scholarly journals Diverse plasma membrane protrusions act as platforms for extracellular vesicle shedding

2021 ◽  
Vol 10 (11) ◽  
Author(s):  
Kirsi Rilla
Keyword(s):  
Plasma Membrane ◽  
Extracellular Vesicle ◽  
Membrane Protrusions ◽  
Vesicle Shedding

Extracellular vesicle interplay in cardiovascular pathophysiology

2021 ◽  
Author(s):  
Sherin Saheera ◽  
Vivek P Jani ◽  
Kenneth W Witwer ◽  
Shelby Kutty
Keyword(s):  
Plasma Membrane ◽  
Cardiovascular System ◽  
Lipid Bilayer ◽  
Cellular Responses ◽  
Extracellular Vesicle ◽  
Cargo Proteins ◽  
And Function ◽  
Intercellular Communications ◽  
Rna And Dna

Extracellular vesicles (EVs) are nanosized lipid bilayer-delimited particles released from cells that mediate intercellular communications and play a pivotal role in various physiological and pathological processes. Subtypes of EVs may include plasma-membrane ectosomes or microvesicles and endosomal-origin exosomes, although functional distinctions remain unclear. EVs carry cargo proteins, nucleic acids (RNA and DNA), lipids, and metabolites. By presenting or transferring this cargo to recipient cells, EVs can trigger cellular responses. Here, we summarize what is known about EV biogenesis, composition, and function, with an emphasis on the role of EVs in cardiovascular system. Additionally, we provide an update on the function of EVs in cardiovascular pathophysiology, further highlighting their potential for diagnostic and therapeutic applications.

scholarly journals Blebs Promote Cell Survival by Assembling Oncogenic Signaling Hubs

2021 ◽  
Author(s):  
Andrew D. Weems ◽  
Erik S. Welf ◽  
Meghan K. Driscoll ◽  
Hanieh Mazloom-Farsibaf ◽  
Bo-Jui Chang ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Surrounding Tissue ◽  
Pi3k Signaling ◽  
Oncogenic Signaling ◽  
Anoikis Resistance ◽  
Cancer Disease ◽  
Substrate Adhesion ◽  
Promote Cell Survival ◽  
Membrane Protrusions ◽  
Signaling Organelles

AbstractFor most human cells, anchorage is a key necessity for survival. Cell-substrate adhesion activates diverse signaling pathways, without which cells undergo anoikis – a form of programmed cell death1. Acquisition of anoikis resistance is a pivotal step in cancer disease progression, as metastasizing cancer cells often lose firm attachment to surrounding tissue2–5. In these poorly attached states, cells often adopt rounded morphologies and form small hemispherical plasma membrane protrusions called blebs6–13. Bleb function has long been investigated in the context of amoeboid migration but is far less deeply examined in other scenarios14–19. Here we show by quantitative subcellular 3D imaging and manipulation of cell morphological states that blebbing triggers the formation of membrane-proximal signaling hubs that initiate signaling cascades leading to anoikis resistance. Specifically, in melanoma cells we discovered that blebbing generates plasma membrane contours that recruit curvature sensing septin proteins, which scaffold constitutively active mutant NRAS and effectors, driving the upregulation of ERK and PI3K signaling. Inhibition of blebs or septins has little effect on the survival of well-adhered cells, but in detached cells causes NRAS mislocalization, reduced MAPK and PI3K signaling, and ultimately, death. These data unveil an unanticipated morphological requirement for mutant NRAS to operate as an effective oncoprotein, suggesting novel clinical targets for the treatment of NRAS-driven melanoma. Furthermore, they define an unforeseen role for blebs as potent signaling organelles capable of integrating myriad cellular information flows into concerted signaling responses, in this case granting robust anoikis resistance.Abstract Figure

scholarly journals Extracellular vesicle budding is inhibited by redundant regulators of TAT-5 flippase localization and phospholipid asymmetry

