Cell membrane repair repurposes mechanisms from various cellular functions, including vesicle trafficking, exocytosis, and endocytosis, to mend the broken membrane. The calcium influx of a membrane injury activates vesicular exocytosis and homo- and heterotypic fusion of cytoplasmic vesicles. However, excessive force applied to the membrane can result in physical damage, such as the shear force applied on the endothelial cells by blood flow, on muscle cells during contraction, on lung alveolar cells during breathing, or by a blunt force trauma to any cell (Cong, Hubmayr, Li, & Zhao, 2017; Demonbreun & McNally, 2016; McNeil & Steinhardt, 2003). sharing sensitive information, make sure youre on a federal Intriguingly, PA preferentially binds the Rho family member Rac1, resulting in nanocluster formation (Maxwell et al., 2018). Schematic representation of the structural features of the protein families implicated in membrane repair. During the repair of sarcolemmal lesions, macrophages recognize exposed phosphatidylserine at the site of . Bissig C, Lenoir M, Velluz M-C, Kufareva I, Abagyan R, Overduin M, & Gruenberg J (2013). EVs are known to be generated in response to plasma membrane injury of single cells, and this is required for successful repair (Jimenez et al., 2014; Scheffer et al., 2014). While initial loss of cortical actin aids in repair by allowing physical access for vesicles to fuse with the plasma membrane, the accumulation of F-actin at the injury site in the minutes following injury, is also required to provide structural support to the repairing/repaired membrane and prevent additional injury due to membrane fragility (Demonbreun et al., 2016; Horn et al., 2017; Jaiswal et al., 2014; McDade, Archambeau, & Michele, 2014; Miyake et al., 2001). Federal government websites often end in .gov or .mil. Shed microvesicles containing streptolysin-O have been shown to also contain annexins A1 and A6 (219). 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). Microfluidic guillotine reveals multiple timescales and mechanical modes of wound response in Stentor coeruleus. Early observations of cells undergoing plasma membrane repair identified that membrane bound vesicles are involved in the process of membrane resealing (Bi, Alderton, & Steinhardt, 1995). Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, Donati MA (1998). The radiation could pass through the cell without damaging the DNA. Following this, accumulation of Annexin 4 and Annexin 6 results in folding and inward contraction of the injured membrane, respectively (Boye et al., 2017). Viral infection controlled by a calcium-dependent lipid-binding module in ALIX. Annexin A1 deficiency does not affect myofiber repair but delays regeneration of injured muscles. As lipids comprise the bulk of the plasma membrane, the acts of injury, resealing, and remodeling all directly impinge upon the plasma membrane lipids. This phase represents restoration of the barrier function of the plasma membrane; however, cells must still undergo a membrane remodeling phase due to the presence of cytoskeletal as well as other repair proteins and lipids that accumulate during the repair process. "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. In addition to PA, PG is another lipid product of PLD activity relevant to membrane repair, and its synthesis has been implicated in the process of membrane repair and repair of epithelial wounds (Arun et al., 2013; Piazza & Marmer, 2007). This dissociation has the effect of allowing Rho GTPase translocation to the membrane where it can interact with signaling lipids. PC), with a conical shaped, charged phospholipid (e.g. However, these repair activities can also be observed at the single-cell level. Each of these provides another mechanism for generating specific membrane lipids acutely in parallel to biosynthetic inputs. Tools. Further, PE and PC head groups can be cleaved and replaced with serine to produce PS (Oropeza, 2017). 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. While intracellular MG53 is a redox-sensitive protein capable of facilitating vesicle aggregation, it is proposed to have multiple functions during 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. 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). Andrews NW, Almeida PE, & Corrotte M (2014). Amongst other causes, this can be due to physical, chemical, infectious, biological, nutritional or immunological factors. Bennett APS, de la Torre-Escudero E, Dermott SSE, Threadgold LT, Hanna REB, Robinson MW. Presence of LBPA at the plasma membrane through vesicle fusion could allow for ALIX recruitment and ESCRT assembly (Bissig et al., 2013); however, the presence of LBPA at membrane wound sites has not been directly observed. The plasma membrane separates the extracellular environment from the cell interior, where biochemical reactions necessary for life occur. While PLC is able to cleave PC, the classic substrate of PLC is PIP2, which upon cleavage generates the membrane bound DAG and the cytosolic inositol trisphosphate (IP3) both of which are increased after injury (Lamb, Harper, McKinney, Rzigalinski, & Ellis, 1997; Vaughan et al., 2014). When the cell is under stress, and the amount of ROS increases, the number of methionine "errors" is ramped up tenfold, allowing new proteins to be even more resistant to attack. and transmitted securely. 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). Thus, it is clear that there is a need to acknowledge the role of lipids as an active participant in the processes of both cell and tissue repair. Cells respond to mechanical stress by rapid disassembly of caveolae. 