Corrotte M, Almeida PE, Tam C, Castro-Gomes T, Fernandes MC, Millis BA, Maugel TK. FOIA Once membrane tension is restored, the poloxamer compound is forced out of the outer membrane leaflet (Houang, Sham, Bates, & Metzger, 2018). One signaling function of lipids is the recruitment of peripheral membrane proteins to the plasma membrane. A surprise arrived when heart muscle cells were analyzed. Drescher DG, Drescher MJ, Selvakumar D, Annam NP. Further, PE and PC head groups can be cleaved and replaced with serine to produce PS (Oropeza, 2017). The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. (C) Plasma membrane is dynamic and individual lipids have the capacity to move laterally within a leaflet (shown in pink) and between the leaflets (shown in blue). Acute and chronic release of lipids and free fatty acids following cell and tissue injury has been widely recognized to be involved in the process of tuning the inflammatory and subsequent tissue repair response. Other cells acquire specialized functions as they mature. However, these repair activities can also be observed at the single-cell level. One of the roles of lipid mobility may be to allow for the movement of individual lipids to form microdomains near the site of injury, which has been shown to be important for repair (Vaughan et al., 2014), perhaps by facilitating lipid-mediated signaling. From PA, cells generate DAG, or cytidine diphosphate-DAG (CDP-DAG), which serve as inputs into the phospholipid biosynthetic pathways (Figure 1A, ,B).B). Self-repairing cells: How single cells heal membrane ruptures and restore lost structures Many organisms and tissues display the ability to heal and regenerate as needed for normal physiology and as a result of pathogenesis. sharing sensitive information, make sure youre on a federal PIP2 also accumulates at the site of membrane injury (Demonbreun et al., 2016; Vaughan et al., 2014). F-actin accumulation is also responsible for providing support to the newly resealed membrane, restoring tension, and preventing subsequent injury. In addition to working on their own, lipids also interact with proteins to coordinate these processes. Intriguingly, PIP2 is needed for PLD activity suggesting the possibility that a feed-forward loop leads to increasing PIP2 concentrations as repair progresses ultimately facilitating the necessary build-up of F-actin (Figure 1B). Houang EM, Haman KJ, Filareto A, Perlingeiro RC, Bates FS, Lowe DA, & Metzger JM (2015). C-terminal di-arginine motif of Cdc42 protein is essential for binding to phosphatidylinositol 4, 5-bisphosphate-containing membranes and inducing cellular transformation, Plasma membraneCortical cytoskeleton interactions: A cell biology approach with biophysical considerations, Control of diverse subcellular processes by a single multi-functional lipid phosphatidylinositol 4, 5-bisphosphate [PI (4, 5) P2], The structural role of cholesterol in cell membranes: from condensed bilayers to lipid rafts. ASM activity at the plasma membrane has been shown to facilitate microvesicle shedding (Bianco et al., 2009). The plasma membrane is not a homogenous mixture of the different lipids described above (Figure 2A). All RightsReserved. Plasma membrane lipids are routinely interconverted as a means to maintain lipid homeostasis and for lipid-mediated signaling. Cell damage. Cell death occurs mainly by two methods: necrosis and apoptosis. Presence of PS at the free membrane wound edge helps directs the annexin proteins to this site in a calcium-dependent manner, where they perform vital functions required for stabilization and shaping of the repairing membrane (see Section 3.3). Local oxidation at the site of membrane injury activates MG53 oligomerization (Cai et al., 2009), which may locally increase membrane rigidity. Very large plasma membrane disruptions (micron diameter) require membrane patching. Inositol is bound to the phosphate group in this phospholipid. Necrosis is a progressive failure of essential metabolic and structural cell components usually in the cytoplasm. Plasma membrane damage increases the fluidity of individual lipids, allowing them more freedom to migrate laterally, rotate, or even flip appearing