2018 ◽  
Vol 115 (6) ◽  
pp. E1127-E1136 ◽  
Author(s):  
Katharina B. Beer ◽  
Jennifer Rivas-Castillo ◽  
Kenneth Kuhn ◽  
Gholamreza Fazeli ◽  
Birgit Karmann ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Extracellular Vesicle ◽  
Endosomal Trafficking ◽  
Vesicle Budding ◽  
Sorting Nexins ◽  
Dnaj Protein ◽  
Membrane Budding ◽  
Pleiotropic Functions

Cells release extracellular vesicles (EVs) that mediate intercellular communication and repair damaged membranes. Despite the pleiotropic functions of EVs in vitro, their in vivo function is debated, largely because it is unclear how to induce or inhibit their formation. In particular, the mechanisms of EV release by plasma membrane budding or ectocytosis are poorly understood. We previously showed that TAT-5 phospholipid flippase activity maintains the asymmetric localization of the lipid phosphatidylethanolamine (PE) in the plasma membrane and inhibits EV budding by ectocytosis in Caenorhabditis elegans. However, no proteins that inhibit ectocytosis upstream of TAT-5 were known. Here, we identify TAT-5 regulators associated with retrograde endosomal recycling: PI3Kinase VPS-34, Beclin1 homolog BEC-1, DnaJ protein RME-8, and the uncharacterized Dopey homolog PAD-1. PI3Kinase, RME-8, and semiredundant sorting nexins are required for the plasma membrane localization of TAT-5, which is important to maintain PE asymmetry and inhibit EV release. PAD-1 does not directly regulate TAT-5 localization, but is required for the lipid flipping activity of TAT-5. PAD-1 also has roles in endosomal trafficking with the GEF-like protein MON-2, which regulates PE asymmetry and EV release redundantly with sorting nexins independent of the core retromer. Thus, in addition to uncovering redundant intracellular trafficking pathways, our study identifies additional proteins that regulate EV release. This work pinpoints TAT-5 and PE as key regulators of plasma membrane budding, further supporting the model that PE externalization drives ectocytosis.

Neurofibromatosis 2 tumor suppressor protein colocalizes with ezrin and CD44 and associates with actin-containing cytoskeleton

1997 ◽  
Vol 110 (18) ◽  
pp. 2249-2260 ◽  
Author(s):  
M. Sainio ◽  
F. Zhao ◽  
L. Heiska ◽  
O. Turunen ◽  
M. den Bakker ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Tumor Suppressor ◽  
Cytochalasin B ◽  
Insoluble Fraction ◽  
Tumor Suppressor Protein ◽  
Homologous Proteins ◽  
Neurofibromatosis 2 ◽  
Erm Proteins ◽  
293 Cells ◽  
Membrane Protrusions

Neurofibromatosis 2 (NF2) protein (merlin; schwannomin) is a tumor suppressor involved in tumorigenesis of NF2-associated and sporadic schwannomas and meningiomas. The protein shares the domain structure of three homologous proteins: ezrin, radixin and moesin (ERM). ERM proteins function as membrane organizers and may act as linkers between plasma membrane molecules, such as CD44 and ICAM-2, and the cytoskeleton. We analyzed the distribution and effects of transfected NF2 protein in COS-1, CHO and 293 cells, and endogenous NF2 protein in U251 glioma cells. The distribution was compared to ezrin, CD44 and F-actin. Both transfected and endogenous NF2 protein localized underneath the plasma membrane in a pattern typical of an ERM protein. In COS-1 transfectants, NF2 protein typically codistributed with ezrin but, in cells with poorly developed actin cytoskeleton, it replaced ezrin in filopodia and ruffling edges. NF2 protein colocalized with CD44, which in transfected cells accumulated into restructured cell membrane protrusions. The association of CD44 and NF2 protein was further suggested by binding of CD44 from cellular lysates to recombinant NF2 protein. Interaction between NF2 protein and the actin-containing cytoskeleton was indicated by partial colocalization, by cytochalasin B-induced coclustering, and by retention of NF2 protein in the detergent-insoluble fraction. Transfected NF2 protein induced morphogenic changes. The cells contained restructured membrane extensions and blebs, and CHO cells expressing NF2 protein were more elongated than control transfectants. In conclusion, NF2 protein possesses functional properties of an ERM family member.

