how does a cell membrane repair itself

Schematic representation of the structural features of the protein families implicated in membrane repair. Gushchina LV, Bhattacharya S, McElhanon KE, Choi JH, Manring H, Beck EX, Weisleder N. (2017). A decrease in membrane tension precedes successful cell-membrane repair. Injury to the plasma membrane also changes the biochemical environment within the cell. Formation of these outward budding vesicles at the plasma membrane is associated with an increase in cytosolic calcium and oxidation, as well as the disruption of the actin cytoskeletonplasma membrane interface (Pollet, Conrard, Cloos, & Tyteca, 2018), and each of these occurs locally in the immediate aftermath of membrane injury (Andrews et al., 2014; Horn & Jaiswal, 2018). Sphingolipids in liver injury, repair and regeneration, Development of Biomimetic Membrane Assemblies on Microspheres for High-Throughput and Multiplexable Studies, Caveolae as plasma membrane sensors, protectors and organizers. The radiation could damage the cell's DNA, but the DNA repairs itself. Caveolae protect endothelial cells from membrane rupture during increased cardiac output. Cell before mitosis showing the location of the centrioles, microtubules, nuclear membrane, nucleolus, and DNA (Let's Talk Science using an image by Aldona via iStockphoto). It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. doi: 10.1042/BSR20220765. 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. An actin-dependent annexin complex mediates plasma membrane repair in muscle. 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. Muscle membrane integrity in Duchenne muscular dystrophy: recent advances in copolymer-based muscle membrane stabilizers. BMC Biol. This process is more efficient when GTPases and their regulatory proteins (which are themselves regulated by lipids) are clustered (Ligeti, Dagher, Hernandez, Koleske, & Settleman, 2004). The wounded cell can survive if a rapid repair respons Membrane Repair: Mechanisms and Pathophysiology PIP2 dynamics after plasma membrane injury support a role for PIP2 in actin assembly during repair as its accumulation near the site of injury is generally delayed. Ligeti E, Dagher M-C, Hernandez SE, Koleske AJ, & Settleman J (2004). These enzymes initiate signaling through the generation of new lipid species, providing an added spatial, as well as a temporal component to lipid signaling, helping to more precisely coordinate the repair response. While no defined roles for PA after membrane injury are known, PA has been observed to rapidly appear at the wound edge (Vaughan et al., 2014), which fits with the fast (650 s) timescale of PA generation by PLD (Petersen et al., 2016). Saarikangas J, Zhao H, & Lappalainen P (2010). Gauthier NC, Fardin MA, Roca-Cusachs P, & Sheetz MP (2011). Unauthorized use of these marks is strictly prohibited. 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). For example, a scallop prevents structural failure from fracture because its shell is comprised of two materials of varying stiffness. While PA mediates targeting to the membrane, Rac1 activity depends on PIP3, suggesting multiple roles for signaling lipids in GTPase activity after repair. 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. Spontaneous formation of a self-healing carbon nanoskin at the liquid-liquid interface. Role of phosphatidylinositol 4, 5-bisphosphate in regulating EHD2 plasma membrane localization. Mammals make up less than 1% of all animals on earth, but they include some of the most well-known species. 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. As she describes, a lesion is followed by a Ca2+-dependent movement of vesicles to the plasma membrane. Interestingly, several methods for PIP2 micro-domain formation may allow for this to occur after plasma membrane injury. This is especially important for membrane signaling functions as the liquid-ordered domains often serve to aggregate membrane-associated proteins (Cebecauer et al., 2018). Modeling membrane shaping by proteins: Focus on EHD2 and NBAR domains. Like the exterior walls of a house, the . Promotion of plasma membrane repair by vitamin E. Idone V, Tam C, Goss JW, Toomre D, Pypaert M, & Andrews NW (2008). The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Leikina E, Defour A, Melikov K, Van der Meulen JH, Nagaraju K, Bhuvanendran S, Jaiswal JK (2015). government site. Healing, Examples of self-repairing cells. The mystery of membrane organization: composition, regulation and roles of lipid rafts. Do Heo W, Inoue T, Park WS, Kim ML, Park BO, Wandless TJ, & Meyer T (2006). 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). In contrast, Annexin 1, one of the earliest responders to plasma membrane injury (Leikina et al., 2015; McNeil, Rescher, Gerke, & McNeil, 2006), does not appear to be essential for plasma membrane repair (Leikina et al., 2015; McNeil et al., 2006). Delivery of membrane (i.e. Before However, these repair activities can also be observed at the single-cell level. Evidence suggests these pores are removed both by endosomal degradative pathways (123, 164, 280) and exosomal shedding (14, 118, 136). Importantly, sequestration of cholesterol alone increased PLD activity, supporting the idea that transient increase in lipid fluidity after membrane injury may be required for PLD-mediated signaling. 