in the opposite leaflet of the membrane. Nam D. Jan 28, 2018 Because it has the Golgi apparatus Explanation: Actually it doesn't heal by itself it is helped by a cell organelle named Golgi apparatus. Gurtner GC, Werner S, Barrandon Y, & Longaker MT (2008). In this way, lipids play an important role in polarizing the cellular response to an injury. While often considered to be a passive resident of the plasma membrane, there is ample evidence to support a more active role of lipids in the process of plasma membrane repair as well as tissue repair. It remains possible that caveolar endocytosis does help partially balance membrane tension, but another possibility is that they serve as mechanosensitive platforms during membrane repair. Use of lipidomics during epidermal wound repair identified that several of the plasma membrane lipids discussed above are enriched during wound repair. Idone V, Tam C, Goss JW, Toomre D, Pypaert M, Andrews NW. There also exists lateral heterogeneity of lipid composition within each leaflet, which is demonstrated by the formation of lipid microdomains, such as the sphingomyelin and cholesterol-rich domains that exist interspersed among the phospholipids throughout the plasma membrane (Cebecauer et al., 2018; Sezgin, Levental, Mayor, & Eggeling, 2017) (Figure 2B). Hall ED, Wang JA, Miller DM, Cebak JE, & Hill RL (2018). and transmitted securely. It also holds the potential for new applications and therapeutic approaches for treating human disease. Microfluidic guillotine for single-cell wound repair studies. Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D, Conversion of phosphatidylcholine to phosphatidylglycerol with phospholipase D and glycerol, Journal of the American Oil Chemists Society. One model explaining membrane injury in dystrophin-deficient muscle fibers proposes that an initial injury causes a local influx of calcium and a local region of hypercontraction. Multiplexed molecular descriptors of pressure ulcers defined by imaging mass spectrometry, Targeting and localized signalling by small GTPases. Single-molecule tracking of small GTPase Rac1 uncovers spatial regulation of membrane translocation and mechanism for polarized signaling, Proceedings of the National Academy of Sciences. Many organisms and tissues display the ability to heal and regenerate as needed for normal physiology and as a result of pathogenesis. Togo T, Krasieva TB, & Steinhardt RA (2000). The basement membrane of the basal cells attaches via hemidesmosomes to the underlying Bowman's layer, while anchoring fibrils pass through . Taverna D, Nanney LB, Pollins AC, Sindona G, & Caprioli R (2011). Thus, while increase in lipid mobility following plasma membrane injury is associated with successful repair, excessive lipid mobility leading to membrane instability is detrimental to the repair process. PIP2 accumulation was observed as early as 4 seconds in mouse myofibers; however, it continued to accumulate even 1 minute post-injury suggesting a role in the later stages of repair (Demonbreun et al., 2016). Treatment with Recombinant Human MG53 Protein Increases Membrane Integrity in a Mouse Model of Limb Girdle Muscular Dystrophy 2B. lipids) is one of the roles proposed for lysosome-mediated repair (Andrews et al., 2014; McNeil, 2002). The publisher's final edited version of this article is available at, Lipids, plasma membrane, membrane injury, tissue repair. Repeated eccentric exercise in healthy subjects (i.e., stepping down for 20 min) is known to induce damage so severe that muscle fibers degenerate over the following days and weeks (91, 131, 199). Furthermore, ASM activity at the injury site would locally produce ceramide from sphingomyelin. This study showed that endocytosis occurs after membrane resealing and is mediated by the CLIC/GEEC pathway effector GRAF1, which is implicated in repair of muscle fiber plasma membrane injury (Lenhart et al., 2015). We here review what is known about the cellular and molecular mechanisms of membrane repair, with particular emphasis on the relevance of repair as it relates to disease pathologies. Cells respond to mechanical stress by rapid disassembly of caveolae. During the repair of sarcolemmal