Touché! STARD3 and STARD3NL tether the ER to endosomes

2016 ◽  
Vol 44 (2) ◽  
pp. 493-498 ◽  
Author(s):  
Léa P. Wilhelm ◽  
Catherine Tomasetto ◽  
Fabien Alpy
Keyword(s):  
Lipid Transfer Protein ◽  
Regulatory Protein ◽  
Direct Interaction ◽  
Lipid Transfer ◽  
Membrane Contact Sites ◽  
Late Endosomes ◽  
Metabolite Exchange ◽  
Membrane Contact ◽  
Domain 3 ◽  
Steroidogenic Acute Regulatory

Membrane contact sites (MCSs) are subcellular regions where the membranes of distinct organelles come into close apposition. These specialized areas of the cell, which are involved in inter-organelle metabolite exchange, are scaffolded by specific complexes. STARD3 [StAR (steroidogenic acute regulatory protein)-related lipid transfer domain-3] and its close paralogue STARD3NL (STARD3 N-terminal like) are involved in the formation of contacts between late-endosomes and the endoplasmic reticulum (ER). The lipid transfer protein (LTP) STARD3 and STARD3NL, which are both anchored on the limiting membrane of late endosomes (LEs), interact with ER-anchored VAP [VAMP (vesicle-associated membrane protein)-associated protein] (VAP-A and VAP-B) proteins. This direct interaction allows ER–endosome contact formation. STARD3 or STARD3NL-mediated ER–endosome contacts, which affect endosome dynamics, are believed to be involved in cholesterol transport.

scholarly journals Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells

2019 ◽  
Vol 77 (14) ◽  
pp. 2839-2857 ◽  
Author(s):  
Elsa Meneses-Salas ◽  
Ana García-Melero ◽  
Kristiina Kanerva ◽  
Patricia Blanco-Muñoz ◽  
Frederic Morales-Paytuvi ◽  
...  
Keyword(s):  
Late Endosome ◽  
Dependent Manner ◽  
Lipid Transfer ◽  
Cholesterol Accumulation ◽  
Membrane Contact Sites ◽  
Late Endosomes ◽  
Membrane Contact ◽  
Domain 3 ◽  
Niemann Pick ◽  
Mutant Cells

Abstract Cholesterol accumulation in late endosomes is a prevailing phenotype of Niemann-Pick type C1 (NPC1) mutant cells. Likewise, annexin A6 (AnxA6) overexpression induces a phenotype reminiscent of NPC1 mutant cells. Here, we demonstrate that this cellular cholesterol imbalance is due to AnxA6 promoting Rab7 inactivation via TBC1D15, a Rab7-GAP. In NPC1 mutant cells, AnxA6 depletion and eventual Rab7 activation was associated with peripheral distribution and increased mobility of late endosomes. This was accompanied by an enhanced lipid accumulation in lipid droplets in an acyl-CoA:cholesterol acyltransferase (ACAT)-dependent manner. Moreover, in AnxA6-deficient NPC1 mutant cells, Rab7-mediated rescue of late endosome-cholesterol export required the StAR-related lipid transfer domain-3 (StARD3) protein. Electron microscopy revealed a significant increase of membrane contact sites (MCS) between late endosomes and ER in NPC1 mutant cells lacking AnxA6, suggesting late endosome-cholesterol transfer to the ER via Rab7 and StARD3-dependent MCS formation. This study identifies AnxA6 as a novel gatekeeper that controls cellular distribution of late endosome-cholesterol via regulation of a Rab7-GAP and MCS formation.

scholarly journals STARD3: A Swiss Army Knife for Intracellular Cholesterol Transport

Contact ◽  
2019 ◽  
Vol 2 ◽  
pp. 251525641985673
Author(s):  
Laetitia Voilquin ◽  
Massimo Lodi ◽  
Thomas Di Mattia ◽  
Marie-Pierre Chenard ◽  
Carole Mathelin ◽  
...  
Keyword(s):  
Lipid Transfer Protein ◽  
Current Knowledge ◽  
Cholesterol Transport ◽  
Lipid Transfer ◽  
Complex Process ◽  
Associated Proteins ◽  
Membrane Contacts ◽  
Intracellular Cholesterol ◽  
Domain 3 ◽  
Steroidogenic Acute Regulatory