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. This causes the exposure of the membrane hydrophobic core and allows proteins to interact with cholesterol. This is due to its protein-binding ability, resulting in protein translocation to the cholesterol-rich regions of plasma membrane (Sheng et al., 2012; Van Meer et al., 2008). 2022 Dec 1;11(1):38. doi: 10.1186/s13619-022-00141-8. Therefore, injury-triggered protein-lipid interactions that result in modified lipids generates signaling that allows for changes in activity and localization of plasma membrane repair machinery. However, lipid signaling also helps to coordinate downstream repair pathways that result in the membrane trafficking and cytoskeletal reorganization required for repair. "Think of a . Int J Mol Sci. 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. Bacterial pore-forming toxins oligomerize and insert in the plasma membrane of target cells forming a diffusible pore. As muscle fibers have strong interfiber connections, muscle injuries may manifest both as shearing of the membrane from increased membrane tension and strain, as well as ripping of plasma membrane regions from fiber retraction or hypercontraction. 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). 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. Cheng JP, Mendoza-Topaz C, Howard G, Chadwick J, Shvets E, Cowburn AS, Nichols BJ (2015). Marmots maintain strong bones during hibernation by building up without breakingdown. Weisleder N, Takizawa N, Lin P, Wang X, Cao C, Zhang Y, Chen P-J (2012). Other cells acquire specialized functions as they mature. After an injury, the biophysical properties of the plasma membrane, and the individual lipids themselves, are altered, eliciting changes to membrane rigidity and fluidity. Delivery of membrane (i.e. Tran DT, Masedunskas A, Weigert R, & Ten Hagen KG (2015). Membrane-stabilizing copolymers confer marked protection to dystrophic skeletal muscle in vivo, Molecular Therapy-Methods & Clinical Development. While PA mediates targeting to the membrane, Rac1 activity depends on PIP3, suggesting multiple roles for signaling lipids in GTPase activity after repair. While this mechanism outlines how ESCRT proteins assemble, the lipid signaling that determines the appropriate spatial localization relative to the membrane injury in order to limit wound expansion has not been elucidated. From PA, cells generate DAG, or cytidine diphosphate-DAG (CDP-DAG), which serve as inputs into the phospholipid biosynthetic pathways (Figure 1A, ,B).B). Injury to the plasma membrane also changes the biochemical environment within the cell. 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. Using these dating methods, it was inferred that fat cells (adipocytes) replace at a rate of 86% per year (BNID 103455). This cytoskeletal assembly is regulated by Rho GTPase activity, which triggers F-actin accumulation at the site of injury. Newer pharmacological approaches for antioxidant neuroprotection in traumatic brain injury. Bethesda, MD 20894, Web Policies While small injuries to the plasma membrane (on the nanometer scale) can be spontaneously resealed due to the line tension imposed by plasma membrane lipids alone (McNeil & Terasaki, 2001), larger membrane injuries (on the micron scale) require a series of coordinated mechanisms to undergo repair. The chemical structure of the cell membrane makes it remarkably flexible, the ideal boundary for rapidly growing and dividing cells. Survival from bacterial pore-forming toxins utilizes both exocytic and endocytic responses. (2017). 'Resealing' is the emergency response required for cell . doi: 10.1016/j.cub.2017.12.034. This allows local and functional diversity between the two leaflets as well as various parts of the single contiguous plasma membrane (Figure 2B). They break down excess or worn-out cell parts. 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. Gushchina LV, Bhattacharya S, McElhanon KE, Choi JH, Manring H, Beck EX, Weisleder N. (2017). The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. 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. 2017 Jul 11;114(28):7283-7288. doi: 10.1073/pnas.1705059114. While tension acts at the level of an entire membrane, the physical properties of the individual lipids and lipid domains dynamically guide the local changes required for adapting to the change in tension. The basement membrane of the basal cells attaches via hemidesmosomes to the underlying Bowman's layer, while anchoring fibrils pass through . Caveolae internalization repairs wounded cells and muscle fibers, Regulation of endocytosis, exocytosis, and shape by membrane tension, Paper presented at the Cold Spring Harbor symposia on quantitative biology. Lamb RG, Harper CC, McKinney JS, Rzigalinski BA, & Ellis EF (1997). This is achieved in part through the activity of lipid modifying enzymes, such as phospholipases, which are activated by the changing biochemical environment after injury. This is called apoptosis. What might membrane injury to muscle fibers look like? Learn whats new on AskNature by signing up for our e-newsletter. A cartoon depicting the potential role of dysferlin-mediated vesicle fusion in membrane repair. 