lesions, macrophages recognize exposed phosphatidylserine at the site of . The calcium influx of a membrane injury activates vesicular exocytosis and homo- and heterotypic fusion of cytoplasmic vesicles. The fluidity of the membrane is determined in part by its composition, with cholesterol and sphingolipid-rich regions being less fluid than those areas comprised primarily of phospholipids. Calcium-activated exocytosis reduces membrane tension and promotes spontaneous repair driven by lipid disorder for injuries hundreds of nanometers in diameter. Middel V, Zhou L, Takamiya M, Beil T, Shahid M, Roostalu U, Nienhaus GU (2016). While lipids are often ascribed a metabolic role as energy storage molecules, they also play important structural and signaling roles in the cell. Mitochondrial redox signaling enables repair of injured skeletal muscle cells. Many of the sphingolipids also contain a glycosidically bound carbohydrate moiety causing formation of the glycosphingolipids. This method of extracellular communication may allow for the proper execution of inflammatory and regenerative responses needed for appropriate tissue remodeling required to restore organ function. If you break a bone, your body immediately begins producing new cells to heal the damage. (2013). Zuzek A, Fan JD, Spaeth CS, & Bittner GD (2013). 2008 Mar 10;180(5):905-14. doi: 10.1083/jcb.200708010. Bookshelf One dead cell is not a big problem. At the population level, the composition of lipids in a membrane can result in formation of signaling platforms that can change the properties of an entire membrane, enabling the cell to finely tune tension, shape, and rigidity. Front Cell Dev Biol. The mystery of membrane organization: composition, regulation and roles of lipid rafts. When a crack moves from the scallops stiff material to the less stiff one, the latter reduces the force at the tip of the crack, thereby stopping it from spreadingfarther. The organization of lipids within the membrane also affects the structure of underlying cortical cytoskeleton. In bacterial and plant cells, a cell wall is attached to the plasma membrane on its outside surface. 2018 Apr 23;28(8):R392-R397. However, to successfully repair the cell also needs to restore the barrier function of the resealed membrane. Cong X, Hubmayr RD, Li C, & Zhao X (2017). For plasma membrane repair to occur successfully, the cell must possess a means to sense that injury has occurred, coordinate the change in activity and localization of repair machinery, and ultimately close the wounded area. Transient change in lipid mobility can have many effects on plasma membrane function related to both structure and signaling, and deciphering which of these are beneficial for repair requires further studies. Membrane lipids: where they are and how they behave. The lipid-mediated cytoskeletal rearrangement described above provides the cell with a mechanism to close the wounded site and add structural support to the newly resealed membrane. Federal government websites often end in .gov or .mil. Disclaimer. (2017). PMC Spiders turn liquid into a strong, stretchy fiber by squeezing it through a small space that helps protein molecules to connect with eachother. Before (2009). Given their ability to traverse away from the site of synthesis (Verweij et al., 2019), the EVs generated during plasma membrane injury may activate both local and distant tissue regeneration responses needed for repair. Bookshelf While PLD is also activated by calcium, recent findings have provided insight into the role of mechanical stress on initiating lipid signaling regulated by PLD (Petersen et al., 2016). Living systems must maintain a proper liquid balance, which is especially difficult in dry conditions. Indeed, mechanical injury of healthy cells transiently increases the mobile fraction of plasma membrane lipids by as much as 9% (Sreetama et al., 2018). Cells are the basic building blocks of all living systems, so cellular processes dictate how physiological processes occur within those systems. The wounded cell can survive if a rapid repair response is mounted that restores boundary integrity. Interestingly, as a result of caveolae flattening, EHD2 dissociates