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Seminars in Cell & Developmental Biology Dec 2016Poxviruses comprise a large family of enveloped DNA viruses that infect vertebrates and invertebrates. Poxviruses, unlike most DNA viruses, replicate in the cytoplasm... (Review)
Review
Poxviruses comprise a large family of enveloped DNA viruses that infect vertebrates and invertebrates. Poxviruses, unlike most DNA viruses, replicate in the cytoplasm and encode enzymes and other proteins that enable entry, gene expression, genome replication, virion assembly and resistance to host defenses. Entry of vaccinia virus, the prototype member of the family, can occur at the plasma membrane or following endocytosis. Whereas many viruses encode one or two proteins for attachment and membrane fusion, vaccinia virus encodes four proteins for attachment and eleven more for membrane fusion and core entry. The entry-fusion proteins are conserved in all poxviruses and form a complex, known as the Entry Fusion Complex (EFC), which is embedded in the membrane of the mature virion. An additional membrane that encloses the mature virion and is discarded prior to entry is present on an extracellular form of the virus. The EFC is held together by multiple interactions that depend on nine of the eleven proteins. The entry process can be divided into attachment, hemifusion and core entry. All eleven EFC proteins are required for core entry and at least eight for hemifusion. To mediate fusion the virus particle is activated by low pH, which removes one or more fusion repressors that interact with EFC components. Additional EFC-interacting fusion repressors insert into cell membranes and prevent secondary infection. The absence of detailed structural information, except for two attachment proteins and one EFC protein, is delaying efforts to determine the fusion mechanism.
Topics: Animals; Cell Fusion; Humans; Membrane Fusion; Models, Biological; Poxviridae; Viral Proteins; Virus Internalization
PubMed: 27423915
DOI: 10.1016/j.semcdb.2016.07.015 -
Autophagy Jun 2022STX17 (syntaxin 17) mediates autophagosome-lysosome fusion, and the translocation of STX17 to autophagosomes is characteristic of this process. STX17 arrives at...
STX17 (syntaxin 17) mediates autophagosome-lysosome fusion, and the translocation of STX17 to autophagosomes is characteristic of this process. STX17 arrives at autophagosomes when they are closed, stays there for approximately 10 min to promote fusion with lysosomes, and leaves when the autolysosomes are mature. However, the mechanism of this transient visit remains largely unknown. Here, we summarize the current knowledge about this phenomenon, including a recently discovered retrieval mechanism, and discuss remaining questions. MAM: mitochondria-associated membrane; SNX: sorting nexin; STX17: syntaxin 17.
Topics: Autophagosomes; Autophagy; Lysosomes; Membrane Fusion; Qa-SNARE Proteins
PubMed: 35613317
DOI: 10.1080/15548627.2022.2079337 -
Journal of Neurochemistry Apr 2021The revolution in genetic technology has ushered in a new age for our understanding of the underlying causes of neurodevelopmental, neuromuscular and neurodegenerative... (Review)
Review
The revolution in genetic technology has ushered in a new age for our understanding of the underlying causes of neurodevelopmental, neuromuscular and neurodegenerative disorders, revealing that the presynaptic machinery governing synaptic vesicle fusion is compromised in many of these neurological disorders. This builds upon decades of research showing that disturbance to neurotransmitter release via toxins can cause acute neurological dysfunction. In this review, we focus on disorders of synaptic vesicle fusion caused either by toxic insult to the presynapse or alterations to genes encoding the key proteins that control and regulate fusion: the SNARE proteins (synaptobrevin, syntaxin-1 and SNAP-25), Munc18, Munc13, synaptotagmin, complexin, CSPα, α-synuclein, PRRT2 and tomosyn. We discuss the roles of these proteins and the cellular and molecular mechanisms underpinning neurological deficits in these disorders.