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. 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). 2008 Mar 10;180(5):905-14. doi: 10.1083/jcb.200708010. The fatty membranes of cells are capable of self-repair using a mechanism that involves calcium-dependent exocytosis. Arp2/3-mediated F-actin formation controls regulated exocytosis in vivo. As described above, damage to the plasma membrane transiently increases the mobility of individual lipids. 2022 Aug 4;11:e80778. (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). It is unclear what role, if any, that IP3 may have in repair, but its role in calcium signaling and the fact that injured cells secrete IP3 for hours post-injury (Lamb et al., 1997) suggest a possible signaling role in repair that may extend beyond the process of membrane resealing, which needs further investigation. Cell membrane disruption initially stimulates repair responses in the wounded cell itself, as described in this chapter, but other cells can subsequently respond to membrane disruption to "help" repair the membrane of the injured cell. The membrane patch may serve only temporarily as a surface barrier replacement that is subsequently remodeled and removed via exocytic and/or endocytic machinery. Clipboard, Search History, and several other advanced features are temporarily unavailable. For example, replacement of a cylindrical lipid (e.g. Patients with muscular dystrophy are more susceptible to injury from eccentric stretch (216), with studies in mouse models suggesting susceptibility to injury can escalate with multiple insults (53). This is notable because it is hypothesized that a beneficial role of decreasing membrane fluidity is preventing the spread of harmful lipid hydroperoxides, which likely form in the oxidative environment near the site of injury (Braughler & Hall, 1992; Hall, Wang, Miller, Cebak, & Hill, 2018). To regulate the composition of plasma membrane lipids, cells utilize vesicle trafficking, which can add lipids (by exocytosis) or remove lipids (by endocytosis) from the plasma membrane. PI5K activity is itself driven by regulators of membrane repair including Rho GTPases (Gilmore & Burridge, 1996) and PLD (Roach et al., 2012). 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. Phospholipids and sphingolipids are connected by the head group choline, found on both PC and sphingomyelin (SM). It also holds the potential for new applications and therapeutic approaches for treating human disease. Lipids also react to the changing biochemical environment to become signaling molecules that determine the spatiotemporal dynamics of protein activation (Eyster, 2007) (Figure 1B). Trends Cell Biol. Zhang KS, Blauch LR, Huang W, Marshall WF, Tang SKY. PS) in the inner leaflet, causes the plasma membrane to attain an overall outward curvature. and transmitted securely. However, to successfully repair the cell also needs to restore the barrier function of the resealed membrane. Physico-chemical and biological considerations for membrane wound evolution and repair in animal cells. the contents by NLM or the National Institutes of Health. Rayens NT, Cook KJ, McKinley SA, Payne CK. 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). Curr Biol. Bethesda, MD 20894, Web Policies This relies upon the coordinated action of the machinery that polarizes the repair response to the site of injury, resulting in resealing of the damaged membrane and subsequent remodeling to return the injured plasma membrane to its pre-injury state. 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. One such mechanism is addition of more membrane via vesicle fusion (Fig 1B ). This process, facilitated by the dysferlin-mediated release of acid sphingomyelinase (Defour et al., 2014) creates microdomains of ceramide from sphingomyelin. Plasma membrane damage needs to be rapidly repaired to avoid cell death. The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. These examples illustrate the far-reaching consequence of lipid movement on structural stability of the plasma membrane and its ability to successfully repair. In mammalian cells the majority of cellular cholesterol is found in the plasma membrane, where it can make up to 50% of lipid content (Van Meer, Voelker, & Feigenson, 2008). Failure of injured cells to repair results in cell death and activates a tissue repair response. Mitochondrial redox signaling enables repair of injured skeletal muscle cells. PLD-mediated activation of PI5K relies on the formation of PA, which itself is able to determine the spatial localization of PI5K as well as cause its activation (Roach et al., 2012). 