from the plasma membrane and translocates to the nucleus where it alters gene transcription (Torrino et al., 2018). When the plasma membrane of eukaryotic cells is mechanically injured, Ca 2+ influx triggers a rapid repair process that involves exocytosis (Reddy et al., 2001; McNeil, 2002; McNeil et al., 2003).Although the precise repair mechanism is still unknown, current hypotheses propose that resealing is directly mediated by the delivery of intracellular membrane to the cell surface. For example, the dynamic arrangement of lipids in the plasma membrane as discussed above, and the electrostatic or chemical changes in lipids due to enzymatic activity of lipid modifying enzymes rapidly affect lipids themselves as well as the target proteins in the plasma membrane (Figure 2B, ,C).C). Annexins are a class of calcium-sensitive proteins that rapidly accumulate at the site of a membrane injury (Potez et al., 2011). The poor repair of these patient cells can be mirrored in healthy cells by increasing their membrane lipid mobility through the removal of cholesterol or by addition of a glucocorticoid (prednisone) (Heier et al., 2013; Sreetama et al., 2018). Van Meer G, Voelker DR, & Feigenson GW (2008). Houang EM, Sham YY, Bates FS, & Metzger JM (2018). 2008 Nov;18(11):552-9. doi: 10.1016/j.tcb.2008.09.001. As lipids comprise the bulk of the plasma membrane, the acts of injury, resealing, and remodeling all directly impinge upon the plasma membrane lipids. Rapid Changes to Endomembrane System of Infected Root Nodule Cells to Adapt to Unusual Lifestyle. Thus, the signaling role of lipids affects membrane structure and how the wound is eventually resealed and remodeled, returning the plasma membrane to homeostasis. Membrane injury causes a local influx of calcium and activation of calpains. Matsuo H, Chevallier J, Mayran N, Le Blanc I, Ferguson C, Faur J, Sadoul R (2004). Muscle membrane integrity in Duchenne muscular dystrophy: recent advances in copolymer-based muscle membrane stabilizers. Live tracking of inter-organ communication by endogenous exosomes in vivo. By clicking the Accept button you agree to the terms of our privacy policy. Spontaneous formation of a self-healing carbon nanoskin at the liquid-liquid interface. Healing of a punctured Xenopus oocyte, where the dark, The regeneration and reorganization of the oral apparatus (green) of Stentor coeruleus ., Wound healing studies in model cells such as Xenopus oocytes and muscle cells, Evidence that oral regeneration in Stentor can be triggered by the loss of, MeSH With larger injuries, the opposing force of membrane tension exceeds the resealing forces of lipid disorder at the edges of the disruption, negating the driving forces of spontaneous membrane resealing. 2022 Aug 4;11:e80778. By studying how the Trypanosoma cruzi parasite enters the cell, Andrews' laboratory discovered that an increase of intracellular calcium was triggering lysosomal . A cartoon depicting the potential role of dysferlin-mediated vesicle fusion in membrane repair. The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. The primary plasma membrane sphingolipid in mammalian cells is sphingomyelin, which utilizes a ceramide backbone (Merrill Jr, 2008). Being the most abundant component of the plasma membrane, lipids are also essential player in the process of plasma membrane repair; however, much of the research committed to identifying the mechanisms of plasma membrane repair has focused on the proteins associated with plasma membrane repair (Cooper & McNeil, 2015). Additionally, in contrast to PS, which recruits proteins directly involved in repair, DAG appears to recruit signaling proteins such as protein kinase C (PKC) (Vaughan et al., 2014; Zuzek, Fan, Spaeth, & Bittner, 2013). HHS Vulnerability Disclosure, Help Additional structural changes the plasma membrane must adopt for repair include molding the shape of the membrane to limit wound expansion as well as pulling in the membrane edges to close the wound. Sci Rep. 2023 Mar 23;13(1):4763. doi: 10.1038/s41598-023-31973-2. Such a role of CLIC/GEEC-mediated endocytosis in membrane remodeling is also supported by the observation that CLIC/GEEC is immediately