Topics: Animals; Exocytosis; Humans; Membrane Fusion; Neurons; Synaptic Transmission; Synaptic Vesicles; Synaptotagmins
PubMed: 32916768
DOI: 10.1111/jnc.15181 -
Chemistry and Physics of Lipids Jan 2015Lipid bilayers play a fundamental role in many biological processes, and a considerable effort has been invested in understanding their behavior and the mechanism of... (Review)
Review
Lipid bilayers play a fundamental role in many biological processes, and a considerable effort has been invested in understanding their behavior and the mechanism of topological changes like fusion and pore formation. Due to the time- and length-scale on which these processes occur, computational methods have proven to be an especially useful tool in their study. With their help, a number of interesting findings about the shape of fusion intermediates could be obtained, and novel hypotheses about the mechanism of topological changes and the involvement of peptides therein were suggested. In this work, we try to present a summary of these developments together with some hitherto unpublished results, featuring, among others, the shape of stalks and fusion pores, possible modes of action of the influenza HA fusion peptide and the SNARE protein complex, the mechanism of supported lipid bilayer formation by vesicle spreading, and the free energy and transition pathway of the fusion process.
Topics: Lipid Bilayers; Membrane Fusion; Models, Molecular; Porosity; Thermodynamics
PubMed: 25087882
DOI: 10.1016/j.chemphyslip.2014.07.010 -
Nature Communications Oct 2023The multi-subunit homotypic fusion and vacuole protein sorting (HOPS) membrane-tethering complex is required for autophagosome-lysosome fusion in mammals, yet...
The multi-subunit homotypic fusion and vacuole protein sorting (HOPS) membrane-tethering complex is required for autophagosome-lysosome fusion in mammals, yet reconstituting the mammalian HOPS complex remains a challenge. Here we propose a "hook-up" model for mammalian HOPS complex assembly, which requires two HOPS sub-complexes docking on membranes via membrane-associated Rabs. We identify Rab39A as a key small GTPase that recruits HOPS onto autophagic vesicles. Proper pairing with Rab2 and Rab39A enables HOPS complex assembly between proteoliposomes for its tethering function, facilitating efficient membrane fusion. GTP loading of Rab39A is important for the recruitment of HOPS to autophagic membranes. Activation of Rab39A is catalyzed by C9orf72, a guanine exchange factor associated with amyotrophic lateral sclerosis and familial frontotemporal dementia. Constitutive activation of Rab39A can rescue autophagy defects caused by C9orf72 depletion. These results therefore reveal a crucial role for the C9orf72-Rab39A-HOPS axis in autophagosome-lysosome fusion.
Topics: Animals; Autophagy; C9orf72 Protein; Catalysis; Guanosine Triphosphate; Mammals; Membrane Fusion; Vacuoles
PubMed: 37821429
DOI: 10.1038/s41467-023-42003-0 -
Nature Reviews. Microbiology Jul 2015Effective antivirals have been developed against specific viruses, such as HIV, Hepatitis C virus and influenza virus. This 'one bug-one drug' approach to antiviral drug... (Review)
Review
Effective antivirals have been developed against specific viruses, such as HIV, Hepatitis C virus and influenza virus. This 'one bug-one drug' approach to antiviral drug development can be successful, but it may be inadequate for responding to an increasing diversity of viruses that cause significant diseases in humans. The majority of viral pathogens that cause emerging and re-emerging infectious diseases are membrane-enveloped viruses, which require the fusion of viral and cell membranes for virus entry. Therefore, antivirals that target the membrane fusion process represent new paradigms for broad-spectrum antiviral discovery. In this Review, we discuss the mechanisms responsible for the fusion between virus and cell membranes and explore how broad-spectrum antivirals target this process to prevent virus entry.
Topics: Animals; Antiviral Agents; Cell Membrane; Humans; Membrane Fusion; Virus Diseases; Virus Internalization
PubMed: 26075364
DOI: 10.1038/nrmicro3475 -
Advanced Biology Jan 2022Cellular membranes exhibit a fascinating variety of different morphologies, which are continuously remodeled by transformations of membrane shape and topology. This... (Review)
Review
Cellular membranes exhibit a fascinating variety of different morphologies, which are continuously remodeled by transformations of membrane shape and topology. This remodeling is essential for important biological processes (cell division, intracellular vesicle trafficking, endocytosis) and can be elucidated in a systematic and quantitative manner using synthetic membrane systems. Here, recent insights obtained from such synthetic systems are reviewed, integrating experimental observations and molecular dynamics simulations with the theory of membrane elasticity. The study starts from the polymorphism of biomembranes as observed for giant vesicles by optical microscopy and small nanovesicles in simulations. This polymorphism reflects the unusual elasticity of fluid membranes and includes the formation of membrane necks or fluid 'worm holes'. The proliferation of membrane necks generates stable multi-spherical shapes, which can form tubules and tubular junctions. Membrane necks are also essential for the remodeling of membrane topology via membrane fission and fusion. Neck fission can be induced by fine-tuning of membrane curvature, which leads to the controlled division of giant vesicles, and by adhesion-induced membrane tension as observed for small nanovesicles. Challenges for future research include the interplay of curvature elasticity and membrane tension during membrane fusion and the localization of fission and fusion processes within intramembrane domains.
