Plasma membrane damage caused by listeriolysin O is not repaired through endocytosis of the membrane pore. PMC The wounded cell can survive if a rapid repair response is mounted that restores boundary integrity. Yasuda S, Townsend D, Michele DE, Favre EG, Day SM, & Metzger JM (2005). Sphingomyelin also confers different properties to the plasma membrane than the phospholipids, not least due to its preferential association with sterols (Ramstedt & Slotte, 2006). Biophys J. 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)). While PA mediates targeting to the membrane, Rac1 activity depends on PIP3, suggesting multiple roles for signaling lipids in GTPase activity after repair. EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription. This phenomenon may be explained by the kinetic energy imparted on the membrane lipids by mechanical disruption, which can result in lipid mixing without relying on membrane tension (Petersen, Chung, Nayebosadri, & Hansen, 2016). Would you like email updates of new search results? While lipids are often ascribed a metabolic role as energy storage molecules, they also play important structural and signaling roles in the cell. An official website of the United States government. After an injury, the biophysical properties of the plasma membrane, and the individual lipids themselves, are altered, eliciting changes to membrane rigidity and fluidity. (2013). Copolymers such as poloxamer 188 avoid this potential issue by only stabilizing the plasma membrane once lipid packing density is sufficiently reduced, such as after an injury. 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 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. For example, Annexin 5 accumulates first to form a lattice structure, which provides a force opposing the tension at the wound edge (Bouter et al., 2011). Sterols, or steroid alcohols, are a third type of plasma membrane lipid, with cholesterol being the predominant form found in mammalian cells. 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. Cell | Definition, Types, Functions, Diagram, Division, Theory, & Facts 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. Intriguingly, PA preferentially binds the Rho family member Rac1, resulting in nanocluster formation (Maxwell et al., 2018). The plasma membrane itself forms the barrier responsible for the hydrostatic pressure experienced by the cell, while the cortical actin cytoskeleton, focal adhesions, and extracellular matrix regulate the structural tension (Burridge & Guilluy, 2016; Gauthier et al., 2012). Instead, there exists distinct inter- and intra-leaflet heterogeneity of lipids. There are many differences between cancer cells and normal cells in noncancerous (benign) or cancerous (malignant) tumors. This site needs JavaScript to work properly. How does the cell membrane self heal? Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis. McDade JR, Archambeau A, & Michele DE (2014). PI5K activity is itself driven by regulators of membrane repair including Rho GTPases (Gilmore & Burridge, 1996) and PLD (Roach et al., 2012). Cell Regen. Gazzerro E, Sotgia F, Bruno C, Lisanti MP, & Minetti C (2010). An official website of the United States government. These examples of organizational heterogeneity, along with the differences among the lipids that comprise the plasma membrane confer a variety of structural and signaling properties to the plasma membrane and allow the plasma membrane to mount and sustain localized signaling despite being fully interconnected and fluid. 1Childrens National Health System, Center for Genetic Medicine Research, 111 Michigan Avenue NW, Washington, DC 20010-2970 USA, 2Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC USA. Evidence suggests these pores are removed both by endosomal degradative pathways (123, 164, 280) and exosomal shedding (14, 118, 136). Thus, each of these lipids contributes significantly to the organization, structure, and function of the plasma membrane as a whole. Cell damage - Wikipedia Lipid-soluble molecules and some small molecules can permeate the membrane, but the lipid bilayer effectively repels the many large . How the cell membrane maintains the integrity of the cell? 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. S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells, S100 and annexin proteins identify cell membrane damage as the Achilles heel of metastatic cancer cells. 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). 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). Bacterial pore-forming, What might membrane injury to muscle fibers look like? While the structural importance of plasma membrane cholesterol is well appreciated, it can also play a role in signaling. 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. Zhang KS, Blauch LR, Huang W, Marshall WF, Tang SKY. J.K.J. Caveolinopathies: from the biology of caveolin-3 to human diseases, Annexins: linking Ca 2+ signalling to membrane dynamics, Regulation of vinculin binding to talin and actin by phosphatidyl-inositol-45-bisphosphate. 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. Calise S, Blescia S, Cencetti F, Bernacchioni C, Donati C, & Bruni P (2012). When . Cell membrane repair repurposes mechanisms from various cellular functions, including vesicle trafficking, exocytosis, and endocytosis, to mend the broken membrane. By clicking the Accept button you agree to the terms of our privacy policy. 