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Current Opinion in Virology Dec 2021The Paramyxoviridae family includes enveloped single-stranded negative-sense RNA viruses such as measles, mumps, human parainfluenza, canine distemper, Hendra, and Nipah... (Review)
Review
The Paramyxoviridae family includes enveloped single-stranded negative-sense RNA viruses such as measles, mumps, human parainfluenza, canine distemper, Hendra, and Nipah viruses, which cause a tremendous global health burden. The ability of paramyxoviral glycoproteins to merge viral and host membranes allows entry of the viral genome into host cells, as well as cell-cell fusion, an important contributor to disease progression. Recent molecular and structural advances in our understanding of the paramyxovirus membrane fusion machinery gave rise to various therapeutic approaches aiming at inhibiting viral infection, spread, and cytopathic effects. These therapeutic approaches include peptide mimics, antibodies, and small molecule inhibitors with various levels of success at inhibiting viral entry, increasing the potential of effective antiviral therapeutic development.
Topics: Animals; Antiviral Agents; Cell Fusion; Cell Membrane; Humans; Membrane Fusion; Paramyxoviridae; Paramyxoviridae Infections
PubMed: 34592709
DOI: 10.1016/j.coviro.2021.09.003 -
Autophagy Jan 2023During macroautophagy/autophagy, autophagosomes fuse with lysosomes to form autolysosomes. After fusion, the autophagosome inner membrane and enclosed substrates are...
During macroautophagy/autophagy, autophagosomes fuse with lysosomes to form autolysosomes. After fusion, the autophagosome inner membrane and enclosed substrates are degraded and transported out of lysosomes for recycling. The lysosomal membrane components are recycled by autophagic lysosome reformation (ALR) to generate new lysosomes. However, the fate of autophagosome outer membrane components on autolysosomes remains unknown. Our recent work discovered that autophagosome outer membrane components are not degraded but are recycled through an unidentified process which we named autophagosomal components recycling (ACR). Further investigation revealed the recycler complex (SNX4-SNX5-SNX17) responsible for ACR. The discovery of ACR not only fills a missing part in autophagy, but also reveals a new recycling pathway on autolysosomes.
Topics: Autophagy; Autophagosomes; Intracellular Membranes; Macroautophagy; Lysosomes; Membrane Fusion
PubMed: 35635187
DOI: 10.1080/15548627.2022.2083807 -
Biomolecules Nov 2022The soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor (SNARE) proteins play a central role in most forms of intracellular membrane... (Review)
Review
The soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor (SNARE) proteins play a central role in most forms of intracellular membrane trafficking, a key process that allows for membrane and biocargo shuffling between multiple compartments within the cell and extracellular environment. The structural organization of SNARE proteins is relatively simple, with several intrinsically disordered and folded elements (e.g., SNARE motif, N-terminal domain, transmembrane region) that interact with other SNAREs, SNARE-regulating proteins and biological membranes. In this review, we discuss recent advances in the development of functional peptides that can modify SNARE-binding interfaces and modulate SNARE function. The ability of the relatively short SNARE motif to assemble spontaneously into stable coiled coil tetrahelical bundles has inspired the development of reduced SNARE-mimetic systems that use peptides for biological membrane fusion and for making large supramolecular protein complexes. We evaluate two such systems, based on peptide-nucleic acids (PNAs) and coiled coil peptides. We also review how the self-assembly of SNARE motifs can be exploited to drive on-demand assembly of complex re-engineered polypeptides.
Topics: SNARE Proteins; Membrane Fusion; Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; Protein Binding; Peptides
PubMed: 36551207
DOI: 10.3390/biom12121779 -
European Biophysics Journal : EBJ Mar 2021Membrane-coated colloidal probes combine the benefits of solid-supported membranes with a more complex three-dimensional geometry. This combination makes them a powerful... (Review)
Review
Membrane-coated colloidal probes combine the benefits of solid-supported membranes with a more complex three-dimensional geometry. This combination makes them a powerful model system that enables the visualization of dynamic biological processes with high throughput and minimal reliance on fluorescent labels. Here, we want to review recent applications of colloidal probes for the study of membrane fusion. After discussing the advantages and disadvantages of some classical vesicle-based fusion assays, we introduce an assay using optical detection of fusion between membrane-coated glass microspheres in a quasi two-dimensional assembly. Then, we discuss free energy considerations of membrane fusion between supported bilayers, and show how colloidal probes can be combined with atomic force microscopy or optical tweezers to access the fusion process with even greater detail.
Topics: Lipid Bilayers; Membrane Fusion; Microscopy, Atomic Force; Optical Tweezers
PubMed: 33599795
DOI: 10.1007/s00249-020-01490-5 -
Trends in Biochemical Sciences Sep 2018A major challenge for a molecular understanding of membrane trafficking has been the elucidation of high-resolution structures of large, multisubunit tethering complexes... (Review)
Review
A major challenge for a molecular understanding of membrane trafficking has been the elucidation of high-resolution structures of large, multisubunit tethering complexes that spatially and temporally control intracellular membrane fusion. Exocyst is a large hetero-octameric protein complex proposed to tether secretory vesicles at the plasma membrane to provide quality control of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated membrane fusion. Breakthroughs in methodologies, including sample preparation, biochemical characterization, fluorescence microscopy, and single-particle cryoelectron microscopy, are providing critical insights into the structure and function of the exocyst. These studies now pose more questions than answers for understanding fundamental functional mechanisms, and they open wide the door for future studies to elucidate interactions with protein and membrane partners, potential conformational changes, and molecular insights into tethering reactions.