Topics: Cell Division; Cell Membrane; Elasticity; Membrane Fusion; Membranes
PubMed: 34859961
DOI: 10.1002/adbi.202101020 -
Biochemical Society Transactions Aug 2022Visualization of cellular dynamics using fluorescent light microscopy has become a reliable and indispensable source of experimental evidence for biological studies.... (Review)
Review
Visualization of cellular dynamics using fluorescent light microscopy has become a reliable and indispensable source of experimental evidence for biological studies. Over the past two decades, the development of super-resolution microscopy platforms coupled with innovations in protein and molecule labeling led to significant biological findings that were previously unobservable due to the barrier of the diffraction limit. As a result, the ability to image the dynamics of cellular processes is vastly enhanced. These imaging tools are extremely useful in cellular physiology for the study of vesicle fusion and endocytosis. In this review, we will explore the power of stimulated emission depletion (STED) and confocal microscopy in combination with various labeling techniques in real-time observation of the membrane transformation of fusion and endocytosis, as well as their underlying mechanisms. We will review how STED and confocal imaging are used to reveal fusion and endocytic membrane transformation processes in live cells, including hemi-fusion; hemi-fission; hemi-to-full fusion; fusion pore opening, expansion, constriction and closure; shrinking or enlargement of the Ω-shape membrane structure after vesicle fusion; sequential compound fusion; and the sequential endocytic membrane transformation from flat- to O-shape via the intermediate Λ- and Ω-shape transition. We will also discuss how the recent development of imaging techniques would impact future studies in the field.
Topics: Cell Membrane; Endocytosis; Exocytosis; Membrane Fusion; Microscopy, Confocal; Secretory Vesicles
PubMed: 35960003
DOI: 10.1042/BST20210263 -
Journal of Cell Science Aug 2022Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are membrane-associated trafficking proteins that confer identity to lipid membranes and... (Review)
Review
Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are membrane-associated trafficking proteins that confer identity to lipid membranes and facilitate membrane fusion. These functions are achieved through the complexing of Q-SNAREs with a specific cognate target R-SNARE, leading to the fusion of their associated membranes. These SNARE complexes then dissociate so that the Q-SNAREs and R-SNAREs can repeat this cycle. Whilst the basic function of SNAREs has been long appreciated, it is becoming increasingly clear that the cell can control the localisation and function of SNARE proteins through posttranslational modifications (PTMs), such as phosphorylation and ubiquitylation. Whilst numerous proteomic methods have shown that SNARE proteins are subject to these modifications, little is known about how these modifications regulate SNARE function. However, it is clear that these PTMs provide cells with an incredible functional plasticity; SNARE PTMs enable cells to respond to an ever-changing extracellular environment through the rerouting of membrane traffic. In this Review, we summarise key findings regarding SNARE regulation by PTMs and discuss how these modifications reprogramme membrane trafficking pathways.
Topics: Membrane Fusion; Protein Processing, Post-Translational; Proteomics; Q-SNARE Proteins; SNARE Proteins
PubMed: 35972760
DOI: 10.1242/jcs.260112 -
Current Biology : CB Apr 2018Cells are largely compartmentalized into numerous interacting organelles with dedicated functions in lipid metabolism, energy generation, or protein turnover. In the... (Review)
Review
Cells are largely compartmentalized into numerous interacting organelles with dedicated functions in lipid metabolism, energy generation, or protein turnover. In the past, each organelle has been considered as an isolated unit with an individual proteome, membrane composition, and shape. However, this view is changing rapidly as organelles communicate via contact sites, fuse directly with each other, or correspond via vesicular carriers. Each of these processes disturbs the initial individual character of each organelle and they thus need to be tightly controlled and regulated.
Topics: Animals; Humans; Intracellular Membranes; Lipid Metabolism; Membrane Fusion; Organelles; Protein Subunits; Protein Transport
PubMed: 29689226
DOI: 10.1016/j.cub.2017.12.012