Intracellular cholesterol transport is a complex process involving specific carrier proteins. Cholesterol-binding proteins, such as the lipid transfer protein steroidogenic acute regulatory-related lipid transfer domain-3 (STARD3), are implicated in cholesterol movements between organelles. Indeed, STARD3 modulates intracellular cholesterol allocation by reducing it from the plasma membrane and favoring its passage from the endoplasmic reticulum (ER) to endosomes, where the protein is localized. STARD3 interacts with ER-anchored partners, notably vesicle-associated membrane protein-associated proteins (VAP-A and VAP-B) and motile sperm domain-containing 2 (MOSPD2), to create ER–endosome membrane contacts. Mechanistic studies showed that at ER–endosome contacts, STARD3 and VAP proteins build a molecular machine able to rapidly transfer cholesterol. This review presents the current knowledge on the molecular and cellular function of STARD3 in intracellular cholesterol traffic.

scholarly journals Nanoscale architecture of a VAP-A-OSBP tethering complex at membrane contact sites

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Eugenio de la Mora ◽  
Manuela Dezi ◽  
Aurélie Di Cicco ◽  
Joëlle Bigay ◽  
Romain Gautier ◽  
...  
Keyword(s):  
Lipid Transfer Protein ◽  
Structural Information ◽  
Transmembrane Protein ◽  
Lipid Transfer ◽  
Oxysterol Binding Protein ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
Golgi Network

AbstractMembrane contact sites (MCS) are subcellular regions where two organelles appose their membranes to exchange small molecules, including lipids. Structural information on how proteins form MCS is scarce. We designed an in vitro MCS with two membranes and a pair of tethering proteins suitable for cryo-tomography analysis. It includes VAP-A, an ER transmembrane protein interacting with a myriad of cytosolic proteins, and oxysterol-binding protein (OSBP), a lipid transfer protein that transports cholesterol from the ER to the trans Golgi network. We show that VAP-A is a highly flexible protein, allowing formation of MCS of variable intermembrane distance. The tethering part of OSBP contains a central, dimeric, and helical T-shape region. We propose that the molecular flexibility of VAP-A enables the recruitment of partners of different sizes within MCS of adjustable thickness, whereas the T geometry of the OSBP dimer facilitates the movement of the two lipid-transfer domains between membranes.

scholarly journals Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex

2019 ◽  
Author(s):  
RS D’Souza ◽  
JY Lim ◽  
A Turgut ◽  
K Servage ◽  
J Zhang ◽  
...  
Keyword(s):  
Cell Migration ◽  
Lipid Transfer Protein ◽  
Calcium Influx ◽  
Focal Adhesions ◽  
Lipid Transfer ◽  
Transfer Protein ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Lipid Exchange ◽  
Membrane Contact

AbstractCoordinated assembly and disassembly of integrin-mediated focal adhesions (FAs) is essential for cell migration. Many studies have shown that FA disassembly requires Ca2+ influx, however our understanding of this process remains incomplete. Here we show that Ca2+ influx via STIM1/Orai1 calcium channels, which cluster near FAs, leads to activation of the GTPase Arf5 via the Ca2+-activated GEF IQSec1, and that both IQSec1 and Arf5 activation are essential for adhesion disassembly. We further show that IQSec1 forms a complex with the lipid transfer protein ORP3, and that Ca2+ influx triggers PKC-dependent translocation of this complex to ER/plasma membrane contact sites adjacent to FAs. In addition to allosterically activating IQSec1, ORP3 also extracts PI4P from the PM, in exchange for phosphatidylcholine. ORP3-mediated lipid exchange is also important for FA turnover. Together, these findings identify a new pathway that links calcium influx to FA turnover during cell migration.

scholarly journals Topological organisation of the phosphatidylinositol 4,5-bisphosphate–phospholipase C resynthesis cycle: PITPs bridge the ER–PM gap

2016 ◽  
Vol 473 (23) ◽  
pp. 4289-4310 ◽  
Author(s):  
Shamshad Cockcroft ◽  
Padinjat Raghu
Keyword(s):  
Phospholipase C ◽  
Mammalian Cells ◽  
Lipid Transfer Protein ◽  
Biochemical Properties ◽  
Lipid Transfer ◽  
Membrane Contact Sites ◽  
Lipid Kinases ◽  
Membrane Compartments ◽  
Membrane Contact ◽  
Reciprocal Transfer