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. Disclaimer. . For example, the cytoskeletal proteins interact with membrane lipids to supply the cortical tension that regulates the global shape of the plasma membrane and produces cell movement (Cebecauer et al., 2018; Sezgin et al., 2017). Amongst other causes, this can be due to physical, chemical, infectious, biological, nutritional or immunological factors. Epub 2008 Mar 3. VBP15, a novel antiinflammatory and membranestabilizer, improves muscular dystrophy without side effects, Cellular mechanisms and signals that coordinate plasma membrane repair. Lipid-soluble molecules and some small molecules can permeate the membrane, but the lipid bilayer effectively repels the many large . All of the above mechanisms for regulating the physical properties of the membrane play important roles in determining how a cell responds to plasma membrane injury and undergoes successful repair. Lee I-H, Kai H, Carlson L-A, Groves JT, & Hurley JH (2015). Roach AN, Wang Z, Wu P, Zhang F, Chan RB, Yonekubo Y, Du G (2012). Annexins can physically manipulate the injured plasma membrane by stabilizing, folding, and contracting in order to facilitate repair (Gerke et al., 2005; Jaiswal & Nylandsted, 2015). 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). Without adequate remodeling, the plasma membrane protein and lipid composition would change dramatically, particularly after repeat injuries, and no longer function as in its pre-injury state. The organization of lipids within the membrane also affects the structure of underlying cortical cytoskeleton. The primary method for PIP2 formation in cells is by the activity of PI(4)P-5 kinase (PI5K) (Kolay, Basu, & Raghu, 2016). Influx of calcium from the extracellular space, as well as locally increased oxidation, both trigger lipid signaling that is required for repair. Self-repair: Our bodies are packages within packages. Water is essential to life. While reassembly of the cortical cytoskeleton in the minutes following injury is known to restore membrane tension (described in Section 3.3), membrane remodeling also contributes to increasing tension. Use the force: membrane tension as an organizer of cell shape and motility. Spatial arrangement of lipids is also known to regulate Rho family GTPase activity (see Section 4.3). Sreetama SC, Chandra G, Van der Meulen JH, Ahmad MM, Suzuki P, Bhuvanendran S, Jaiswal JK (2018). Sheng R, Chen Y, Gee HY, Stec E, Melowic HR, Blatner NR, Fujiwara TK (2012). By clicking the Accept button you agree to the terms of our privacy policy. EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription. Calcium-regulated exocytosis is required for cell membrane resealing. The long held dogma in the cardiac biology community was that these cells do not . If you break a bone, your body immediately begins producing new cells to heal the damage. A surprise arrived when heart muscle cells were analyzed. 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. Multiplexed molecular descriptors of pressure ulcers defined by imaging mass spectrometry, Targeting and localized signalling by small GTPases. For example, shear force on the plasma membrane, such as that experienced during a mechanical injury, results in lipid mixing, which increases the mobility of signaling lipids and proteins residing in stable lipid microdomains (Petersen et al., 2016). Cell damage. Alteration in this response inhibits the subsequent stages, tissue regeneration and remodeling, leading to increased tissue scarring. When . This causes the exposure of the membrane hydrophobic core and allows proteins to interact with cholesterol. Marmots maintain strong bones during hibernation by building up without breakingdown. One such mechanism for this may be mediated by the protein MG53. Just like cells have membranes to hold everything in, these mini-organs are also bound in a double layer of phospholipids to insulate their little compartments within the larger cells. This may allow these lipids and proteins to interact with new partners that were unavailable due to spatial segregation prior to injury. (2011). Accumulation of GRAF1 at the repair site occurs 2 minutes after injury, supporting its potential role in membrane remodeling following resealing. The plasma membrane separates the extracellular environment from the cell interior, where biochemical reactions necessary for life occur. This is due to their lack of integration into the membrane under normal lipid packing conditions. In mammalian cells, lipids formed upon the phosphate and glycerol (e.g. At each of these levels the structural and signaling aspects of lipids are critical for the cell to mount an efficient response to plasma membrane injury. Please enable it to take advantage of the complete set of features! 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). Copyright 2015 the American Physiological Society. By studying how the Trypanosoma cruzi parasite enters the cell, Andrews' laboratory discovered that an increase of intracellular calcium was triggering lysosomal . The .gov means its official. 