Bridge-like lipid transfer protein 3A (BLTP3A) is associated with membranes of the late endocytic pathway and is an effector of CASM

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

Published: Sept. 28, 2024

Recent studies have identified a family of rod-shaped proteins which includes VPS13 and ATG2 are thought to mediate unidirectional lipid transport at intracellular membrane contacts by bridge-like mechanism. Here, we show that one such protein, BLTP3A/UHRF1BP1, associates with VAMP7-positive vesicles via its C-terminal region anchors them lysosomes the binding chorein domain containing N-terminal Rab7. Upon damage lysosomal membranes resulting mATG8 recruitment their surface CASM, BLTP3A first dissociates from but then reassociates an interaction LIR motif mATG8. Such is mutually exclusive leaves domain, i.e. proposed entry site lipids into this proteins, available for another membrane, possibly ER. Our findings reveal effector potentially as part mechanism help repair or minimize lysosome delivering lipids.

Language: Английский

---

In silico modeling human VPS13 proteins associated with donor and target membranes suggests lipid transfer mechanisms

Proteins Structure Function and Bioinformatics, Journal Year: 2022, Volume and Issue: 91(4), P. 439 - 455

Published: Nov. 21, 2022

Abstract The VPS13 protein family constitutes a novel class of bridge‐like lipid transferases. Autosomal recessive inheritance mutations in genes is associated with the development neurodegenerative diseases humans. Bioinformatic approaches previously recognized domain architecture these proteins. In this study, we model first ever full‐length structures four human homologs VPS13A, VPS13B, VPS13C, and VPS13D association membranes, to investigate their transfer ability potential structural membrane leaflets. We analyze evolutionary conservation physicochemical properties proteins, focusing on conserved C‐terminal amphipathic helices that disturb organelle surfaces that, adjoined, resemble traditional Venetian gondola. gondola domains share significant homology droplet surface‐binding introduce silico protein‐membrane models displaying mode donor target present action for protein‐mediated transfer.

Language: Английский

---

Neurodegenerative and Neurodevelopmental Roles for Bulk Lipid Transporters VPS13A and BLTP2

Movement Disorders, Journal Year: 2025, Volume and Issue: unknown

Published: March 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.

Language: Английский

---

BLTP2 orchestrates lysobisphosphatidic acid synthesis and exosome biogenesis via SCAMP3-dependent ER contacts in tumorigenesis

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

---

Structural basis of lipid transfer by a bridge-like lipid-transfer protein

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

Published: April 23, 2025

Language: Английский

---

VPS13 and bridge-like lipid transporters, mechanisms, and mysteries

Frontiers in Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: April 28, 2025

Bridge-like lipid transporters (BLTPs) have recently been revealed as key regulators of intraorganellar trafficking, with their loss being associated defective synaptic signalling and congenital neurological diseases. This group consists five protein subfamilies [BLTP1-3, autophagy-related 2 (ATG2), vacuolar sorting 13 (VPS13)], which mediate minimally selective transfer between cellular membranes. Deceptively simple in both structure presumed function, this review addresses open questions to how bridge-like work, the functional consequences bulk on signalling, summarises some recent studies that shed light surprising level regulation specificity found family transporters.

Language: Английский

---

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

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

Published: Jan. 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.

Language: Английский

---

Bridge-Like Lipid Transfer Proteins (BLTPs) in C. elegans: From Genetics to Structures and Functions

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

Published: Jan. 1, 2023

In eukaryotic cells, lipid transfer can occur at membrane contact sites (MCS) to facilitate the exchange of various lipids between two adjacent cellular organelle membranes. Lipid proteins (LTPs), including shuttle LTP or bridge-like (BLTP), transport MCS and are critical for diverse processes, metabolism, trafficking, cell signaling. BLTPs (BLTP1-5, ATG2 VPS13 family proteins) contain lipid-accommodating hydrophobic repeating β-groove (RBG) domains that allow bulk through MCS. Compared with vesicular LTP, have been only recently identified. Their functions regulatory mechanisms currently being unraveled in model organisms by approaches. this review, we summarize genetics, structural features, biological BLTP genetically tractable organism C. elegans. We discuss our recent studies findings on elegans LPD-3, a prototypical megaprotein ortholog BLTP1, identified evolutionarily conserved multicellular human cells. also highlight areas future research using complementary systems Given emerging links several diseases, Parkinson's disease Alkuraya-Kučinskas syndrome, discovering roles their regulation action should contribute new advances basic biology potential therapeutic development related disorders.

Language: Английский

---

Neurodegenerative and neurodevelopmental roles for bulk lipid transporters VPS13A and BLTP2 in movement disorders

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

Published: Dec. 30, 2024

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. Objectives To determine the age-of-onset tissue-specific roles VPS13A BLTP2 disorder using Drosophila models. Methods We generated knockdowns ortholog ( Vps13 ) hobbit neurons muscles . analyzed age-dependent locomotor behavior, neurodegeneration, synapse development function. Results Neuron-specific loss caused neurodegeneration followed by age- onset deficits reduced lifespan, while muscle-specific affected only revealing myopathy as independent comorbidities disease. In contrast, neuronal resulted severe defects without muscle impaired synaptogenesis neurotransmission neuromuscular junction (NMJ). Conclusions maintains survival, orchestrates synaptic development. function does not play a role defects. phenotypic BLTP provides mechanistic insights into distinct trajectories for BLTP-associated

Language: Английский

---

VPS13B is localized at the cis-trans Golgi complex interface and is a functional partner of FAM177A1

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 18, 2023

Mutations in VPS13B, a member of protein family implicated bulk lipid transport between adjacent membranes, cause Cohen syndrome. VPS13B is known to be concentrated the Golgi complex, but its precise location within this organelle and thus site(s) where it achieves remains unclear. Here we show that localized at interface cis trans sub-compartments complex re-formation after Brefeldin A (BFA) induced disruption delayed

Language: Английский

---