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Journal of Biochemistry Feb 2024Blebs are membrane structures formed by the detachment of the plasma membrane from the underlying actin cytoskeleton. It is now clear that a wide variety of cells,... (Review)
Review
Blebs are membrane structures formed by the detachment of the plasma membrane from the underlying actin cytoskeleton. It is now clear that a wide variety of cells, including cancer cells, actively form blebs for cell migration and cell survival. The expansion of blebs has been regarded as the passive ballooning of the plasma membrane by an abrupt increase in intracellular pressure. However, recent studies revealed the importance of 'cytoplasmic zoning', i.e. local changes in the hydrodynamic properties and the ionic and protein content of the cytoplasm. In this review, we summarize the current understanding of the molecular mechanisms behind cytoplasmic zoning and its role in bleb expansion.
Topics: Cytoplasm; Cytosol; Cell Membrane; Actin Cytoskeleton; Actins
PubMed: 37943501
DOI: 10.1093/jb/mvad084 -
The Journal of Cell Biology Apr 2024The compartmentalization of the plasma membrane (PM) is a fundamental feature of cells. The diffusivity of membrane proteins is significantly lower in biological than in...
The compartmentalization of the plasma membrane (PM) is a fundamental feature of cells. The diffusivity of membrane proteins is significantly lower in biological than in artificial membranes. This is likely due to actin filaments, but assays to prove a direct dependence remain elusive. We recently showed that periodic actin rings in the neuronal axon initial segment (AIS) confine membrane protein motion between them. Still, the local enrichment of ion channels offers an alternative explanation. Here we show, using computational modeling, that in contrast to actin rings, ion channels in the AIS cannot mediate confinement. Furthermore, we show, employing a combinatorial approach of single particle tracking and super-resolution microscopy, that actin rings are close to the PM and that they confine membrane proteins in several neuronal cell types. Finally, we show that actin disruption leads to loss of compartmentalization. Taken together, we here develop a system for the investigation of membrane compartmentalization and show that actin rings compartmentalize the PM.
Topics: Actins; Cell Membrane; Ion Channels; Animals; Rats; Neurons; Models, Chemical
PubMed: 38252080
DOI: 10.1083/jcb.202310138 -
Cytoskeleton (Hoboken, N.J.) Jan 2024Tau was originally identified as a microtubule associated protein, and subsequently recognized to constitute the fibrillar assemblies found in Alzheimer disease and...
Tau was originally identified as a microtubule associated protein, and subsequently recognized to constitute the fibrillar assemblies found in Alzheimer disease and related neurodegenerative tauopathies. Point mutations in the microtubule associated protein tau (MAPT) gene cause dominantly inherited tauopathies, and most predispose it to aggregate. This indicates tau aggregation underlies pathogenesis of tauopathies. Our work has suggested that tau functions as a prion, forming unique intracellular pathological assemblies that subsequently move to other cells, inducing further aggregation that underlies disease progression. Remarkably, in simple cells tau forms stably propagating aggregates of distinct conformation, termed strains. Each strain induces a unique and, in some cases, transmissible, neuropathological phenotype upon inoculation into a mouse model. After binding heparan sulfate proteoglycans on the plasma membrane, tau assemblies enter cells via macropinocytosis. From within a vesicle, if not trafficked to the endolysosomal system, tau subsequently enters the cytoplasm, where it becomes a template for its own replication, apparently after processing by valosin containing protein. The smallest seed unit is a stable monomer, which suggests that initial folding events in tau presage subsequent pathological aggregation. The study of tau prions has raised important questions about basic cell biological processes that underlie their replication and propagation, with implications for therapy of tauopathies.
Topics: Mice; Animals; tau Proteins; Prions; Tauopathies; Cell Membrane; Cytoskeleton; Brain
PubMed: 37950616
DOI: 10.1002/cm.21806 -
Nature Communications Jul 2023Salt-overly-sensitive 1 (SOS1) is a unique electroneutral Na/H antiporter at the plasma membrane of higher plants and plays a central role in resisting salt stress. SOS1...
Salt-overly-sensitive 1 (SOS1) is a unique electroneutral Na/H antiporter at the plasma membrane of higher plants and plays a central role in resisting salt stress. SOS1 is kept in a resting state with basal activity and activated upon phosphorylation. Here, we report the structures of SOS1. SOS1 forms a homodimer, with each monomer composed of transmembrane and intracellular domains. We find that SOS1 is locked in an occluded state by shifting of the lateral-gate TM5b toward the dimerization domain, thus shielding the Na/H binding site. We speculate that the dimerization of the intracellular domain is crucial to stabilize the transporter in this specific conformation. Moreover, two discrete fragments and a residue W1013 are important to prevent the transition of SOS1 to an alternative conformational state, as validated by functional complementation assays. Our study enriches understanding of the alternate access model of eukaryotic Na/H exchangers.
