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• W4254319938 abstract "What are the key players in membrane fusion? Membrane fusion is essential to life. It is required for the trafficking of material between cells and cellular compartments, for the mixing of genetic information between organisms and for the sculpting of tissues during development. Membrane fusion is also necessary for infection by enveloped viruses (Figure 1). If membranes could fuse spontaneously, chaos would rule. Trillions of intracellular vesicles and organelles would merge and cells would promiscuously fuse, eliminating all cellular compartments as well as cellularity itself. Luckily, even close and long-lived contact between biological membranes does not result in fusion. Membrane fusion is inhibited by the dense packing of proteins at the contact sites between biological membranes and by the high energy barriers associated with membrane deformation, lipid mixing and fusion-pore expansion. For fusion to become energetically favorable the membranes must overcome the repulsion forces generated by the charged hydrated phospholipids and mix with minimal exposure of their hydrophobic cores. Only proteins are sufficiently complex to coordinate, execute and control such an event, and so began the quest for the missing fusogens of intracellular membranes, cells and viruses. What are fusogens and when were they first discovered? Fusogens are the proteins that act on the membranes to overcome the forces preventing spontaneous membrane fusion and ensure fusion occurs in a controlled and regulated manner. The first fusogens identified were the viral fusogens. Their existence is immediately apparent in enveloped viruses, such as influenza, HIV, hepatitis, dengue and Zika, which have transmembrane glycoproteins on their surface that are responsible for the attachment and fusion of the viral and host membranes. Three structurally distinct classes of viral fusogens have been described so far. Class I fusogens are mostly α-helical, class II fusogens are mostly made of β sheets, and class III contain a mixture of both. Despite their different architectures, viral fusogens share striking mechanistic similarities. Upon activation, all three classes form extended trimers anchored at one end by their transmembrane domains and expose a hydrophobic fusion peptide or amphiphilic loop that inserts into the target membrane. At this stage, the two interacting domains are positioned in different membranes. Subsequent regulated refolding of the fusogenic complex into a hairpin-like structure draws the fusion peptide and transmembrane domains to the same end of the molecule, thereby generating a pulling force that brings the two membranes into close apposition (to a distance of ∼1 nm). Insertion of hydrophobic peptides into the target membrane is thought to generate the local membrane stresses necessary for membrane deformation and lipid mixing between the membranes. Once the bilayers are brought into such close apposition, the accumulated energy is thought to drive fusion through the formation of a hemifusion stalk-like connection, in which only the contacting proximal leaflets of the membranes are fused while the inner leaflets remain intact. Expansion of the hemifusion stalk, and the subsequent fusion of the distal leaflets, completes the reaction by opening a fusion pore that allows the contents of the two compartments to mix. Fusion pore expansion represents the final energy barrier that must be crossed before membrane fusion becomes irreversible. While there is ample evidence that viral fusogens mediate fusion through hemifusion, it is not fully understood how their conformational changes and oligomerization mediate the distinct stages of the hemifusion pathway. The plot thickens: are fusogens also found inside cells? Intracellular fusogens, acting on the endoplasmic side of the membrane to fuse vesicles and organelles, are also abundant and diverse. The most studied and best understood are the SNARE proteins that mediate the fusion of vesicles to their target organelle (Figure 1). They include target membrane proteins SNAP-25 and syntaxin (collectively termed Q-SNAREs or t-SNAREs) and secretory vesicle-associated membrane proteins, synaptobrevins (also known as VAMP, R-SNARE or v-SNARE). When expressed on opposing membranes along with synaptotagmin, these fusogens interact to form a four-helix bundle through interactions of the three different Q-SNAREs with the R-SNARE. Assembly of a four-helix bundle across the two membranes performs a similar function to the hairpin structure of viral fusogens in drawing the two membranes together, and is thought to mediate fusion through hemifusion. However, unlike viral fusogens, which are only required on the viral envelope, SNAREs are bilateral fusogens that mediate fusion via heterotypic interactions across the two fusing membranes. Not all fusogens draw the membranes together by assembling across the two membranes. Dynamin, which is best known for its function in fission of vesicles from the plasma membrane during endocytosis, mediates membrane fusion by self-assembling into rings at the necks of membrane buds where it couples GTP hydrolysis to conformational changes, leading to ring constriction and membrane auto-fusion (i.e. when the cell’s membrane fuses with itself; see Primer on the dynamin superfamily in this issue). Several small dynamin-like GTPases have been implicated in organelle fusion, including: atlastins (in animals) and Sey1p (in yeast), which are required for homotypic fusion of endoplasmic reticulum (ER) tubules; mitofusin/Fzo1p proteins, which mediate mitochondrial outer membrane fusion; and OPA1/Mgm1, which is associated with mitochondrial inner membrane fusion. The sequence homology between atlastins, mitofusins and dynamin-1 extends beyond the GTPase domain, suggesting that they use similar molecular mechanisms to mediate membrane fusion. However, some intracellular fusogens have yet to be identified, including those responsible for the formation of autophagosomes and the nuclear membrane. What is the Holy Grail of developmental cell–cell fusion? Cell–cell fusion is a ubiquitous phenomenon during development of most organisms (Figure 1). Our lives begin with sperm–egg fusion, which is a conserved paradigm in sexually reproducing organisms. Epithelial cells of the eye fuse to form the eye lens syncytia. Macrophage fusion produces either multinucleated osteoclasts, which function in bone resorption, or giant cells, which form at sites of chronic inflammation. In addition, muscle cells fuse to form multinucleated skeletal muscle fibers during muscle development from flies to humans (Figure 1). Fusogens have also been implicated in neuronal repair, stem-cell