A conserved megaprotein-based molecular bridge critical for lipid trafficking and cold resilience DOI Creative Commons

Changnan Wang,

Bingying Wang, Taruna Pandey

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 10, 2022

Cells adapt to cold by increasing levels of unsaturated phospholipids and membrane fluidity through conserved homeostatic mechanisms. Here we report an exceptionally large evolutionarily protein LPD-3 in C. elegans that mediates lipid trafficking confer resilience. We identify lpd-3 mutants a mutagenesis screen for genetic suppressors the desaturase FAT-7. bridges endoplasmic reticulum (ER) plasma membranes (PM), forming structurally predicted hydrophobic tunnel trafficking. exhibit abnormal phospholipid distribution, diminished FAT-7 abundance, organismic vulnerability cold, are rescued Lecithin comprising phospholipids. Deficient homologues Zebrafish mammalian cells cause defects similar those observed elegans. As mutations BLTP1, human orthologue lpd-3, Alkuraya-Kucinskas syndrome, family proteins may serve as highway critical ER-associated non-vesicular resilience stress eukaryotic cells.

Language: Английский

Mitochondria at the crossroads of health and disease DOI Creative Commons
Anu Suomalainen, Jodi Nunnari

Cell, Journal Year: 2024, Volume and Issue: 187(11), P. 2601 - 2627

Published: May 1, 2024

Mitochondria reside at the crossroads of catabolic and anabolic metabolism—the essence life. How their structure function are dynamically tuned in response to tissue-specific needs for energy, growth repair, renewal is being increasingly understood. respond intrinsic extrinsic stresses can alter cell organismal by inducing metabolic signaling within cells distal tissues. Here, we review how centrality mitochondrial functions manifests health a broad spectrum diseases aging.

Language: Английский

Citations

110
ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling DOI Creative Commons
William Hancock‐Cerutti, Zheng Wu, Peng Xu

et al.

The Journal of Cell Biology, Journal Year: 2022, Volume and Issue: 221(7)

Published: June 3, 2022

Mutations in VPS13C cause early-onset, autosomal recessive Parkinson’s disease (PD). We have established that encodes a lipid transfer protein localized to contact sites between the ER and late endosomes/lysosomes. In current study, we demonstrate depleting HeLa cells causes an accumulation of lysosomes with altered profile, including di-22:6-BMP, biomarker PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. addition, DNA-sensing cGAS-STING pathway, which was recently implicated PD pathogenesis, is activated these cells. This activation results from combination elevated mitochondrial DNA cytosol defect degradation STING, lysosome-dependent process. These suggest link ER-lysosome innate immune model human cell line place pathways relevant pathogenesis.

Language: Английский

Citations

72
ATG9 vesicles comprise the seed membrane of mammalian autophagosomes DOI Creative Commons
Taryn J. Olivas, Yumei Wu, Shenliang Yu

et al.

The Journal of Cell Biology, Journal Year: 2023, Volume and Issue: 222(7)

Published: April 28, 2023

As the autophagosome forms, its membrane surface area expands rapidly, while volume is kept low. Protein-mediated transfer of lipids from another organelle to likely drives this expansion, but as these are only introduced into cytoplasmic-facing leaflet organelle, full growth also requires lipid scramblase activity. ATG9 harbors activity and essential formation; however, whether integrated mammalian autophagosomes remains unclear. Here we show that in absence transport, vesicles already competent collect proteins found on mature autophagosomes, including LC3-II. Further, use styrene-maleic acid particles reveal nanoscale organization protein LC3-II membranes; each fully expanding autophagosomes. The ratios two at different stages maturation demonstrate not continuously integrated, rather present seed become diluted membrane.

Language: Английский

Citations

60
RBG Motif Bridge-Like Lipid Transport Proteins: Structure, Functions, and Open Questions DOI Creative Commons
Michael G. Hanna, Andrés Guillén-Samander, Pietro De Camilli

et al.

Annual Review of Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 39(1), P. 409 - 434

Published: July 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.

Language: Английский

Citations

54
Multiple interactions mediate the localization of BLTP2 at ER-PM contacts to control plasma membrane dynamics DOI Creative Commons
Anbang Dai, Peng Xu, Chase Amos

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

Summary BLTP2/KIAA0100, a bridge-like lipid transfer protein, was reported to localize at contacts of the endoplasmic reticulum (ER) with either plasma membrane (PM) or recycling tubular endosomes depending on cell type. Our findings suggest that mediating bulk transport between ER and PM is key function this protein as BLTP2 tethers only after they become continuous it also macropinosomes in process fusing PM. We further identify interactions underlying binding PM, including phosphoinositides, adaptor proteins FAM102A FAM102B, N-BAR domain membrane-connected tubules. The absence results accumulation intracellular vacuoles, many which are connected membrane, pointing role control dynamics.

Language: Английский

Citations

2
In situ architecture of the lipid transport protein VPS13C at ER–lysosome membrane contacts DOI Creative Commons
Shujun Cai, Yumei Wu, Andrés Guillén-Samander

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(29)

Published: July 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.

Language: Английский

Citations

62
Structural and biochemical insights into lipid transport by VPS13 proteins DOI Creative Commons
Jyoti Adlakha, Zhouping Hong, Peiqi Li

et al.

The Journal of Cell Biology, Journal Year: 2022, Volume and Issue: 221(5)

Published: March 31, 2022

VPS13 proteins are proposed to function at contact sites between organelles as bridges for lipids move directionally and in bulk organellar membranes. VPS13s anchored membranes via interactions with receptors, including both peripheral integral membrane proteins. Here we present the crystal structure of adaptor binding domain (VAB) complexed a Pro-X-Pro peptide recognition motif one such receptor, protein Mcp1p, show biochemically that other motifs bind VAB same site. We further demonstrate Mcp1p another interacts directly human VPS13A, XK, scramblases. This finding supports an emerging paradigm partnership lipid transport Scramblases can re-equilibrate leaflets removed from or inserted into cytosolic leaflet donor acceptor organelles, respectively, course protein-mediated transport.

Language: Английский

Citations

54
A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane DOI Creative Commons
Andrés Guillén-Samander, Yumei Wu, S. Sebastian Pineda

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(35)

Published: Aug. 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.

Language: Английский

Citations

53
A possible role for VPS13-family proteins in bulk lipid transfer, membrane expansion and organelle biogenesis DOI Creative Commons
Thomas J. Melia, Karin M. Reinisch

Journal of Cell Science, Journal Year: 2022, Volume and Issue: 135(5)

Published: March 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.

Language: Английский

Citations

51
Vps13-like proteins provide phosphatidylethanolamine for GPI anchor synthesis in the ER DOI Creative Commons

Alexandre Toulmay,

Fawn B. Whittle,

Jerry Yang

et al.

The Journal of Cell Biology, Journal Year: 2022, Volume and Issue: 221(3)

Published: Jan. 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

Language: Английский

Citations

48