doi: 10.7554/eLife.80778. Mammals make up less than 1% of all animals on earth, but they include some of the most well-known species. PS) in the inner leaflet, causes the plasma membrane to attain an overall outward curvature. 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. Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis, Lipid peroxidation induces cholesterol domain formation in model membranes. BMC Biol. Temporary increase in plasma membrane tension coordinates the activation of exocytosis and contraction during cell spreading. 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. HHS Vulnerability Disclosure, Help Lamb RG, Harper CC, McKinney JS, Rzigalinski BA, & Ellis EF (1997). Multiplexed molecular descriptors of pressure ulcers defined by imaging mass spectrometry, Targeting and localized signalling by small GTPases. Int J Mol Sci. The variety of possible phospholipid interconversions, such as these, allows the cell to rapidly change the lipid composition of the plasma membrane. Plasma membrane lipids and proteins interact with the extracellular matrix (ECM) and the cortical actin network, both of which provide sources of tension that support the structure of the membrane. By studying how the Trypanosoma cruzi parasite enters the cell, Andrews' laboratory discovered that an increase of intracellular calcium was triggering lysosomal . The tension forces acting on the plasma membrane are generally applied by three sources: the difference in hydrostatic pressure between the cell interior and extracellular space, the cortical cytoskeletal network, and the extracellular matrix to which the cell is attached (Gauthier, Masters, & Sheetz, 2012; Kozlov & Chernomordik, 2015) (Figure 2B). 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). Two-way traffic on the road to plasma membrane repair. In this review, we have discussed how lipids working at the individual as well as at the population level facilitate the proper orchestration of the repair response. 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. The major differences between normal cells and cancer cells relate to growth, communication, cell repair and death, "stickiness" and spread, appearance, maturation, evasion of the immune system, function and blood supply . However, uninjured muscle cells from Limb Girdle Muscular Dystrophy 2B (LGMD2B) patients show increased membrane fluidity, which is associated with their poor membrane repair ability (Sreetama et al., 2018). The .gov means its official. How skin heals is a good example of the role of cellular processes. Gurtner GC, Werner S, Barrandon Y, & Longaker MT (2008). Plasma membrane lipids are routinely interconverted as a means to maintain lipid homeostasis and for lipid-mediated signaling. The plasma membrane consists of a lipid bilayer that is semipermeable. These membrane invaginations require the presence of caveolin proteins, loss of which can result in poor membrane repair and muscular dystrophy (Gazzerro, Sotgia, Bruno, Lisanti, & Minetti, 2010; Minetti et al., 1998). Eukaryotic cells have been confronted throughout their evolution with potentially lethal plasma membrane injuries, including those caused by osmotic stress, by infection from bacterial toxins and parasites, and by mechanical and ischemic stress. Taverna D, Nanney LB, Pollins AC, Sindona G, & Caprioli R (2011). 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). Accessibility 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. This preferential association between different lipids results in an important feature of the plasma membrane its transverse and lateral heterogeneity. 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. Marmots maintain strong bones during hibernation by building up without breakingdown. The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. F-actin reorganization during repair is coordinated by the activity of lipids through their regulation of signaling proteins (reviewed in (Horn & Jaiswal, 2018)), as well as through direct interaction with actin-binding proteins such as F-actin bundling by the Annexin A2-S100 A11 complex (Jaiswal et al., 2014). Dr. Norma Andrews overviews the mechanisms of cellular plasma membrane repair. Subsequent insult(s) of eccentric stretch result in a more severe wound and global hypercontraction, producing fiber retraction within the muscle bundle (53). Cell Calcium. Thus, caveolae may serve a signaling function during membrane repair (see Section 4). Hall ED, Wang JA, Miller DM, Cebak JE, & Hill RL (2018). 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. The Importance of Pore-Forming Toxins in Multiple Organ Injury and Dysfunction. Regulation of actin binding proteins by PIP2 occurs in part through electrostatic interactions (Senju et al., 2017), suggesting that clusters of PIP2 molecules may be necessary to achieve build-up of F-actin itself. As lipids comprise the bulk of the plasma membrane, the acts of injury, resealing, and remodeling all directly impinge upon the plasma membrane lipids. 