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. The antioxidant requirement for plasma membrane repair in skeletal muscle. Multiplexed molecular descriptors of pressure ulcers defined by imaging mass spectrometry, Targeting and localized signalling by small GTPases. The plasma membrane is a dynamic barrier that separates the cell interior from the extracellular space (Figure 2C). The plasma membrane separates the extracellular environment from the cell interior, where biochemical reactions necessary for life occur. 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). This may allow these lipids and proteins to interact with new partners that were unavailable due to spatial segregation prior to injury. In this way, lipids play an important role in polarizing the cellular response to an injury. Many of the sphingolipids also contain a glycosidically bound carbohydrate moiety causing formation of the glycosphingolipids. Matsuo H, Chevallier J, Mayran N, Le Blanc I, Ferguson C, Faur J, Sadoul R (2004). Stem cell extracellular vesicles: extended messages of regeneration, Annual review of pharmacology and toxicology. A cartoon depicting the potential role of dysferlin-mediated vesicle fusion in membrane repair. These domains decrease the local fluidity in the membrane relative to the regions comprised primarily of phospholipids. Modeling membrane shaping by proteins: Focus on EHD2 and NBAR domains. doi: 10.1016/j.cub.2017.12.034. This occurs primarily through the direct interaction of PIP2 with actin-binding proteins, and change in PIP2 distribution has been shown to precede actin build-up at the plasma membrane (Nebl, Oh, & Luna, 2000; Senju & Lappalainen, 2019; Tran, Masedunskas, Weigert, & Ten Hagen, 2015). (A) The plasma membrane is a fluid-mosaic of lipids, including glycerophospholipids, sphingolipids, and cholesterol, as well as plasma membrane-associated proteins. To achieve these tasks, cells employ signaling networks, which respond to the changing microenvironment after injury and activate the diverse plasma membrane repair mechanisms with precise control in time and space. 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). Blood cells called platelets release clotting factors to stop the bleeding; white blood cells rid the area of foreign materials and release molecules to coordinate healing; cells called fibroblasts start rebuilding using proteins called collagen; new blood vessels form; and skin cells called keratinocytes create the newsurface. Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding? From PA, cells generate DAG, or cytidine diphosphate-DAG (CDP-DAG), which serve as inputs into the phospholipid biosynthetic pathways (Figure 1A, ,B).B). In contrast to PC, sphingomyelin forms a taller and narrower cylinder, which along with the configuration of its acyl chains, allowing this lipid to pack more tightly than phospholipids (Cebecauer et al., 2018). Analysis of Dysferlin Direct Interactions with Putative Repair Proteins Links Apoptotic Signaling to Ca. Shed microvesicles containing streptolysin-O have been shown to also contain annexins A1 and A6 (219). Poloxamer 188 facilitates the repair of alveolus resident cells in ventilator-injured lungs, American journal of respiratory and critical care medicine. As she describes, a lesion is followed by a Ca2+-dependent movement of vesicles to the plasma membrane. Plasma membrane wounding and repair in pulmonary diseases, American Journal of Physiology-Lung Cellular and Molecular Physiology, Membrane repair: mechanisms and pathophysiology. In response to an injury, a sudden change in hydrostatic pressure and local disassembly of the cortical cytoskeleton causes a rapid drop in membrane tension (Jaiswal et al., 2014; Miyake, McNeil, Suzuki, Tsunoda, & Sugai, 2001; Togo et al., 2000). Sarcolemmal repair is a slow process and includes EHD2, Effect of oxidative stress on membrane structure: small-angle X-ray diffraction analysis. Please enable it to take advantage of the complete set of features! 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). How does the cell membrane self heal? 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. In a similar manner, PS signaling may be involved in the early recruitment of other membrane repair proteins such as dysferlin (McDade et al., 2014; Middel et al., 2016) and MG53 (Cai et al., 2009). Mitochondrial fragmentation and ROS signaling in wound response and repair. Constitutive fusion of biosynthetic vesicles is a major mechanism for delivery of new lipids and proteins, which helps to build and maintain the plasma membrane. Calcium entry after plasma membrane injury is required for repair. The observation, that endocytosis may not be required for resealing through the removal of pore-forming toxins but instead acts as a mechanosensor to buffer membrane tension, may also explain how endocytosis participates in the repair of mechanical damage, where no membrane-spanning pores need to be removed. Lenhart KC, ONeill TJ, Cheng Z, Dee R, Demonbreun AR, Li J, Taylor JM (2015). Local oxidation at the site of membrane injury activates MG53 oligomerization (Cai et al., 2009), which may locally increase membrane rigidity. Before 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). The site is secure. Marmots maintain strong bones during hibernation by building up without breakingdown. Similar to PS, DAG directly binds proteins to provide its signaling function; however, because it is generated de novo after injury, an additional temporal component to signaling is achieved. Cholesterol interacts with both phospholipids and sphingolipids, and its interactions with these lipids play a crucial role in determining the overall physical properties of the plasma membrane. Alterations in Phosphatidylcholine Metabolism of StretchInjured Cultured Rat Astrocytes. 