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Seminars in Cell & Developmental Biology Dec 2016Autophagy, a conserved self-eating process for the bulk degradation of cytoplasmic materials, involves double-membrane autophagosomes formed when an isolation membrane... (Review)
Review
Autophagy, a conserved self-eating process for the bulk degradation of cytoplasmic materials, involves double-membrane autophagosomes formed when an isolation membrane emerges and their direct fusion with lysosomes for degradation. For the early biogenesis of autophagosomes and their later degradation in lysosomes, membrane fusion is necessary, although different sets of genes and autophagy-related proteins involved in distinct fusion steps have been reported. To clarify the molecular mechanism of membrane fusion in autophagy, to not only expand current knowledge of autophagy, but also benefit human health, this review discusses key findings that elucidate the unique membrane dynamics of autophagy.
Topics: Animals; Autophagosomes; Autophagy; Autophagy-Related Proteins; Humans; Membrane Fusion; SNARE Proteins
PubMed: 27422330
DOI: 10.1016/j.semcdb.2016.07.009 -
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 -
Seminars in Cell & Developmental Biology Sep 2015Mature skeletal muscle forms from the fusion of skeletal muscle precursor cells, myoblasts. Myoblasts fuse to other myoblasts to generate multinucleate myotubes during... (Review)
Review
Mature skeletal muscle forms from the fusion of skeletal muscle precursor cells, myoblasts. Myoblasts fuse to other myoblasts to generate multinucleate myotubes during myogenesis, and myoblasts also fuse to other myotubes during muscle growth and repair. Proteins within myoblasts and myotubes regulate complex processes such as elongation, migration, cell adherence, cytoskeletal reorganization, membrane coalescence, and ultimately fusion. Recent studies have identified cell surface proteins, intracellular proteins, and extracellular signaling molecules required for the proper fusion of muscle. Many proteins that actively participate in myoblast fusion also coordinate membrane repair. Here we will review mammalian membrane fusion with specific attention to proteins that mediate myoblast fusion and muscle repair.
Topics: Animals; Cell Adhesion; Cell Membrane; Humans; Intracellular Signaling Peptides and Proteins; Membrane Fusion; Muscle Development; Muscle, Skeletal; Myoblasts; Wound Healing
PubMed: 26537430
DOI: 10.1016/j.semcdb.2015.10.026 -
Cell Reports Mar 2023La Crosse virus, responsible for pediatric encephalitis in the United States, and Schmallenberg virus, a highly teratogenic veterinary virus in Europe, belong to the...
La Crosse virus, responsible for pediatric encephalitis in the United States, and Schmallenberg virus, a highly teratogenic veterinary virus in Europe, belong to the large Orthobunyavirus genus of zoonotic arthropod-borne pathogens distributed worldwide. Viruses in this under-studied genus cause CNS infections or fever with debilitating arthralgia/myalgia syndromes, with no effective treatment. The main surface antigen, glycoprotein Gc (∼1,000 residues), has a variable N-terminal half (Gc) targeted by the patients' antibody response and a conserved C-terminal moiety (Gc) responsible for membrane fusion during cell entry. Here, we report the X-ray structure of post-fusion La Crosse and Schmallenberg virus Gc, revealing the molecular determinants for hairpin formation and trimerization required to drive membrane fusion. We further experimentally confirm the role of residues in the fusion loops and in a vestigial endoplasmic reticulum (ER) translocation sequence at the Gc-Gc junction. The resulting knowledge provides essential molecular underpinnings for future development of potential therapeutic treatments and vaccines.
Topics: Humans; Child; Orthobunyavirus; Membrane Glycoproteins; Membrane Fusion; Glycoproteins; La Crosse virus
PubMed: 36827185
DOI: 10.1016/j.celrep.2023.112142 -
Traffic (Copenhagen, Denmark) Jul 2019Vesicular transport between different membrane compartments is a key process in cell biology required for the exchange of material and information. The complex machinery... (Review)
Review
Vesicular transport between different membrane compartments is a key process in cell biology required for the exchange of material and information. The complex machinery that executes the formation and delivery of transport vesicles has been intensively studied and yielded a comprehensive view of the molecular principles that underlie the budding and fusion process. Tethering also represents an essential step in each trafficking pathway. It is mediated by Rab GTPases in concert with so-called tethering factors, which constitute a structurally diverse family of proteins that share a similar role in promoting vesicular transport. By simultaneously binding to proteins and/or lipids on incoming vesicles and the target compartment, tethers are thought to bridge donor and acceptor membrane. They thus provide specificity while also promoting fusion. However, how tethering works at a mechanistic level is still elusive. We here discuss the recent advances in the structural and biochemical characterization of tethering complexes that provide novel insight on how these factors might contribute the efficiency of fusion.
Topics: Animals; Cell Membrane; Humans; Membrane Fusion; Transport Vesicles; Vesicular Transport Proteins
PubMed: 31062920
DOI: 10.1111/tra.12655 -
The Journal of Membrane Biology Jun 2022Membrane fusion is an essential process for the survival of eukaryotes and the entry of enveloped viruses into host cells. A proper understanding of the mechanism of... (Review)
Review
Membrane fusion is an essential process for the survival of eukaryotes and the entry of enveloped viruses into host cells. A proper understanding of the mechanism of membrane fusion would provide us a handle to manipulate several biological pathways, and design efficient vaccines against emerging and re-emerging viral infections. Although fusion proteins take the central stage in catalyzing the process, role of lipid composition is also of paramount importance. Lipid composition modulates membrane organization and dynamics and impacts the lipid-protein (peptide) interaction. Moreover, the intrinsic curvature of lipids has strong impact on the formation of stalk and hemifusion diaphragm. Detection of transiently stable intermediates remains the bottleneck in the understanding of fusion mechanism. In order to circumvent this challenge, analytical methods can be employed to determine the kinetic parameters from ensemble average measurements of observables, such as lipid mixing, content mixing, and content leakage. The current review aims to present an analytical method that would aid our understanding of the fusion mechanism, provides a better insight into the role of lipid shape, and discusses the interplay of lipid and peptide in membrane fusion.
Topics: Kinetics; Lipids; Membrane Fusion; Peptides
PubMed: 35435451
DOI: 10.1007/s00232-022-00233-1 -
Proceedings of the National Academy of... May 2023Among the current five Variants of Concern, infections caused by SARS-CoV-2 B.1.617.2 (Delta) variant are often associated with the greatest severity. Despite recent...
Among the current five Variants of Concern, infections caused by SARS-CoV-2 B.1.617.2 (Delta) variant are often associated with the greatest severity. Despite recent advances on the molecular basis of elevated pathogenicity using recombinant proteins, the architecture of intact Delta virions remains veiled. Moreover, pieces of molecular evidence for the detailed mechanism of S-mediated membrane fusion are missing. Here, we showed the pleomorphic nature of Delta virions from electron beam inactivated samples and reported the in situ structure and distribution of S on the authentic Delta variant. We also captured the virus-virus fusion events, which provided pieces of structural evidence for Delta's attenuated dependency on cellular factors for fusion activation, and proposed a model of S-mediated membrane fusion. Besides, site-specific glycan analysis revealed increased oligomannose-type glycosylation of native Delta S than that of the WT S. Together, these results disclose distinctive factors of Delta being the most virulent SARS-CoV-2 variant.
Topics: Humans; SARS-CoV-2; COVID-19; Membrane Fusion; Glycosylation; Spike Glycoprotein, Coronavirus
PubMed: 37094167
DOI: 10.1073/pnas.2213332120 -
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