Caffeine-Induced Surface Blebbing and Budding in the Acellular Slime Mold Physarum polycephalum

1983 ◽  
Vol 38 (7-8) ◽  
pp. 589-599 ◽  
Author(s):  
J. Kukulies ◽  
W. Stockem ◽  
K. E. Wohlfarth-Bottermann
Keyword(s):  
Plasma Membrane ◽  
Fine Structure ◽  
Surface Area ◽  
Physarum Polycephalum ◽  
Fold Increase ◽  
Total Surface Area ◽  
Slime Mold ◽  
Tris Buffer ◽  
Membrane Protrusions ◽  
Electron Microscopical

The mechanism of plasma membrane proliferation was studied in the acellular slime mold Physarum polycephalum with the aid of light and electron microscopical techniques. Treatment of protoplasmic drops with a Tris-buffered 15 mᴍ caffeine solution causes surface blebbing and budding over periods of 5-90 min. The process of surface blebbing is coupled to a 5-10-fold increase of the surface area in conjunction with characteristic changes in cytoplasmic morphol­ogy. Successive constriction of blebs exhibiting different sizes and degree of hyalo-granuloptasmic separation leads to the formation of numerous spherical caffeine droplets. During the process of surface budding and droplet formation the total surface area of the original (genuine) protoplasmic drop is not reduced, but continues to grow.Freeze-etch studies show that caffeine concomitantly causes characteristic changes in the fine structure of the plasma membrane. During the initial phase of surface blebbing the original density of intramembranous particles (IMP) is reduced from 3676/μm2 to 1669/μm2 and the PF:EF ratio (IMP/μm2 protoplasmic face: exoplasmic face) shifts from 2.4:1 to 2.8:1. When surface budding is completed the IMP-density in the plasma membrane of single caffeine droplets increases again to 2289/μm2 and the PF:EF ratio changes to 1.5:1. Simultaneously, the isolated caffeine droplets produce numerous small hyaline membrane protrusions, which are pinched off and contain no IMP. Control experiments demonstrate that Tris-buffer without caffeine also shows a weak capacity to induce surface blebbing, to change the IMP-density and the PF:EF ratio (2443/μm2; 1.5:1); but Tris-buffer fails to cause surface budding. On the other hand, different concentrations of sucrose (25-200 mᴍ) can supress to a certain degree both caffeine- and Tris-buffer-induced surface blebbing, but not caffeine-dependent surface budding.The caffeine-effect is reversible insofar as protoplasmic drops with blebbing and budding activity recover to normal morphology, fine structure and locomotion when transferred to physiological conditions.The mechanisms of successive changes in plasma membrane morphology as well as the mode of a participation of the actomyosin system in cell surface dynamics are discussed.

Gelsolin is an endogenous inhibitor of syncytiotrophoblast extracellular vesicle shedding in pregnancy

2016 ◽  
Vol 6 (4) ◽  
pp. 333-339 ◽  
Author(s):  
Neil A. Nadkarni ◽  
Augustine Rajakumar ◽  
Nikita Mokhashi ◽  
Suzanne D. Burke ◽  
Sarosh Rana ◽  
...  
Keyword(s):  
Extracellular Vesicle ◽  
Endogenous Inhibitor ◽  
Vesicle Shedding ◽  
In Pregnancy

scholarly journals So far, yet so close: α-Catenin dimers help migrating cells get together

2017 ◽  
Vol 216 (11) ◽  
pp. 3437-3439
Author(s):  
Laura Machesky ◽  
Vania M.M. Braga
Keyword(s):  
Plasma Membrane ◽  
Epithelial Cells ◽  
Active Plasma ◽  
Cell Biol ◽  
Membrane Protrusions ◽  
Freely Moving ◽  
And Migration ◽  
Migrating Cells