Topics: Animals; Exocytosis; Exosomes; Humans; Membrane Fusion; SNARE Proteins
PubMed: 30055895
DOI: 10.1016/j.tibs.2018.06.012 -
FEBS Letters Sep 2019Phosphatidic acid (PA) is the simplest cellular glycerophospholipid characterized by unique biophysical properties: a small headgroup; negative charge; and a... (Review)
Review
Phosphatidic acid (PA) is the simplest cellular glycerophospholipid characterized by unique biophysical properties: a small headgroup; negative charge; and a phosphomonoester group. Upon interaction with lysine or arginine, PA charge increases from -1 to -2 and this change stabilizes protein-lipid interactions. The biochemical properties of PA also allow interactions with lipids in several subcellular compartments. Based on this feature, PA is involved in the regulation and amplification of many cellular signalling pathways and functions, as well as in membrane rearrangements. Thereby, PA can influence membrane fusion and fission through four main mechanisms: it is a substrate for enzymes producing lipids (lysophosphatidic acid and diacylglycerol) that are involved in fission or fusion; it contributes to membrane rearrangements by generating negative membrane curvature; it interacts with proteins required for membrane fusion and fission; and it activates enzymes whose products are involved in membrane rearrangements. Here, we discuss the biophysical properties of PA in the context of the above four roles of PA in membrane fusion and fission.
Topics: Animals; Cell Membrane; Humans; Membrane Fusion; Phosphatidic Acids
PubMed: 31365767
DOI: 10.1002/1873-3468.13563 -
Frontiers in Cellular and Infection... 2022A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders.... (Review)
Review
A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia. Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia. In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a "decentralized" information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.
Topics: COVID-19; Cellular Senescence; Humans; Membrane Fusion; Neurodegenerative Diseases; SARS-CoV-2; Viruses
PubMed: 35531328
DOI: 10.3389/fcimb.2022.845580 -
Annual Review of Virology Sep 2021Viral fusion glycoproteins catalyze membrane fusion during viral entry. Unlike most enzymes, however, they lack a conventional active site in which formation or scission... (Review)
Review
Viral fusion glycoproteins catalyze membrane fusion during viral entry. Unlike most enzymes, however, they lack a conventional active site in which formation or scission of a specific covalent bond is catalyzed. Instead, they drive the membrane fusion reaction by cojoining highly regulated changes in conformation to membrane deformation. Despite the challenges in applying inhibitor design approaches to these proteins, recent advances in knowledge of the structures and mechanisms of viral fusogens have enabled the development of small-molecule inhibitors of both class I and class II viral fusion proteins. Here, we review well-validated inhibitors, including their discovery, targets, and mechanism(s) of action, while highlighting mechanistic similarities and differences. Together, these examples make a compelling case for small-molecule inhibitors as tools for probing the mechanisms of viral glycoprotein-mediated fusion and for viral glycoproteins as druggable targets.
Topics: Membrane Fusion; Viral Envelope Proteins; Viral Fusion Proteins; Virus Internalization
PubMed: 34197186
DOI: 10.1146/annurev-virology-022221-063725 -
Chembiochem : a European Journal of... Apr 2020The combination of supramolecular functional systems with biomolecular chemistry has been a fruitful exercise for decades, leading to a greater understanding of... (Review)
Review
The combination of supramolecular functional systems with biomolecular chemistry has been a fruitful exercise for decades, leading to a greater understanding of biomolecules and to a great variety of applications, for example, in drug delivery and sensing. Within these developments, the phospholipid bilayer membrane, surrounding live cells, with all its functions has also intrigued supramolecular chemists. Herein, recent efforts from the supramolecular chemistry community to mimic natural functions of lipid membranes, such as sensing, molecular recognition, membrane fusion, signal transduction, and gated transport, are reviewed.
Topics: Biological Transport; Coordination Complexes; Drug Carriers; Humans; Lipid Bilayers; Membrane Fusion; Phospholipids; Signal Transduction
PubMed: 31803982
DOI: 10.1002/cbic.201900646 -
European Biophysics Journal : EBJ Mar 2021In the past decade, we developed various fluorescence-based methods for monitoring membrane fusion, membrane docking, distances between membranes, and membrane... (Review)
Review
In the past decade, we developed various fluorescence-based methods for monitoring membrane fusion, membrane docking, distances between membranes, and membrane curvature. These tools were mainly developed using liposomes as model systems, which allows for the dissection of specific interactions mediated by, for example, fusion proteins. Here, we provide an overview of these methods, including two-photon fluorescence cross-correlation spectroscopy and intramembrane Förster energy transfer, with asymmetric labelling of inner and outer membrane leaflets and the calibrated use of transmembrane energy transfer to determine membrane distances below 10 nm. We discuss their application range and their limitations using examples from our work on protein-mediated vesicle docking and fusion.
Topics: Fluorescence; Liposomes; Membrane Fusion
PubMed: 33787948
DOI: 10.1007/s00249-021-01516-6