activated in response to decreased membrane tension and has the capacity to turn over large amounts of plasma membrane (Thottacherry et al., 2018). These functions also require modulating the membrane area, such as through the processes of exocytosis and endocytosis or by changing the existing membrane architecture (Kozlov & Chernomordik, 2015; Nassoy & Lamaze, 2012). During regeneration, sphingolipids such as sphingosine 1-phosphate (S1P) are known for their growth promoting effect on tissue resident stem cells (Calise et al., 2012; Nojima, Freeman, Gulbins, & Lentsch, 2015). PI5K activity is itself driven by regulators of membrane repair including Rho GTPases (Gilmore & Burridge, 1996) and PLD (Roach et al., 2012). Sealing of transected neurites of rat B104 cells requires a diacylglycerol PKC-dependent pathway and a PKA-dependent pathway, Sezgin, Levental, Mayor, & Eggeling, 2017, Gauthier, Fardin, Roca-Cusachs, & Sheetz, 2011, Miyake, McNeil, Suzuki, Tsunoda, & Sugai, 2001, Skalman, Holst, Larsson, & Lundmark, 2018, Gazzerro, Sotgia, Bruno, Lisanti, & Minetti, 2010, Petersen, Chung, Nayebosadri, & Hansen, 2016, Lee, Kai, Carlson, Groves, & Hurley, 2015, Campelo, Fabrikant, McMahon, & Kozlov, 2010, Lamb, Harper, McKinney, Rzigalinski, & Ellis, 1997, Ligeti, Dagher, Hernandez, Koleske, & Settleman, 2004, Tran, Masedunskas, Weigert, & Ten Hagen, 2015, Godin, Vergen, Prakash, Pagano, & Hubmayr, 2011, Gurtner, Werner, Barrandon, & Longaker, 2008, Taverna, Nanney, Pollins, Sindona, & Caprioli, 2011, Nojima, Freeman, Gulbins, & Lentsch, 2015. These phospholipids are important for the formation of other molecules that are involved in cell signaling and help to bind proteins and carbohydrates to the outer cell membrane. Plasma membrane repair relies on the coordinated activity of repair machinery, which carries out vesicle fusion to the membrane, membrane shedding, and polymerization of F-actin at the site of repair (Horn & Jaiswal, 2018). As dysferlin may only be detected at injury sites with antibodies recognizing COOH-terminal epitopes, and not several antibodies to NH. Spatiotemporal dynamics of actin remodeling and endomembrane trafficking in alveolar epithelial type I cell wound healing. While PA mediates targeting to the membrane, Rac1 activity depends on PIP3, suggesting multiple roles for signaling lipids in GTPase activity after repair. Using these dating methods, it was inferred that fat cells (adipocytes) replace at a rate of 86% per year (BNID 103455). In the subsequent sections, we will discuss how this is achieved and utilized by the cell. When cells have DNA damage but fail to undergo apoptosis, they may be on the road to cancer. Sarcolemmal repair is a slow process and includes EHD2, Effect of oxidative stress on membrane structure: small-angle X-ray diffraction analysis. sharing sensitive information, make sure youre on a federal For example, venomous snakes store precursor molecules to instantly synthesize a suite of toxins via enzyme-mediated cascades. Neurite transection produces cytosolic oxidation, which enhances plasmalemmal repair. PI (3, 4, 5) P3 and PI (4, 5) P2 lipids target proteins with polybasic clusters to the plasma membrane, The membrane and lipids as integral participants in signal transduction: lipid signal transduction for the non-lipid biochemist. Ceramide microdomains formed by the activity of extracellular acid sphingomyelinase near the site of injury could appear on the extracellular leaflet (resulting in endocytosis) or the inner leaflet either by selective flipping across the membrane bilayer (Pollet et al., 2018) or through diffusion of sphingomyelinase through the wounded area to act on inner leaflet sphingomyelin found proximal to the wound edge. The plasma membrane, also called the cell membrane, is the membrane found in all cells that separates the interior of the cell from the outside environment. Rac1, a Rho family GTPase required for repair (Verboon & Parkhurst, 2015), forms nanoclusters at sites enriched in PA and PIP3, whose roles in regulating Rac1 appear to be non-overlapping (Maxwell et al., 2018). The radiation could damage the DNA so badly that the cell dies. J.K.J. Ligeti E, Dagher M-C, Hernandez