Epithelial cells in tissues use their actin cytoskeletons to stick together, whereas unattached cells make active plasma membrane protrusions to migrate. In this issue, Wood et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201612006) show that the junction component α-catenin is critical in freely moving cells to promote adhesion and migration.

scholarly journals Membrane-MEDYAN: Simulating Deformable Vesicles Containing Complex Cytoskeletal Networks

2021 ◽  
Author(s):  
Haoran Ni ◽  
Garegin A. Papoian
Keyword(s):  
Plasma Membrane ◽  
Leading Edge ◽  
Membrane Dynamics ◽  
New Model ◽  
Biological Matter ◽  
Membrane Cytoskeleton ◽  
Filament Bundles ◽  
Membrane Protrusions ◽  
Cytoskeletal Networks ◽  
Shed Light

AbstractThe plasma membrane defines the shape of the cell and plays an indispensable role in bridging intra- and extra-cellular environments. Mechanochemical interactions between plasma membrane and cytoskeleton are vital for cell biomechanics and mechanosensing. A computational model that comprehensively captures the complex, cell-scale cytoskeleton-membrane dynamics is still lacking. In this work, we introduce a triangulated membrane model that accounts for membrane’s elastic properties, as well as for membrane-filament steric interactions. The corresponding force-field was incorporated into the active biological matter simulation platform, MEDYAN (“Mechanochemical Dynamics of Active Networks”). Simulations using the new model shed light on how actin filament bundling affects generation of tubular membrane protrusions. In particular, we used membrane-MEDYAN simulations to investigate protrusion initiation and dynamics while varying geometries of filament bundles, membrane rigidities and local G-Actin concentrations. We found that bundles’ protrusion propensities sensitively depend on the synergy between bundle thickness and inclination angle at which the bundle approaches the membrane. The new model paves the way for simulations of biological systems involving intricate membrane-cytoskeleton interactions, such as occurring at the leading edge and the cortex, eventually helping to uncover the fundamental principles underlying the active matter organization in the vicinity of the membrane.

scholarly journals Evaluation of plasmatic extracellular vesicles by size

2021 ◽  
Author(s):  
Laura Cantone ◽  
Mirjam Hoxha ◽  
Chiara Favero ◽  
Luca Ferrari ◽  
Valentina Bollati
Keyword(s):  
Plasma Membrane ◽  
Blood Plasma ◽  
Extracellular Vesicles ◽  
High Precision ◽  
Extracellular Vesicle ◽  
Nanoparticle Tracking Analysis ◽  
Research Needs ◽  
Plasma Samples ◽  
Constant Flow ◽  
Syringe Pump

Abstract Extracellular vesicles (EVs) play a key role in many physiological and pathological processes [1]. EVs are a heterogeneous group of membrane-confined particles including endosome-derived exosomes and plasma membrane-originated microvesicles. The expanding field of extracellular vesicle research needs reproducible and accurate methods to characterize EVs [2]. EV profiling can be challenging due to the small size and heterogeneity. This protocol aims to provide a method to isolate EVs and facilitate high-precision particle quantitation by Nanoparticle Tracking Analysis (NTA)[3, 4]. NTA is commonly used to determine EV concentration and diameter [5, 6]. The protocol here described refers to the isolation of EVs from blood-plasma samples by using ultracentrifugation and then quantification and sizing of EVs with NTA by NanoSight NS300 system (Malvern Panalytical Ltd., Malvern, UK) provided with a syringe pump module enabling analysis in constant flow for improved sample statistics.

scholarly journals Author response: Ciliary Rab28 and the BBSome negatively regulate extracellular vesicle shedding

2019 ◽  
Author(s):  
Jyothi S Akella ◽  
Stephen P Carter ◽  
Ken Nguyen ◽  
Sofia Tsiropoulou ◽  
Ailis L Moran ◽  
...  
Keyword(s):  
Extracellular Vesicle ◽  
Author Response ◽  
Vesicle Shedding
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