Phospholipase C (PLC) is a receptor-regulated enzyme that hydrolyses phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) at the plasma membrane (PM) triggering three biochemical consequences, the generation of soluble inositol 1,4,5-trisphosphate (IP3), membrane-associated diacylglycerol (DG) and the consumption of PM PI(4,5)P2. Each of these three signals triggers multiple molecular processes impacting key cellular properties. The activation of PLC also triggers a sequence of biochemical reactions, collectively referred to as the PI(4,5)P2 cycle that culminates in the resynthesis of this lipid. The biochemical intermediates of this cycle and the enzymes that mediate these reactions are topologically distributed across two membrane compartments, the PM and the endoplasmic reticulum (ER). At the PM, the DG formed during PLC activation is rapidly converted into phosphatidic acid (PA) that needs to be transported to the ER where the machinery for its conversion into PI is localised. Conversely, PI from the ER needs to be rapidly transferred to the PM where it can be phosphorylated by lipid kinases to regenerate PI(4,5)P2. Thus, two lipid transport steps between membrane compartments through the cytosol are required for the replenishment of PI(4,5)P2 at the PM. Here, we review the topological constraints in the PI(4,5)P2 cycle and current understanding how these constraints are overcome during PLC signalling. In particular, we discuss the role of lipid transfer proteins in this process. Recent findings on the biochemical properties of a membrane-associated lipid transfer protein of the PITP family, PITPNM proteins (alternative name RdgBα/Nir proteins) that localise to membrane contact sites are discussed. Studies in both Drosophila and mammalian cells converge to provide a resolution to the conundrum of reciprocal transfer of PA and PI during PLC signalling.

MLN64 and MENTHO, two mediators of endosomal cholesterol transport

2006 ◽  
Vol 34 (3) ◽  
pp. 343-345 ◽  
Author(s):  
F. Alpy ◽  
C. Tomasetto
Keyword(s):  
Metastatic Lymph Node ◽  
Regulatory Protein ◽  
Steroidogenic Acute Regulatory Protein ◽  
Cholesterol Transport ◽  
Lipid Transfer ◽  
Transmembrane Helices ◽  
Late Endosomes ◽  
Start Domain ◽  
Steroidogenic Acute Regulatory

MLN64 (metastatic lymph node 64) and MENTHO (MLN64 N-terminal homologue) are two late-endosomal proteins that share a conserved region of four transmembrane helices with three short intervening loops called the MENTAL domain (MLN64 N-terminal domain). This domain mediates MLN64 and MENTHO homo- and hetero-interactions, targets both proteins to late endosomes and binds cholesterol in vivo. In addition to the MENTAL domain, MLN64 contains a cholesterol-specific START domain [StAR (steroidogenic acute regulatory protein)-related lipid transfer domain]. The START domain is a protein module of approx. 210 residues that binds lipids, including sterols, and is present in 15 distinct proteins in mammals. Thus MLN64 and MENTHO define discrete cholesterol-containing subdomains within the membrane of late endosomes where they may function in cholesterol transport. The MENTAL domain might serve to maintain cholesterol at the membrane of late endosomes prior to its shuttle to cytoplasmic acceptor(s) through the START domain.

scholarly journals VPS13: A lipid transfer protein making contacts at multiple cellular locations

2018 ◽  
Vol 217 (10) ◽  
pp. 3322-3324 ◽  
Author(s):  
Mingming Gao ◽  
Hongyuan Yang
Keyword(s):  
Lipid Transfer Protein ◽  
Lipid Transfer ◽  
Transfer Protein ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Cell Biol ◽  
Evolutionarily Conserved ◽  
Membrane Contact

The evolutionarily conserved VPS13 proteins localize to multiple membrane contact sites though their function and regulation has been elusive. Bean et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201804111) found that competitive adaptors control the different localizations of yeast Vps13p, while Kumar et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201807019) provide biochemical and structural evidence for VPS13 proteins in the nonvesicular transport of phospholipids.

scholarly journals Nanoscale architecture of a VAP-A-OSBP tethering complex at membrane contact site

2020 ◽  
Author(s):  
Eugenio de la Mora ◽  
Manuela Dezi ◽  
Aurélie Di Cicco ◽  
Joëlle Bigay ◽  
Romain Gautier ◽  
...  
Keyword(s):  
Lipid Transfer Protein ◽  
Structural Information ◽  
Transmembrane Protein ◽  
Lipid Transfer ◽  
Oxysterol Binding Protein ◽  
Transfer Protein ◽  
Membrane Contact Sites ◽  
Membrane Contact ◽  
Golgi Network

SummaryMembrane contact sites (MCS) are subcellular regions where two organelles appose their membranes to exchange small molecules, including lipids. Structural information on how proteins form MCS is scarce. We designed an in vitro MCS with two membranes and a pair of tethering proteins suitable for cryo-tomography analysis. It includes VAP-A, an ER transmembrane protein interacting with a myriad of cytosolic proteins, and oxysterol-binding protein (OSBP), a lipid transfer protein that transports cholesterol from the ER to the trans Golgi network. We show that VAP-A is a highly flexible protein, allowing formation of MCS of variable intermembrane distance. The tethering part of OSBP contains a central, dimeric, and helical T-shape region. We propose that the molecular flexibility of VAP-A enables the recruitment of partners of different sizes within MCS of adjustable thickness, whereas the T geometry of the OSBP dimer facilitates the movement of the two lipid-transfer domains between membranes.

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