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

VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites DOI Creative Commons
Mélody Subra, Manuela Dezi, Joëlle Bigay

et al.

Developmental Cell, Journal Year: 2023, Volume and Issue: 58(2), P. 121 - 138.e9

Published: Jan. 1, 2023

Language: Английский

Citations

25
Mitochondrial membrane lipids in the regulation of bioenergetic flux DOI Creative Commons

Stephen Thomas Decker,

Katsuhiko Funai

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(9), P. 1963 - 1978

Published: Aug. 23, 2024

SummaryOxidative phosphorylation (OXPHOS) occurs through and across the inner mitochondrial membrane (IMM). Mitochondrial membranes contain a distinct lipid composition, aided by biosynthetic machinery localized in IMM class-specific transporters that limit traffic out of mitochondria. This unique composition appears to be essential for functions mitochondria, particularly OXPHOS, its effects on direct lipid-to-protein interactions, properties, cristae ultrastructure. review highlights biological significance lipids, with particular spotlight role lipids bioenergetics. We describe pathways biosynthesis provide evidence their roles physiology, implications human disease, mechanisms which they regulate

Language: Английский

Citations

15
Lysosome damage triggers acute formation of ER to lysosomes membrane tethers mediated by the bridge-like lipid transport protein VPS13C DOI Open Access
Xinbo Wang, Peng Xu, Amanda Bentley‐DeSousa

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 8, 2024

Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease (PD). Here we show that VPS13C, bridge-like lipid transport protein and PD gene, sensor of stress/damage. Upon membrane perturbation, VPS13C rapidly relocates from the cytosol surface lysosomes where it tethers their membranes ER. This recruitment depends Rab7 requires signal at damaged releases an inhibited state which hinders access its VAB domain lysosome-bound Rab7. While another protein, LRRK2, also recruited stressed/damaged lysosomes, occurs much later stages by different mechanisms. Given VPS13 proteins bulk transport, these findings suggest delivery part early protective response damage.

Language: Английский

Citations

14
The bridge-like lipid transport protein VPS13C/PARK23 mediates ER–lysosome contacts following lysosome damage DOI Creative Commons

X.F. Wang,

Peng Xu, Amanda Bentley‐DeSousa

et al.

Nature Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 10, 2025

Language: Английский

Citations

1
Requirement of Xk and Vps13a for the P2X7-mediated phospholipid scrambling and cell lysis in mouse T cells DOI Creative Commons
Yuta Ryoden, Katsumori Segawa, Shigekazu Nagata

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(7)

Published: Feb. 9, 2022

A high extracellular adenosine triphosphate (ATP) concentration rapidly and reversibly exposes phosphatidylserine (PtdSer) in T cells by binding to the P2X7 receptor, which ultimately leads necrosis. Using mouse cell transformants expressing P2X7, we herein performed CRISPR/Cas9 screening for molecules responsible P2X7-mediated PtdSer exposure. In addition Eros, is required localization of plasma membrane, this identified Xk Vps13a as essential components process. present at its paralogue, Xkr8, functions a phospholipid scramblase. lipid transporter cytoplasm. Blue-native polyacrylamide gel electrophoresis indicated that interacted membrane. null mutation or blocked exposure, internalization phosphatidylcholine, cytolysis. formed complex splenic cells, was crucial ATP-induced exposure cytolysis CD25+CD4+ cells. XK VPS13A are McLeod syndrome chorea-acanthocytosis, both characterized progressive movement disorder cognitive behavior changes. Our results suggest scrambling activity mediated maintaining homeostasis immune nerve systems.

Language: Английский

Citations

37
Sequence Analysis and Structural Predictions of Lipid Transfer Bridges in the Repeating Beta Groove (RBG) Superfamily Reveal Past and Present Domain Variations Affecting Form, Function and Interactions of VPS13, ATG2, SHIP164, Hobbit and Tweek DOI Creative Commons
Tim P. Levine

Contact, Journal Year: 2022, Volume and Issue: 5, P. 251525642211343 - 251525642211343

Published: Jan. 1, 2022

Lipid transfer between organelles requires proteins that shield the hydrophobic portions of lipids as they cross cytoplasm. In last decade a new structural form lipid protein (LTP) has been found: long grooves made beta-sheet bridge at membrane contact sites. Eukaryotes have five families bridge-like LTPs: VPS13, ATG2, SHIP164, Hobbit and Tweek. These are unified into single superfamily through their bridges being composed just one domain, called repeating beta groove (RBG) which builds rod shaped multimers with hydrophobic-lined hydrophilic exterior. Here, sequences predicted structures RBG were analyzed in depth. Phylogenetics showed eukaryotic common ancestor contained all proteins, duplicated VPS13s. The current set appears to arisen even earlier ancestors from shorter forms 4 domains. extreme ends most amphipathic helices might be an adaptation for direct or indirect bilayer interaction, although this yet tested. exception is C-terminus instead coiled-coil. Finally, exterior surfaces shown conserved residues along length, indicating sites partner interactions almost unknown. findings can inform future cell biological biochemical experiments.

