiovascular Disease (CAP-CVD), 5Howard Hughes Correspondence: robert{at}hsph.harvard.edu, twalther{at}hsph.harvard.edu

Язык: Английский

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