BLTP2 orchestrates lysobisphosphatidic acid synthesis and exosome biogenesis via SCAMP3-dependent ER contacts in tumorigenesis DOI Creative Commons
Jingru Wang, Dongchen Li,

Yazhou Liu

et al.

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

Published: April 21, 2025

Abstract Multivesicular bodies (MVBs) contain intraluminal vesicles (ILVs) designated for degradation in lysosomes or release as exosomes cell-to-cell communication. The mechanisms governing ILV/exosome formation are not fully understood. Here, we show that the integral endoplasmic reticulum (ER) membrane protein bridge-like lipid transfer 2 (BLTP2; KIAA0100) is indispensable and secretory carrier 3 (SCAMP3) recruits BLTP2 to ER–MVB contact sites (MCSs) a Rab5-dependent manner. Our results indicate this recruitment hindered by NEDD4-mediated ubiquitination of SCAMP3. Depletion was found impede selectively diminish levels cone-shaped phospholipids, including bis(monoacylglycero)phosphate (BMP) BMP precursor phosphatidylglycerol (PG) within endosomes. knockout also hampered cell proliferation tumorigenicity, which could be restored significant extent supplementation with from wild-type cells. Since associated acute monocytic leukemia highly expressed breast cancer, our findings suggest transfers BMP/LBPA PG MVBs synthesis promotes at SCAMP3-dependent MCSs, process crucial tumorigenesis.

Language: Английский

A novel superfamily of bridge-like lipid transfer proteins DOI Creative Commons
Sarah D. Neuman, Tim P. Levine, Arash Bashirullah

et al.

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 32(11), P. 962 - 974

Published: April 28, 2022

Language: Английский

Citations

79
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
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 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

52
Phosphatidylethanolamine DOI

Mackenzie T. Primrose,

Steven M. Claypool

Trends in Endocrinology and Metabolism, Journal Year: 2024, Volume and Issue: 35(10), P. 929 - 930

Published: July 24, 2024

Language: Английский

Citations

12
A role for Vps13-mediated lipid transfer at the ER–endosome contact site in ESCRT-mediated sorting DOI Creative Commons
S. Suzuki, Matthew West, Yichen Zhang

et al.

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(4)

Published: Feb. 6, 2024

Endosomes are specialized organelles that function in the secretory and endocytic protein sorting pathways. Endocytosed cell surface receptors transporters destined for lysosomal degradation sorted into intraluminal vesicles (ILVs) at endosomes by endosomal complexes required transport (ESCRT) proteins. The (multivesicular bodies, MVBs) then fuse with lysosome. During maturation, number of ILVs increases, but size does not decrease despite consumption limiting membrane during ILV formation. Vesicle-mediated trafficking is thought to provide lipids support MVB biogenesis. However, we have uncovered an unexpected contribution a large bridge-like lipid transfer protein, Vps13, this process. Here, reveal Vps13-mediated ER–endosome contact sites ESCRT pathway. We propose Vps13 may play critical role supplying endosome, ensuring continuous ESCRT-mediated

Language: Английский

Citations

10
Systematic analysis of membrane contact sites in Saccharomyces cerevisiae uncovers modulators of cellular lipid distribution DOI Creative Commons
Inês Gomes Castro, Shawn P. Shortill, Samantha K. Dziurdzik

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Nov. 10, 2022

Actively maintained close appositions between organelle membranes, also known as contact sites, enable the efficient transfer of biomolecules cellular compartments. Several such sites have been described well their tethering machineries. Despite these advances we are still far from a comprehensive understanding function and regulation most sites. To systematically characterize site proteomes, established high-throughput screening approach in Saccharomyces cerevisiae based on co-localization imaging. We imaged split fluorescence reporters for six different several which poorly characterized, background 1165 strains expressing mCherry-tagged yeast protein that has punctate distribution (a hallmark sites), under strong TEF2 promoter. By scoring both events effects reporter size abundance, discovered over 100 new potential residents effectors yeast. Focusing newly identified residents, three homologs Vps13 Atg2 multiple These proteins share lipid transport domain, thus expanding this family transporters. Analysis another candidate, Ypr097w, now call Lec1 (Lipid-droplet Ergosterol Cortex 1), revealed previously uncharacterized dynamically shifts droplets cell cortex, plays role ergosterol cell. Overall, our analysis expands universe creates rich database to mine functions, tethers, regulators.

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

34
The Vps13-like protein BLTP2 is pro-survival and regulates phosphatidylethanolamine levels in the plasma membrane to maintain its fluidity and function DOI Creative Commons
Subhrajit Banerjee, Stephan Daetwyler, Xiaofei Bai

et al.

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

Published: Feb. 5, 2024

Lipid transport proteins (LTPs) facilitate nonvesicular lipid exchange between cellular compartments and have critical roles in homeostasis

Language: Английский

Citations

8