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). This helps to remodel the newly repaired plasma membrane (Middel et al., 2016), but may also serve to potentiate tissue inflammation. Visualizing cytoplasmic flow during single-cell wound healing in Stentor coeruleus. These same processes also work to dynamically control membrane fluidity by regulating the distribution of phospholipids, sphingolipids, and cholesterol in the membrane. 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. Mitochondrial redox signaling enables repair of injured skeletal muscle cells. How does the cell membrane self heal? Federal government websites often end in .gov or .mil. Similar inter-leaflet heterogeneity exists among sphingolipids, with the glycosphingolipids maintained exclusively in the outer leaflet. Charged phospholipids such as PIP2, PS, and PE are almost exclusively found on the inner leaflet, while the glycosphingolipids are only found on the outer leaflet. 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. Shear stress on the plasma membrane also results in the dissociation of the negative regulator RhoGDI and its binding partner Rho (Shao et al., 2018). Annexin-A5 assembled into two-dimensional arrays promotes cell membrane repair. Development of cell therapy and regenerative medicine using stem cells is expanding the medical industry and businesses as well as increasing the understanding of the nature of the cell itself. Membrane repair is a conserved physiologic process in multiple tissues Organ Type of mechanical force Principal cells stressed Cell wounding Enzymes that generate lipid signaling after plasma membrane injury (in red) include the phospholipases C and D (PLC and PLD), phosphatidyloinositol kinases (PI5K and PI3K), and sphingomyelinase (SMase). Horn A, Van der Meulen JH, Defour A, Hogarth M, Sreetama SC, Reed A, Jaiswal JK. Schematic representation of the structural features of the protein families implicated in membrane repair. Caveolae protect endothelial cells from membrane rupture during increased cardiac output. 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). Cell wounding activates phospholipase D in primary mouse keratinocytes. 2008 Dec 31. PKC, in turn, influences a wide variety of downstream pathways known to facilitate repair including vesicle fusion, Rho GTPase patterning, as well as repair potentiation (Togo, 2004; Vaughan et al., 2014; Zuzek et al., 2013). Scheffer LL, Sreetama SC, Sharma N, Medikayala S, Brown KJ, Defour A, & Jaiswal JK (2014). This is especially important for membrane signaling functions as the liquid-ordered domains often serve to aggregate membrane-associated proteins (Cebecauer et al., 2018). 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). Careers, Unable to load your collection due to an error. 2022 Dec 1;11(1):38. doi: 10.1186/s13619-022-00141-8. SM utilizes the ceramide (Cer) backbone and can be used to generate the signaling lipid sphingosine-1-phosphate (S1P). Boye TL, Maeda K, Pezeshkian W, Snder SL, Haeger SC, Gerke V, Nylandsted J. 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). 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. Lysosome fusion is required for the process of repair (Reddy, Caler, & Andrews, 2001). 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. Togo T, Krasieva TB, & Steinhardt RA (2000). Houang EM, Haman KJ, Filareto A, Perlingeiro RC, Bates FS, Lowe DA, & Metzger JM (2015). Eukaryotic cells have been shown to utilize calcium-activated exocytosis to reduce membrane tension and promote repair via lipid-disorder driven attractions. Thus, DAG acts as a scaffold that initiates and coordinates downstream signaling pathways within a tight spatial and temporal window rather than as a marker of membrane injury for fast-acting structural proteins. 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. Bouter A, Gounou C, Brat R, Tan S, Gallois B, Granier T, Brisson AR. 