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. 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. For example, venomous snakes store precursor molecules to instantly synthesize a suite of toxins via enzyme-mediated cascades. Similar to the changes in tension described above, the fluidity of the plasma membrane is also dynamic after injury. 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). 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). This allows local and functional diversity between the two leaflets as well as various parts of the single contiguous plasma membrane (Figure 2B). Many organisms and tissues display the ability to heal and regenerate as needed for normal physiology and as a result of pathogenesis. ESCRT machinery is required for plasma membrane repair. Lysosome - Genome.gov Biosci Rep. 2023 Feb 27;43(2):BSR20220765. 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. 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). 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, 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). (2017). 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). Radiation Effects on Cells & DNA | Let's Talk Science Membrane damage: Damage to the cell membrane disturbs the state of cell electrolytes, e.g. In mammalian cells, lipids formed upon the phosphate and glycerol (e.g. As dysferlin may only be detected at injury sites with antibodies recognizing COOH-terminal epitopes, and not several antibodies to NH. The publisher's final edited version of this article is available at, Lipids, plasma membrane, membrane injury, tissue repair. 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). Along with the annexins, which act quickly to physically manipulate the membrane itself, reassembly of the cytoskeleton plays a crucial role in restoring membrane tension in the later stages of repair. The spatial arrangement of lipids at the plasma membrane is not only important for GTPase recruitment, but also for their activity. For example, lipid composition, distribution, and inter-lipid interactions actively control the rigidity and tension acting upon the plasma membrane, which in turn regulates cellular functions such as vesicle fusion, cell motility, and membrane resealing (Diz-Muoz, Fletcher, & Weiner, 2013; Gauthier, Fardin, Roca-Cusachs, & Sheetz, 2011; Togo, Krasieva, & Steinhardt, 2000). As these features change dynamically, tension forces experienced by the plasma membrane are not static and the cells ability to respond to them appropriately allows for essential functions such as change in morphology, movement, adhering to new substrates, cell division, and membrane fusion. Lipids also react to the changing biochemical environment to become signaling molecules that determine the spatiotemporal dynamics of protein activation (Eyster, 2007) (Figure 1B). Regulation of the actin cytoskeleton-plasma membrane interplay by phosphoinositides. Lipids contribute to cellular physiology at both an individual and population level. The plasma membrane has a unique lipid composition that helps distinguish its structural and functional properties from the other internal membrane-bound compartments. Cell Energy, Cell Functions | Learn Science at Scitable - Nature Treatment with Recombinant Human MG53 Protein Increases Membrane Integrity in a Mouse Model of Limb Girdle Muscular Dystrophy 2B. During the S stage, the cell The wounded cell can survive if a rapid repair respons Membrane Repair: Mechanisms and Pathophysiology See this image and copyright information in PMC. Bethesda, MD 20894, Web Policies Membrane repair is a conserved physiologic process in multiple tissues Organ Type of mechanical force Principal cells stressed Cell wounding Membrane Healing Further, the complexity of signaling afforded by lipids allows the cell to coordinate a highly organized response to injury across space and time (Figure 1B). 2008 Dec 31. Accumulation of GRAF1 at the repair site occurs 2 minutes after injury, supporting its potential role in membrane remodeling following resealing. Endocytosis can also occur at sites of membrane invagination known as caveolae, and caveolae internalization has been implicated in membrane repair (Corrotte et al., 2013). Dr. Norma Andrews overviews the mechanisms of cellular plasma membrane repair. Int J Mol Sci. Plasma membrane lipids are routinely interconverted as a means to maintain lipid homeostasis and for lipid-mediated signaling. What might membrane injury to muscle fibers look like? 8600 Rockville Pike What happens when cell membrane is damaged? - Studybuff The .gov means its official. Definition. 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.