Topics: Arabidopsis; Arabidopsis Proteins; Antiporters; Cell Membrane; Sodium-Hydrogen Exchangers; Gene Expression Regulation, Plant
PubMed: 37495621
DOI: 10.1038/s41467-023-40215-y -
Current Opinion in Cell Biology Dec 2023Every cell becomes two through a carefully orchestrated process of division. Prior to division, contractile machinery must first be assembled at the cell midzone to... (Review)
Review
Every cell becomes two through a carefully orchestrated process of division. Prior to division, contractile machinery must first be assembled at the cell midzone to ensure that the cut, when it is made, bisects the two separated copies of the genetic material. Second, this contractile machinery must be dynamically tethered to the limiting plasma membrane so as to bring the membrane with it as it constricts. Finally, the connecting membrane must be severed to generate two physically separate daughter cells. In several organisms across the tree of life, Endosomal Sorting Complex Required for Transport (ESCRT)-III family proteins aid cell division by forming composite polymers that function together with the Vps4 AAA-ATPase to constrict and cut the membrane tube connecting nascent daughter cells from the inside. In this review, we discuss unique features of ESCRT-III that enable it to play this role in division in many archaea and eukaryotes.
Topics: Endosomal Sorting Complexes Required for Transport; Cell Division; Cell Membrane
PubMed: 37944425
DOI: 10.1016/j.ceb.2023.102274 -
Biochemical Society Transactions Oct 2023Glycerophospholipids, sphingolipids and cholesterol assemble into lipid bilayers that form the scaffold of cellular membranes, in which proteins are embedded. Membrane... (Review)
Review
Glycerophospholipids, sphingolipids and cholesterol assemble into lipid bilayers that form the scaffold of cellular membranes, in which proteins are embedded. Membrane composition and membrane protein profiles differ between plasma and intracellular membranes and between the two leaflets of a membrane. Lipid distributions between two leaflets are mediated by lipid translocases, including flippases and scramblases. Flippases use ATP to catalyze the inward movement of specific lipids between leaflets. In contrast, bidirectional flip-flop movements of lipids across the membrane are mediated by scramblases in an ATP-independent manner. Scramblases have been implicated in disrupting the lipid asymmetry of the plasma membrane, protein glycosylation, autophagosome biogenesis, lipoprotein secretion, lipid droplet formation and communications between organelles. Although scramblases in plasma membranes were identified over 10 years ago, most progress about scramblases localized in intracellular membranes has been made in the last few years. Herein, we review the role of scramblases in regulating lipid distributions in cellular membranes, focusing primarily on intracellular membrane-localized scramblases.
Topics: Cell Membrane; Lipid Bilayers; Intracellular Membranes; Membrane Proteins; Adenosine Triphosphate; Phospholipids; Phospholipid Transfer Proteins
PubMed: 37767549
DOI: 10.1042/BST20221455 -
ACS Nano May 2024Light-driven modulation of neuronal activity at high spatial-temporal resolution is becoming of high interest in neuroscience. In addition to optogenetics, nongenetic...
Light-driven modulation of neuronal activity at high spatial-temporal resolution is becoming of high interest in neuroscience. In addition to optogenetics, nongenetic membrane-targeted nanomachines that alter the electrical state of the neuronal membranes are in demand. Here, we engineered and characterized a photoswitchable conjugated compound (BV-1) that spontaneously partitions into the neuronal membrane and undergoes a charge transfer upon light stimulation. The activity of primary neurons is not affected in the dark, whereas millisecond light pulses of cyan light induce a progressive decrease in membrane resistance and an increase in inward current matched to a progressive depolarization and action potential firing. We found that illumination of BV-1 induces oxidation of membrane phospholipids, which is necessary for the electrophysiological effects and is associated with decreased membrane tension and increased membrane fluidity. Time-resolved atomic force microscopy and molecular dynamics simulations performed on planar lipid bilayers revealed that the underlying mechanism is a light-driven formation of pore-like structures across the plasma membrane. Such a phenomenon decreases membrane resistance and increases permeability to monovalent cations, namely, Na, mimicking the effects of antifungal polyenes. The same effect on membrane resistance was also observed in nonexcitable cells. When sustained light stimulations are applied, neuronal swelling and death occur. The light-controlled pore-forming properties of BV-1 allow performing "on-demand" light-induced membrane poration to rapidly shift from cell-attached to perforated whole-cell patch-clamp configuration. Administration of BV-1 to retinal explants or primary visual cortex elicited neuronal firing in response to short trains of light stimuli, followed by activity silencing upon prolonged light stimulations. BV-1 represents a versatile molecular nanomachine whose properties can be exploited to induce either photostimulation or space-specific cell death, depending on the pattern and duration of light stimulation.