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. Gauthier NC, Fardin MA, Roca-Cusachs P, & Sheetz MP (2011). Phospholipids in particular show inter-leaflet heterogeneity. With their calcium and lipid affinities spanning a wide spectrum, annexins accumulate slightly differently from each other at the site of injury and perform different functions to facilitate repair of the wounded plasma membrane (see Section 4.1). Each of these provides another mechanism for generating specific membrane lipids acutely in parallel to biosynthetic inputs. Given their integral role in forming the structural backbone of the membrane, lipids are ideally placed to act as damage sensors, initiating early signaling that sets the stage for subsequent repair machinery. Inherent plasticity and microfracture toughening mechanisms work together to prevent antlers from breaking. If you break a bone, your body immediately begins producing new cells to heal the damage. The second stage of tissue repair, regeneration, makes use of signaling by different lipids, one of which is sphingolipid. McNeil AK, Rescher U, Gerke V, & McNeil PL (2006). This allows small GTPases, such as Rac1 and Cdc42 to preferentially bind the negatively charged PIP2 and PIP3 (Johnson, Erickson, & Cerione, 2012; Maxwell et al., 2018; Remorino et al., 2017). Disclaimer. Lipids may serve as ligands for specific proteins, or act as a scaffold to bring cytosolic proteins to the plasma membrane. Neurite transection produces cytosolic oxidation, which enhances plasmalemmal repair. An official website of the United States government. Cell damage. Matsuo H, Chevallier J, Mayran N, Le Blanc I, Ferguson C, Faur J, Sadoul R (2004). If the cell is damaged beyond repair, lysosomes can help it to self-destruct in a process called programmed . Sarcolemmal repair is a slow process and includes EHD2, Effect of oxidative stress on membrane structure: small-angle X-ray diffraction analysis. This dissociation has the effect of allowing Rho GTPase translocation to the membrane where it can interact with signaling lipids. These mediators promote wound resolution by acting upon the immune and endothelial cells and help to control the duration and nature of the immune and phagocytic cell infiltration at the injury site (Serhan, 2014). However, these repair activities can also be observed at the single-cell level. They include glycerophosphocholines, glycerophosphoglycerols, glycerophosphoinositols, as well as triacylglycerols (Taverna, Nanney, Pollins, Sindona, & Caprioli, 2011). Zhu H, Lin P. h., De G, Choi K. h., Takeshima H, Weisleder N, & Ma J (2012). Weisleder N, Takizawa N, Lin P, Wang X, Cao C, Zhang Y, Chen P-J (2012). Jaiswal JK, Lauritzen SP, Scheffer L, Sakaguchi M, Bunkenborg J, Simon SM, Nylandsted J (2014). 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. Intriguingly, PA preferentially binds the Rho family member Rac1, resulting in nanocluster formation (Maxwell et al., 2018). 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. The organization of lipids within the membrane also affects the structure of underlying cortical cytoskeleton. (2011). Drescher DG, Drescher MJ, Selvakumar D, Annam NP. This is due to their lack of integration into the membrane under normal lipid packing conditions. sharing sensitive information, make sure youre on a federal Physico-chemical and biological considerations for membrane wound evolution and repair in animal cells. Following injury, lysosomes are known to fuse with the damaged membrane and may deposit LBPA at the site of injury, which would in turn facilitate ALIX-mediated vesicle shedding. Careers. For example, a scallop prevents structural failure from fracture because its shell is comprised of two materials of varying stiffness. 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). One dead cell is not a big problem. Rapid Changes to Endomembrane System of Infected Root Nodule Cells to Adapt to Unusual Lifestyle. Before Sinha B, Kster D, Ruez R, Gonnord P, Bastiani M, Abankwa D, Johannes L (2011). The radiation could damage the DNA so badly that the cell dies. 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. Int J Mol Sci. Calise S, Blescia S, Cencetti F, Bernacchioni C, Donati C, & Bruni P (2012). 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. and transmitted securely. In. Senju Y, Kalimeri M, Koskela EV, Somerharju P, Zhao H, Vattulainen I, & Lappalainen P (2017). Each month, well bring you a selection of compelling updates to this ever-growing library of biological strategies and innovations. The structural role of lipids described above illustrates how their ability to modify the biophysical properties of the plasma membrane is beneficial for resealing. In the subsequent sections, we will discuss how this is achieved and utilized by the cell. Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, Donati MA (1998). 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. Requirement for annexin A1 in plasma membrane repair, Repairing a torn cell surface: make way, lysosomes to the rescue, Plasma membrane disruption: repair, prevention, adaptation, Annual review of cell and developmental biology, Coping with the inevitable: how cells repair a torn surface membrane, Biochemistry of lipids, lipoproteins and membranes. Self-repair: Our bodies are packages within packages. official website and that any information you provide is encrypted The chemical structure of the cell membrane makes it remarkably flexible, the ideal boundary for rapidly growing and dividing cells. Class Mammalia (breast): Bats, cats, whales, horses, humans. The long held dogma in the cardiac biology community was that these cells do not . 