scholarly journals The PKD-Dependent Biogenesis of TGN-to-Plasma Membrane Transport Carriers

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1618
Author(s):  
Yuichi Wakana ◽  
Felix Campelo
Keyword(s):  
Cell Surface ◽  
Membrane Trafficking ◽  
Surface Protein ◽  
Membrane Contact Sites ◽  
Tissue Organization ◽  
Constitutive Secretion ◽  
Membrane Contact ◽  
Golgi Network ◽  
Organelle Membrane ◽  
And Control

Membrane trafficking is essential for processing and transport of proteins and lipids and to establish cell compartmentation and tissue organization. Cells respond to their needs and control the quantity and quality of protein secretion accordingly. In this review, we focus on a particular membrane trafficking route from the trans-Golgi network (TGN) to the cell surface: protein kinase D (PKD)-dependent pathway for constitutive secretion mediated by carriers of the TGN to the cell surface (CARTS). Recent findings highlight the importance of lipid signaling by organelle membrane contact sites (MCSs) in this pathway. Finally, we discuss our current understanding of multiple signaling pathways for membrane trafficking regulation mediated by PKD, G protein-coupled receptors (GPCRs), growth factors, metabolites, and mechanosensors.

scholarly journals Mammalian PITPs at the Golgi and ER-Golgi Membrane Contact Sites

Contact ◽  
2020 ◽  
Vol 3 ◽  
pp. 251525642096417
Author(s):  
Shamshad Cockcroft ◽  
Sima Lev
Keyword(s):  
Membrane Trafficking ◽  
Golgi Membrane ◽  
Intracellular Membrane ◽  
Functional Studies ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Biochemical Genetic ◽  
Membrane Contact ◽  
Intracellular Membrane Transport ◽  
Exchange Activity

Phosphatidylinositol (PI)-transfer proteins (PITPs) have been long recognized as proteins that modulate phosphoinositide levels in membranes through their intrinsic PI/PC-exchange activity. Recent studies from flies and mammals suggest that certain PITPs bind phosphatidic acid (PA) and possess PI/PA-exchange activity. Phosphoinositides and PA play critical roles in cell signaling and membrane trafficking, and numerous biochemical, genetic and functional studies have shown that PITPs regulate cellular lipid metabolism, various signaling pathways and intracellular membrane transport events. In this mini-review, we discuss the function of mammalian PITPs at the Golgi and ER-Golgi membrane contact sites (MCS) and highlight DAG (Diacylglycerol) as a central hub of PITPs functions. We describe PITPs-associated phospho-signaling network at the ER-Golgi interface, and share our perspective on future studies related to PITPs at MCSs.

scholarly journals Kv2 potassium channels form endoplasmic reticulum/plasma membrane junctions via interaction with VAPA and VAPB

2018 ◽  
Vol 115 (31) ◽  
pp. E7331-E7340 ◽  
Author(s):  
Ben Johnson ◽  
Ashley N. Leek ◽  
Laura Solé ◽  
Emily E. Maverick ◽  
Tim P. Levine ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
Membrane Trafficking ◽  
Neuronal Cultures ◽  
Physical Relationship ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Hek Cells ◽  
C Terminus ◽  
Membrane Contact

Kv2.1 exhibits two distinct forms of localization patterns on the neuronal plasma membrane: One population is freely diffusive and regulates electrical activity via voltage-dependent K+ conductance while a second one localizes to micrometer-sized clusters that contain densely packed, but nonconducting, channels. We have previously established that these clusters represent endoplasmic reticulum/plasma membrane (ER/PM) junctions that function as membrane trafficking hubs and that Kv2.1 plays a structural role in forming these membrane contact sites in both primary neuronal cultures and transfected HEK cells. Clustering and the formation of ER/PM contacts are regulated by phosphorylation within the channel C terminus, offering cells fast, dynamic control over the physical relationship between the cortical ER and PM. The present study addresses the mechanisms by which Kv2.1 and the related Kv2.2 channel interact with the ER membrane. Using proximity-based biotinylation techniques in transfected HEK cells we identified ER VAMP-associated proteins (VAPs) as potential Kv2.1 interactors. Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays. CD4 chimeras containing sequence from the Kv2.1 C terminus were used to identify a noncanonical VAP-binding motif. VAPs were first identified as proteins required for neurotransmitter release in Aplysia and are now known to be abundant scaffolding proteins involved in membrane contact site formation throughout the ER. The VAP interactome includes AKAPs, kinases, membrane trafficking machinery, and proteins regulating nonvesicular lipid transport from the ER to the PM. Therefore, the Kv2-induced VAP concentration at ER/PM contact sites is predicted to have wide-ranging effects on neuronal cell biology.

scholarly journals Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 598 ◽  
Author(s):  
Anna Picca ◽  
Riccardo Calvani ◽  
Hélio José Coelho-Junior ◽  
Francesco Landi ◽  
Roberto Bernabei ◽  
...  
Keyword(s):  
Quality Control ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Quality Control ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Age Related ◽  
Bidirectional Communication ◽  
Membrane Contact ◽  
Organelle Membrane

Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca2+ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson’s disease as a prototypical geroscience condition.

scholarly journals CARTS biogenesis requires VAP–lipid transfer protein complexes functioning at the endoplasmic reticulum–Golgi interface