transdifferentiation and cancer metastasis, especially after infection by enveloped viruses. However, only four families of fusogens mediating cell–cell fusion have been identified so far. The first family are the syncytins, which mediate fusion of epithelial cells in the placenta of several species, including humans, to generate the syncytiotrophoblast, which separates fetal and maternal blood. Syncytins are in fact class I viral fusogens encoded by endogenous retroviral envelope genes that maintained their original fusogenic function in the organism. The second family of eukaryotic fusogens includes the FF proteins (which were identified in the nematode Caenorhabditis elegans, where they are responsible for fusing approximately one-third of all somatic cells during development), and HAP2/GCS1 (which is essential for gamete fusion in flowering plants, some invertebrates and protists, and can be found in the genomes of all major eukaryotic taxa except fungi). Strikingly, the FF and HAP2 proteins are structural homologs of class II viral fusogens, implying that they diverged from a common ancestor. Despite having no sequence identity, these viral and cellular class II fusogens belong in the same structural class defining the fusexins, a superfamily of fusogens essential for sexual reproduction and exoplasmic merger of plasma membranes. The fusexins are a fascinating family that have maintained the same structural core but diversified the mechanism of fusion. While viral fusogens are only required on the viral membrane, FFs are needed in the two fusing membranes to drive fusion. Recent screens in mice have identified two muscle-specific proteins, myomaker (TMEM8c) and myomixer (myomerger/minion) that are essential for muscle fusion. Co-expression of myomaker and myomixer in fibroblasts that do not normally fuse results in cell fusion, demonstrating that these proteins are sufficient to fuse mammalian cells. Myomaker and myomerger have no obvious similarities to the known viral fusogens. It has been suggested that the size and domain architecture of myomixer is reminiscent of FAST proteins, a fourth class of cellular fusogens encoded by non-enveloped reoviruses. Following initial viral infection, FAST proteins mediate the fusion of infected cells with non-infected cells as a mode of cell–cell transmission and immune evasion. Yet, their mechanism is clearly distinct from viral fusogens as they lack a fusion peptide and do not seem to mediate fusion through hemifusion. The precise mechanism of FAST proteins and myomaker/myomixer awaits elucidation. Moreover, the vast majority of cellular fusogens, including those responsible for fertilization in vertebrates and fungi, and muscle fusion in arthropods, remain unidentified or uncharacterized, leaving fundamental gaps in our knowledge about the mechanisms of cell–cell fusion. Joining the quest, how can I tell if my protein is a fusogen? A fusogen, by definition, must be essential for fusion and present at the sites of membrane fusion. Care should be taken to distinguish between a true fusogen acting on the membranes directly during fusion and proteins involved in regulating or preparing the membranes for fusion (i.e., during recognition and tethering/adhesion). Fusogens should be able to mediate membrane fusion in the absence of additional co-factors when expressed on artificial membranes in vitro. Hence, a bona fide fusogen will be expressed at the time and place of membrane fusion and its activity will be both essential and sufficient to drive fusion of diverse membranes. What happens when fusogens are dysregulated? Fusogens have the capacity to control cell fate, modulate behavior and create a barrier for cell invasion. They have enormous therapeutic potential, including the possibility of harnessing their activity to deliver drugs or missing genes to specific cells in the organism. Inhibition of fusogen function can also have therapeutic benefits in the form of vaccines or contraceptives that prevent the delivery of genetic material. But, unregulated and non-specific fusion can have catastrophic consequences. At the subcellular level, fusogens must be tightly regulated to maintain the membrane compartmentalization and organelle identities that enable eukaryotes to carry out different metabolic and biosynthetic activities within spatially distinct chemical environments. Defects in both SNAREs and dynamin have been linked to several human diseases, including neurocutaneous CEDNIK syndrome and centronuclear myopathy. Moreover, cells with reduced mitochondrial fusion accumulate mitochondria lacking mitochondrial DNA, leading to respiration defects and neurodegenerative diseases, such as Charcot–Marie–Tooth syndrome and dominant optic atrophy. Atlastin is essential for ER fusion and functions in sensory neurons; mutations in atlastin-1 have been linked to spastic paraplegia and hereditary sensory neuropathy. Loss of fusogen function has been associated with various diseases and conditions, such as infertility and muscle dystrophies. Non-specific expression of cellular or viral fusogens (e.g. after infection by an enveloped virus) can lead to fusion of cells within a tumor or between cancer cells and macrophages. The resulting heterokaryons may acquire metastatic properties by increasing their genetic and epigenetic diversity through fusion. There are 18 known retroviral elements in the human genome that encode intact viral fusogens, although their contribution to cell fusion during normal development or disease is not fully understood. The quest continues: what do we still have to learn? The mechanics and chemistry of biological membranes have driven the evolution of fusogenic proteins mediating diverse physiological phenomena. Even for the best-characterized fusogens, a comprehensive view of how the proteins and lipids work together to drive this process is still largely missing. New technologies enabling the dissection of the fusion reaction with high temporal and spatial resolution will help define how fusogens generate the forces required for membrane fusion and elucidate the precise role of different mechanistic domains in this process. Priority must also be given to identifying the missing cellular fusogens to elucidate the mechanisms of cell–cell fusion and unravel the evolutionary relationship between viral and cellular fusogens. The authors have a patent related to this topic: 2012 Antinematodal methods and compositions. Podbilewicz, B., Avinoam, O., and White, J.M., WO Patent 2,012,104,837." @default.
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• W4254319938 date "2018-04-01" @default.
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• W4254319938 title "Fusogens" @default.
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