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). This raises the intriguing possibility that MG53 may affect plasma membrane structural properties. However, shear force on the membrane increases the kinetic energy required for lipid mixing (i.e. An official website of the United States government. This cell membrane provides a protective barrier around the cell and regulates which materials can pass in or out. Stem cell extracellular vesicles: extended messages of regeneration, Annual review of pharmacology and toxicology. Glycerol-3-phosphate is used to generate PA as well as PG through the intermediate phosphatidylglycerol phosphate (PGP). The basement membrane plays an important role in cellular functions, including those involved in healing, by controlling the binding of growth factors and their local concentrations between cell layers. 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). A surprise arrived when heart muscle cells were analyzed. Of potential interest in this regard is the unconventional phospholipid lysobisphosphatidic acid (LBPA), which is found on endolysosomes. Cell Regen. and A.H. acknowledge NIH for financial support - NIAMS (R01AR055686) and NICHD (U54HD090257) and thank our lab members for useful discussions and inputs during the course of writing and editing this work. Inherent plasticity and microfracture toughening mechanisms work together to prevent antlers from breaking. HHS Vulnerability Disclosure, Help 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. Rather than these roles being separated from each other, they overlap significantly such that one can easily be an extension of the other. 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. As discussed above, sphingolipids in the plasma membrane are an important regulator of plasma membrane repair. Use the force: membrane tension as an organizer of cell shape and motility. Petersen EN, Chung H-W, Nayebosadri A, & Hansen SB (2016). Below we describe the biochemical signaling role of lipids in facilitating plasma membrane repair. Spiders turn liquid into a strong, stretchy fiber by squeezing it through a small space that helps protein molecules to connect with eachother. Accumulation of GRAF1 at the repair site occurs 2 minutes after injury, supporting its potential role in membrane remodeling following resealing. Calcium also initiates lipid signaling after plasma membrane injury by activating phospholipases, such as phospholipase C (PLC). This is due to their lack of integration into the membrane under normal lipid packing conditions. Cholesterol modulates cell signaling and protein networking by specifically interacting with PDZ domain-containing scaffold proteins. Do Heo W, Inoue T, Park WS, Kim ML, Park BO, Wandless TJ, & Meyer T (2006). Cells are the basic building blocks of all living systems, so cellular processes dictate how physiological processes occur within those systems. The radiation could prevent the DNA from replicating correctly. Copyright 2015 the American Physiological Society. 2021 Sep 29;9:753625. doi: 10.3389/fcell.2021.753625. The organization of lipids within the membrane also affects the structure of underlying cortical cytoskeleton. Activated calpains cleave dysferlin within a motif specifically encoded by alternately spliced exon 40a (230). How does the cell membrane self heal? 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). 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). Calcium entry after plasma membrane injury is required for repair. Tailored protection against plasmalemmal injury by annexins with different Ca2+ sensitivities, Sphingolipids and the formation of sterol-enriched ordered membrane domains, Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. Abrams ST, Wang L, Yong J, Yu Q, Du M, Alhamdi Y, Cheng Z, Dart C, Lane S, Yu W, Toh CH, Wang G. Biomedicines. Epub 2023 Mar 3. 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. 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. 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. cell, in biology, the basic membrane-bound unit that contains the fundamental molecules of life and of which all living things are composed. If the cell is damaged beyond repair, lysosomes can help it to self-destruct in a process called programmed . Shao S, Liao X, Xie F, Deng S, Liu X, Ristaniemi T, & Liu B (2018). Lee I-H, Kai H, Carlson L-A, Groves JT, & Hurley JH (2015). Sezgin E, Levental I, Mayor S, & Eggeling C (2017). 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. FOIA In response to increased stress on the plasma membrane, caveolae have been proposed to act as mechanosensors, buffering membrane tension in response to mechanical stress (Cheng et al., 2015; Sinha et al., 2011). In this review, we will focus on the role of lipids during plasma membrane repair by discussing their functions as both structural and signaling molecules. Thus, the signaling role of lipids affects membrane structure and how the wound is eventually resealed and remodeled, returning the plasma membrane to homeostasis. Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding? It has since become evident that in addition to resealing, remodeling of the plasma membrane through vesicle fusion (exocytosis), vesicle internalization (endocytosis), and shedding (ectocytosis) also contribute to the repair process (reviewed in (Horn & Jaiswal, 2018)). One such mechanism is addition of more membrane via vesicle fusion (Fig 1B ). (2017). As structural components of the plasma membrane, lipids are responsible for contributing to membrane tension, rigidity, and overall shape. 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. 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.
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