2022 Dec 14;10(12):3256. doi: 10.3390/biomedicines10123256. Not only is the composition and organization of the plasma membrane in constant flux, the membrane itself also must interact with forces being applied to it from all directions. Despite the many different types of tissue, there is a common repair program involved in tissue repair. How does the cell membrane self heal? Compared with cytosolic antioxidants, which can be detrimental to repair (Spaeth et al., 2012), vitamin E is membrane-localized and could therefore allow for the local buildup of oxidized lipids at the site of injury while preventing the global spread of lipid oxidation. In addition to their structural role in shaping the physical properties of the plasma membrane, lipids also play an important signaling role in maintaining plasma membrane integrity. The nanoclusters appear to form specifically at the boundary of ordered raft domains and disordered domains where signaling lipids such as PIP3 and PIP2 are found. Alterations in Phosphatidylcholine Metabolism of StretchInjured Cultured Rat Astrocytes. 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. Muscle fibers are subject to huge variations in membrane tension, due to their contractile activity. Zuzek A, Fan JD, Spaeth CS, & Bittner GD (2013). 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). Honeybee immune systems depend more on protein diversity thanquantity. Lipid domaindependent regulation of single-cell wound repair, Rho family GTPases bring a familiar ring to cell wound repair. Examples of self-repairing cells. Repair of muscle fibers lacking the dysferlin protein, which results in reduced membrane stability, is improved by the presence of extracellular (oxidized) MG53 protein, suggesting that this protein can act on the outer leaflet of the plasma membrane to improve plasma membrane in diseased cells. PTRF Anchors MG53 to Cell Injury Site for Initiation of Membrane Repair. Togo T, Krasieva TB, & Steinhardt RA (2000). and transmitted securely. Calcium-activated exocytosis reduces membrane tension and promotes spontaneous repair driven by lipid disorder for injuries hundreds of nanometers in diameter. The goal of signaling during plasma membrane repair is to generate a polarized response such that the repair machinery can be spatially and temporally localized and activated at the repair site. Phospholipid signalling through phospholipase D and phosphatidic acid. The second stage of tissue repair, regeneration, makes use of signaling by different lipids, one of which is sphingolipid. 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. Phospholipids in particular show inter-leaflet heterogeneity. Tam C, Idone V, Devlin C, Fernandes MC, Flannery A, He X, Andrews NW (2010). These observations suggest that lipids are not bystanders during the repair process, but are instead actively involved in organizing the playing field on which repair machinery operates. This role of lipids extends further by way of regulating the response of proteins during the repair process as well as long-term gene expression-based adaptations required for the recovery of injured cells and tissues. They consist of a variety of lipid mediators derived from the omega-3 essential fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and include lipoxins, resolvins and protectins. Phosphatidylinositol is found in many cell types and tissues, but is particularly abundant in the brain. Neurite transection produces cytosolic oxidation, which enhances plasmalemmal repair. The structural role of lipids may extend into the signaling role, which can then impact back on the structural characteristics of the repairing membrane by changing the composition or distribution of individual lipids. GTPases are molecular switches that require the cycling of nucleotides to remain active. Sarcolemmal repair is a slow process and includes EHD2, Effect of oxidative stress on membrane structure: small-angle X-ray diffraction analysis. Bacterial pore-forming toxins oligomerize and insert in the plasma membrane of target cells forming a diffusible pore. Bissig C, Lenoir M, Velluz M-C, Kufareva I, Abagyan R, Overduin M, & Gruenberg J (2013). doi: 10.1016/j.cub.2017.12.034. Cambridge (MA): Harvard Stem Cell Institute; 2008. 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). The membrane phosphoinositides, and PIP2 in particular, play an important role in regulating the interaction of F-actin with the plasma membrane (Kapus & Janmey, 2013; Saarikangas, Zhao, & Lappalainen, 2010). Due to the differences in the three-dimensional conformations of membrane lipids, a change in their distribution changes the lipid packing density in a given lipid domain. Necrosis is a progressive failure of essential metabolic and structural cell components usually in the cytoplasm. While initial depolymerization of the local F-actin network is thought to assist with vesicle fusion and membrane shedding, delayed accumulation of F-actin may facilitate repair either by working in coordination with myosin to pull the wounded membrane edges toward each other or by providing a barrier and stabilizing function for the newly formed membrane.

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