Language: Английский

Citations

33
Interaction between VPS13A and the XK scramblase is important for VPS13A function in humans DOI Open Access
Jae-Sook Park,

Yiying Hu,

Nancy M. Hollingsworth

et al.

Journal of Cell Science, Journal Year: 2022, Volume and Issue: 135(17)

Published: Aug. 11, 2022

VPS13 family proteins form conduits between the membranes of different organelles through which lipids are transferred. In humans, there four paralogs, and mutations in genes encoding each them associated with inherited disorders. contain multiple conserved domains. The Vps13 adaptor-binding (VAB) domain binds to adaptor that recruit specific membrane contact sites. This work demonstrates importance a VPS13A function. pleckstrin homology (PH) at C-terminal region is required complex XK scramblase for co-localization within cell. Alphafold modeling was used predict an interaction surface XK. Mutations this disrupt both formation two proteins. Mutant alleles found patients disease truncate PH domain. phenotypic similarities McLeod syndrome caused by XK, respectively, argue loss VPS13A-XK basis diseases.

Language: Английский

Citations

29
Bacterial AsmA-Like Proteins: Bridging the Gap in Intermembrane Phospholipid Transport DOI Creative Commons
Sujeet Kumar, Natividad Ruiz

Contact, Journal Year: 2023, Volume and Issue: 6

Published: Jan. 1, 2023

In eukaryotic cells, nonvesicular lipid transport between organelles is mediated by lipid-transfer proteins. Recently, a new class of these transporters has been described to facilitate the bulk inter-organelle at contact sites forming bridge-like structures with hydrophobic groove through which lipids travel. Because their predicted structure composed repeating β-groove (RBG) domains, they have named RBG protein superfamily. Early studies on proteins VPS13 and ATG2 recognized resemblance that bacterial Lpt system, transports newly synthesized lipopolysaccharides (LPS) inner outer membranes (IMs OMs) Gram-negative bacteria. didermic bacteria, IMs OMs are separated an aqueous periplasmic compartment traversed built β-jelly roll domains from several provides for LPS molecules travel across periplasm. Despite structural functional similarities AsmA-like family recently emerged as likely ancestor long sought-after transfer phospholipids IM OM. Here, we review our current understanding function proteins, mainly focusing recent led proposal mediate phospholipid OMs.

Language: Английский

Citations

17
Endoplasmic Reticulum Membrane Contact Sites, Lipid Transport, and Neurodegeneration DOI
Andrés Guillén-Samander, Pietro De Camilli

Cold Spring Harbor Perspectives in Biology, Journal Year: 2022, Volume and Issue: 15(4), P. a041257 - a041257

Published: Sept. 19, 2022

Andrés Guillén-Samander1,2 and Pietro De Camilli1,2 1Departments of Neuroscience Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration Repair, Yale University School Medicine, New Haven, Connecticut 06520, USA 2Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, Maryland 20815, Correspondence: pietro.decamilli{at}yale.edu

Language: Английский

Citations

27
SHIP164 is a chorein motif lipid transfer protein that controls endosome–Golgi membrane traffic DOI Creative Commons
Michael G. Hanna,

Patreece Suen,

Yumei Wu

et al.

The Journal of Cell Biology, Journal Year: 2022, Volume and Issue: 221(6)

Published: May 2, 2022

Cellular membranes differ in protein and lipid composition as well the protein–lipid ratio. Thus, progression of membranous organelles along traffic routes requires mechanisms to control bilayer chemistry their abundance relative proteins. The recent structural functional characterization VPS13-family proteins has suggested a mechanism through which lipids can be transferred bulk from one membrane another at contact sites, thus independently vesicular traffic. Here, we show that SHIP164 (UHRF1BP1L) shares transfer properties with these is localized on subpopulation vesicle clusters early endocytic pathway whose cargo includes cation-independent mannose-6-phosphate receptor (MPR). Loss disrupts retrograde Golgi complex. Our findings raise possibility may play role

Language: Английский

Citations

26