2015 ◽  
Vol 26 (25) ◽  
pp. 4686-4699 ◽  
Author(s):  
Yuichi Wakana ◽  
Richika Kotake ◽  
Nanako Oyama ◽  
Motohide Murate ◽  
Toshihide Kobayashi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Protein ◽  
Cell Surface ◽  
Lipid Transfer Protein ◽  
Protein Complexes ◽  
Lipid Transfer ◽  
Trans Golgi Network ◽  
Transfer Protein ◽  
Membrane Contact Sites ◽  
Golgi Network

Vesicle-associated membrane protein–associated protein (VAP) is an endoplasmic reticulum (ER)-resident integral membrane protein that controls a nonvesicular mode of ceramide and cholesterol transfer from the ER to the Golgi complex by interacting with ceramide transfer protein and oxysterol-binding protein (OSBP), respectively. We report that VAP and its interacting proteins are required for the processing and secretion of pancreatic adenocarcinoma up-regulated factor, whose transport from the trans-Golgi network (TGN) to the cell surface is mediated by transport carriers called “carriers of the trans-Golgi network to the cell surface” (CARTS). In VAP-depleted cells, diacylglycerol level at the TGN was decreased and CARTS formation was impaired. We found that VAP forms a complex with not only OSBP but also Sac1 phosphoinositide phosphatase at specialized ER subdomains that are closely apposed to the trans-Golgi/TGN, most likely reflecting membrane contact sites. Immobilization of ER–Golgi contacts dramatically reduced CARTS production, indicating that association–dissociation dynamics of the two membranes are important. On the basis of these findings, we propose that the ER–Golgi contacts play a pivotal role in lipid metabolism to control the biogenesis of transport carriers from the TGN.

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.

PI4P/PS countertransport by ORP10 at ER–endosome membrane contact sites regulates endosome fission

2021 ◽  
Vol 221 (1) ◽  
Author(s):  
Asami Kawasaki ◽  
Akiko Sakai ◽  
Hiroki Nakanishi ◽  
Junya Hasegawa ◽  
Tomohiko Taguchi ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Binding Protein ◽  
Dependent Manner ◽  
Oxysterol Binding Protein ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Lipid Exchange ◽  
Membrane Contact ◽  
Phosphatidylinositol 4

Membrane contact sites (MCSs) serve as a zone for nonvesicular lipid transport by oxysterol-binding protein (OSBP)-related proteins (ORPs). ORPs mediate lipid countertransport, in which two distinct lipids are transported counterdirectionally. How such lipid countertransport controls specific biological functions, however, remains elusive. We report that lipid countertransport by ORP10 at ER–endosome MCSs regulates retrograde membrane trafficking. ORP10, together with ORP9 and VAP, formed ER–endosome MCSs in a phosphatidylinositol 4-phosphate (PI4P)-dependent manner. ORP10 exhibited a lipid exchange activity toward its ligands, PI4P and phosphatidylserine (PS), between liposomes in vitro, and between the ER and endosomes in situ. Cell biological analysis demonstrated that ORP10 supplies a pool of PS from the ER, in exchange for PI4P, to endosomes where the PS-binding protein EHD1 is recruited to facilitate endosome fission. Our study highlights a novel lipid exchange at ER–endosome MCSs as a nonenzymatic PI4P-to-PS conversion mechanism that organizes membrane remodeling during retrograde membrane trafficking.

scholarly journals The ER cholesterol sensor SCAP promotes CARTS biogenesis at ER–Golgi membrane contact sites

2020 ◽  
Vol 220 (1) ◽  
Author(s):  
Yuichi Wakana ◽  
Kaito Hayashi ◽  
Takumi Nemoto ◽  
Chiaki Watanabe ◽  
Masato Taoka ◽  
...  
Keyword(s):  
Lipid Transfer ◽  
Golgi Membrane ◽  
Proteolytic Activation ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Defective Mutant ◽  
Transport Defect ◽  
Membrane Contact ◽  
Phosphatidylinositol 4 ◽  
Golgi Network

In response to cholesterol deprivation, SCAP escorts SREBP transcription factors from the endoplasmic reticulum to the Golgi complex for their proteolytic activation, leading to gene expression for cholesterol synthesis and uptake. Here, we show that in cholesterol-fed cells, ER-localized SCAP interacts through Sac1 phosphatidylinositol 4-phosphate (PI4P) phosphatase with a VAP–OSBP complex, which mediates counter-transport of ER cholesterol and Golgi PI4P at ER–Golgi membrane contact sites (MCSs). SCAP knockdown inhibited the turnover of PI4P, perhaps due to a cholesterol transport defect, and altered the subcellular distribution of the VAP–OSBP complex. As in the case of perturbation of lipid transfer complexes at ER–Golgi MCSs, SCAP knockdown inhibited the biogenesis of the trans-Golgi network–derived transport carriers CARTS, which was reversed by expression of wild-type SCAP or a Golgi transport–defective mutant, but not of cholesterol sensing–defective mutants. Altogether, our findings reveal a new role for SCAP under cholesterol-fed conditions in the facilitation of CARTS biogenesis via ER–Golgi MCSs, depending on the ER cholesterol.

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