SE, Koleske AJ, & Settleman J (2004). Verweij FJ, Revenu C, Arras G, Dingli F, Loew D, Pegtel DM, Zimmermann P (2019). The cell membrane is an extremely pliable structure composed primarily of two layers of phospholipids (a "bilayer"). There are many differences between cancer cells and normal cells in noncancerous (benign) or cancerous (malignant) tumors. However, whether caveolae facilitate repair by buffering membrane tension remains unclear because, unlike the capacity of CLIC/GEEC endocytosis, caveolae make up a small portion (as small as 0.03%) of the membrane area and are not found ubiquitously in all cells (Gauthier et al., 2012; Sinha et al., 2011). Exocytic fusion reduces membrane tension, and vesicle-vesicle fusion events provide a patch as a replacement for the membrane barrier missing at the disruption site. In some cases, these forces are benign, such as membrane protrusion driven by cortical actin polymerization (Pontes, Monzo, & Gauthier, 2017). This suggests the possibility that caveolae could act as mechanosensors that facilitate adaptation to membrane injury through gene transcription, although this remains to be explored. Prior to increase in shear force, PLD associates with lipid rafts, physically segregated from its activator PIP2 and its substrate PC (Petersen et al., 2016). As MG53 interacts with the plasma membrane in a cholesterol-dependent manner ((Zhu et al., 2012); see Section 4), its extracellular role may involve a mode of action similar to poloxamer 188, where it inserts within membranes in a disordered lipid environment. sharing sensitive information, make sure youre on a federal Instead, distinct inter- and intra-leaflet heterogeneity exists. Bennett APS, de la Torre-Escudero E, Dermott SSE, Threadgold LT, Hanna REB, Robinson MW. PMC Another broad group of lipid carriers that are recognized for their role in activating stem cells are extracellular vesicles (EVs), which are released locally at the site of injury or from a distant site and through their lipid and other cargoes regulate regeneration of injured tissues by way of stem cell activation (Riazifar, Pone, Ltvall, & Zhao, 2017). The product of PC metabolism by PLD is the signaling lipid PA (Cazzolli, Shemon, Fang, & Hughes, 2006). This cytoskeletal assembly is regulated by Rho GTPase activity, which triggers F-actin accumulation at the site of injury. Acid sphingomyelinase activity triggers microparticle release from glial cells. Direct lipid modification of proteins, such as GTPases, provides another method to regulate protein localization and activity (Casey, 1995). However, in addition to this role, restoring membrane tension is another role that has been proposed for endocytosis after the membrane is resealed following a pore forming toxin injury (Skalman, Holst, Larsson, & Lundmark, 2018). Howard AC, McNeil AK, & McNeil PL (2011). Remorino A, De Beco S, Cayrac F, Di Federico F, Cornilleau G, Gautreau A, Coppey M (2017). Sinha B, Kster D, Ruez R, Gonnord P, Bastiani M, Abankwa D, Johannes L (2011). While PC exists in both the inner and outer leaflet of the plasma membrane, the charged phospholipids PE, PI, and PS are almost exclusively maintained within the inner leaflet (Nicolson, 2014; van Meer, 1989). Furthermore, individual lipids may be modified by proteins, which generate new lipid species that can change membrane structural properties (red, Cer) or be used for signaling (purple, DAG). Marg A, Schoewel V, Timmel T, Schulze A, Shah C, Daumke O, & Spuler S (2012). Liquids, mostly water, make up 70 to 90% of all living systems, and the loss of even a small percentage can mean the difference between life and death. They break down excess or worn-out cell parts. Similar benefits have been attributed to membrane stabilizing copolymers such as poloxamer 188, that improved repair after physiological mechanical injury (Plataki, Lee, Rasmussen, & Hubmayr, 2011), and injury to dystrophic cells (Houang et al., 2015; Yasuda et al., 2005). Furthermore, exposure of the plasma membrane hydrophobic core as a result of reduced lipid packing provides the opportunity for injury-triggered lipid signaling through the binding of cholesterol (see Section 4). Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. Unlike sharks or alligators, for example, whose teeth are generally all the same size and shape, mammals have differently shaped teeth in different areas of the jaws to target specific foods or foraging strategies. Gazzerro E, Sotgia F, Bruno C, Lisanti MP, & Minetti C (2010). "Knowledge of how single cells repair and regenerate themselves underpins our mechanistic understanding of cell biology and could guide treatments for conditions involving cellular damage." These examples illustrate the ability of cells to heal wounds and regenerate missing structures. Membrane proteins also help locally shape and provide rigidity to the plasma membrane by interacting with specific lipids or lipid domains (Cebecauer et al., 2018). Biophys J. In fact, cells are able to perform hundreds, even thousands, of chemical transformations at the same time under life-friendly conditions (ambient temperature and pressure in an aqueous environment). PA is itself generated primarily from glycerol-3-phosphate, which is a product of glycolysis. Slabodnick M, Prevo B, Gross P, Sheung J, Marshall W. J Vis Exp. This results in the replacement of half of the body's adipocytes in 8 years. The site is secure. Alterations in Phosphatidylcholine Metabolism of StretchInjured Cultured Rat Astrocytes. This mechanism is particularly intriguing in light of the redox-sensitive nature of MG53. Plasma membrane damage needs to be rapidly repaired to avoid cell death. For example, caveolae are the site for assembling membrane repair proteins such as EHD2 and MG53 (Cai et al., 2009; Daumke et al., 2007; Marg et al., 2012). Jaiswal JK, Lauritzen SP, Scheffer L, Sakaguchi M, Bunkenborg J, Simon SM, Nylandsted J (2014). Before While the local accumulation of proteins such as annexins acts to stabilize the structurally unstable membrane after injury, remodeling of the membrane itself can achieve a similar outcome. This homeostatic process of vesicle fusion that maintains the plasma membrane at rest also enables plasma membrane repair through regulated fusion of vesicles triggered by calcium influx following plasma membrane injury (Horn & Jaiswal, 2018; McNeil & Steinhardt, 2003). This allows for the movement and patterning of lipids into signaling domains, changing the spatial arrangement of proteins that selectively interact with a particular lipid species. For example, membrane shedding is a known mechanism of plasma membrane repair, which functions to limit the lateral expansion of the wound area (Andrews, Almeida, & Corrotte, 2014; Horn & Jaiswal, 2018). Arp2/3-mediated F-actin formation controls regulated exocytosis in vivo. Epub 2017 Jun 26. In addition to allowing for the lateral translocation of membrane lipids, injury-triggered increase in membrane fluidity also results in reduced lipid packing. Semin Cell Dev Biol. Endogenous mechanisms of repair in healthy cells appear to mimic the beneficial effect provided by poloxamer 188 by allowing for transient increases in lipid mobility while restricting fluidity increase to a relatively small spatial or temporal window. Here we will discuss the current knowledge of how lipids facilitate plasma membrane repair by regulating membrane structure and signaling to coordinate the repair response, and will briefly note how lipid involvement extends beyond plasma membrane repair to the tissue repair response. Mechanistically, the process of membrane shedding is mediated by the endosomal sorting complexes required for transport (ESCRT) proteins (Jimenez et al., 2014; Scheffer et al., 2014). Spontaneous resealing of plasma membrane, Spontaneous resealing of plasma membrane injuries in the nanometer range is opposed by, Calcium-activated exocytosis reduces membrane tension, Calcium-activated exocytosis reduces membrane tension and promotes spontaneous repair driven by lipid disorder, Very large plasma membrane disruptions (micron diameter) require membrane patching. Boye TL, Maeda K, Pezeshkian W, Snder SL, Haeger SC, Gerke V, Nylandsted J. Similarly, peak PIP2 accumulation at the injury site occurred 45 seconds post-injury in Xenopus oocytes (Vaughan et al., 2014).

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