Topics: Neurons; Animals; Cell Membrane; Light; Lipid Bilayers; Molecular Dynamics Simulation; Rats; Mice; Optogenetics
PubMed: 38687909
DOI: 10.1021/acsnano.4c01672 -
ACS Chemical Neuroscience Apr 2024Serotonin (5-HT) is a vital modulatory neurotransmitter responsible for regulating most behaviors in the brain. An inefficient 5-HT synaptic function is often linked to... (Review)
Review
Serotonin (5-HT) is a vital modulatory neurotransmitter responsible for regulating most behaviors in the brain. An inefficient 5-HT synaptic function is often linked to various mental disorders. Primarily, membrane proteins controlling the expression and activity of 5-HT synthesis, storage, release, receptor activation, and inactivation are critical to 5-HT signaling in synaptic and extra-synaptic sites. Moreover, these signals represent information transmission across membranes. Although the lipid membrane environment is often viewed as fairly stable, emerging research suggests significant functional lipid-protein interactions with many synaptic 5-HT proteins. These protein-lipid interactions extend to almost all the primary lipid classes that form the plasma membrane. Collectively, these lipid classes and lipid-protein interactions affect 5-HT synaptic efficacy at the synapse. The highly dynamic lipid composition of synaptic membranes suggests that these lipids and their interactions with proteins may contribute to the plasticity of the 5-HT synapse. Therefore, this broader protein-lipid model of the 5-HT synapse necessitates a reconsideration of 5-HT's role in various associated mental disorders.
Topics: Humans; Serotonin; Signal Transduction; Synapses; Cell Membrane; Lipids; Synaptic Transmission
PubMed: 38499042
DOI: 10.1021/acschemneuro.3c00823 -
Experimental Cell Research Oct 2023Organelles are dynamic entities whose functions are essential for the optimum functioning of cells. It is now known that the juxtaposition of organellar membranes is... (Review)
Review
Organelles are dynamic entities whose functions are essential for the optimum functioning of cells. It is now known that the juxtaposition of organellar membranes is essential for the exchange of metabolites and their communication. These functional apposition sites are termed membrane contact sites. Dynamic membrane contact sites between various sub-cellular structures such as mitochondria, endoplasmic reticulum, peroxisomes, Golgi apparatus, lysosomes, lipid droplets, plasma membrane, endosomes, etc. have been reported in various model systems. The burgeoning area of research on membrane contact sites has witnessed several manuscripts in recent years that identified the contact sites and components involved. Several methods have been developed to identify, measure and analyze the membrane contact sites. In this manuscript, we aim to discuss important methods developed to date that are used to study membrane contact sites.
Topics: Mitochondrial Membranes; Mitochondria; Cell Membrane; Endoplasmic Reticulum; Endosomes
PubMed: 37633408
DOI: 10.1016/j.yexcr.2023.113756 -
Current Opinion in Cell Biology Aug 2023Lipid phosphoinositides are master regulators of multiple cellular functions. Misregulation of the activity of the lipid kinases that generate phosphoinositides is... (Review)
Review
Lipid phosphoinositides are master regulators of multiple cellular functions. Misregulation of the activity of the lipid kinases that generate phosphoinositides is causative of human diseases, including cancer, neurodegeneration, developmental disorders, immunodeficiencies, and inflammatory disease. This review will present a summary of recent discoveries on the roles of two phosphoinositide kinases (PI4KA and PIKfyve), which have emerged as targets for therapeutic intervention. Phosphatidylinositol 4-kinase alpha (PI4KA) generates PI4P at the plasma membrane and PIKfyve generates PI(3,5)P at endo-lysosomal membranes. Both of these enzymes exist as multi-protein mega complexes that are under myriad levels of regulation. Human disease can be caused by either loss or gain-of-function of these complexes, so understanding how they are regulated will be essential in the design of therapeutics. We will summarize insight into how these enzymes are regulated by their protein-binding partners, with a major focus on the unanswered questions of how their activity is controlled.
Topics: Humans; Cell Membrane; Lysosomes; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Signal Transduction
PubMed: 37453227
DOI: 10.1016/j.ceb.2023.102207