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. These phospholipids are derived from glycerol-3-phosphate, itself a product of cellular metabolism that is enzymatically modified into phosphatidic acid (PA). 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. Alkaloid molecules protect plants from bacterial infections. 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. The radiation could damage the cell's DNA, but the DNA repairs itself. Clipboard, Search History, and several other advanced features are temporarily unavailable. Slabodnick M, Prevo B, Gross P, Sheung J, Marshall W. J Vis Exp. Lipids are a class of biomolecules, which are generally insoluble in water, and may refer to fatty acids, sterols, mono-, di-, and triglycerides, as well as phospholipids, among others. The radiation could prevent the DNA from replicating correctly. Yet to be fully understood is whether core membrane repair machinery exists in all cells, or whether evolutionary adaptation has resulted in multiple compensatory repair pathways that specialize in different tissues and cells within our body. Calcium also initiates lipid signaling after plasma membrane injury by activating phospholipases, such as phospholipase C (PLC). In this case, cholesterol actually increases the fluidity among these lipids, which prevents them from forming a gel-like phase that is incompatible with the overall fluid nature of the plasma membrane (Krause & Regen, 2014). (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). 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. 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. Verweij FJ, Revenu C, Arras G, Dingli F, Loew D, Pegtel DM, Zimmermann P (2019). Local oxidation at the site of membrane injury activates MG53 oligomerization (Cai et al., 2009), which may locally increase membrane rigidity. 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). FOIA Labazi M, McNeil AK, Kurtz T, Lee TC, Pegg RB, Angeli JPF, McNeil PL (2015). 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). Survival from bacterial pore-forming toxins utilizes both exocytic and endocytic responses. Along with DAG, IP3 is also generated by the activity of PLC. 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. Phospholipid biosynthetic pathways require the addition of different head groups to the DAG backbone. Would you like email updates of new search results? The cell membrane is an extremely pliable structure composed primarily of two layers of phospholipids (a "bilayer"). This causes the exposure of the membrane hydrophobic core and allows proteins to interact with cholesterol. The primary method for PIP2 formation in cells is by the activity of PI(4)P-5 kinase (PI5K) (Kolay, Basu, & Raghu, 2016). FRET biosensor allows spatiotemporal observation of shear stress-induced polar RhoGDI activation. Thus, each of these lipids contributes significantly to the organization, structure, and function of the plasma membrane as a whole. The most abundant component of the cells plasma membrane is the lipids. Bethesda, MD 20894, Web Policies eCollection 2021. Plasma membrane lipids containing the alkanoamine sphingosine are called sphingolipids. Microfluidic guillotine reveals multiple timescales and mechanical modes of wound response in Stentor coeruleus. Gauthier NC, Masters TA, & Sheetz MP (2012). Alteration in this response inhibits the subsequent stages, tissue regeneration and remodeling, leading to increased tissue scarring. Das S, Yin T, Yang Q, Zhang J, Wu YI, & Yu J (2015). 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). The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 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). Daumke O, Lundmark R, Vallis Y, Martens S, Butler PJG, & McMahon HT (2007). Why does our body heal itself? These lipids also exist at the boundary of lipid-ordered domains, such as lipid rafts, indicating that GTPases are targeted to these regions where protein accumulation at the membrane is common (Moissoglu et al., 2014), increasing their relative signaling capacity. Disclaimer. Gazzerro E, Sotgia F, Bruno C, Lisanti MP, & Minetti C (2010). Living systems do this using structures or waterproof materials to prevent or slow liquid movement. These roles of lipids in plasma membrane repair include both a structural role and a signaling role. 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. National Library of Medicine This raises the intriguing possibility that MG53 may affect plasma membrane structural properties. The vast majority of biochemical assembly and break down processeseven by the most complex organismsoccur within cells.