how does a cell membrane repair itself

Marmots maintain strong bones during hibernation by building up without breakingdown. The site is secure. F-actin accumulation is also responsible for providing support to the newly resealed membrane, restoring tension, and preventing subsequent injury. 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). Lipid-soluble molecules and some small molecules can permeate the membrane, but the lipid bilayer effectively repels the many large . While it is unclear whether caveolae can provide structural assistance to the damaged membrane in the context of a large membrane injury (as opposed to sub-injury threshold stress, (Sinha et al., 2011)), caveolae may still provide a signaling function during the repair process. Phosphatidylinositol is found in many cell types and tissues, but is particularly abundant in the brain. These same processes also work to dynamically control membrane fluidity by regulating the distribution of phospholipids, sphingolipids, and cholesterol in the membrane. Eukaryotic cells have been shown to utilize calcium-activated exocytosis to reduce membrane tension and promote repair via lipid-disorder driven attractions. Cholesterol and various proteins are also embedded within the . Stem cell medicine brings a new paradigm to modern medicine which has relied heavily on medicine or surgery. MG53 nucleates assembly of cell membrane repair machinery. The .gov means its official. Similarly, peak PIP2 accumulation at the injury site occurred 45 seconds post-injury in Xenopus oocytes (Vaughan et al., 2014). 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). This is in part achieved through the activity of lipid modifying enzymes, such as kinases, phosphatases, and phospholipases. 2015 Sep;45:2-9. doi: 10.1016/j.semcdb.2015.09.023. Similar inter-leaflet heterogeneity exists among sphingolipids, with the glycosphingolipids maintained exclusively in the outer leaflet. Gradients of Rac1 nanoclusters support spatial patterns of Rac1 signaling. Calcium-regulated exocytosis is required for cell membrane resealing. The plasma membrane is semi-permeable, allowing the cell to communicate with and utilize resources from its surrounding environment. Interphase has three stages: G1, S and G2. Phospholipids and sphingolipids are connected by the head group choline, found on both PC and sphingomyelin (SM). Tam C, Idone V, Devlin C, Fernandes MC, Flannery A, He X, Andrews NW (2010). PA is then used to create other phospholipids including PI, PC, PS, and PE, through the use of the DAG backbone. In the case of lipid mobility, this principle is exemplified by the observation that decreasing the excessive lipid mobility in LGMD2B patient cells using a membrane permeant modified glucocorticoid improves repair (Sreetama et al., 2018). This process is itself facilitated by mechanisms that regulate membrane tension, in particular the re-establishment of the actin cortex. 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). Alteration in this response inhibits the subsequent stages, tissue regeneration and remodeling, leading to increased tissue scarring. Indeed, mechanical injury of healthy cells transiently increases the mobile fraction of plasma membrane lipids by as much as 9% (Sreetama et al., 2018). The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. Modeling membrane shaping by proteins: Focus on EHD2 and NBAR domains. The primary method for PIP2 formation in cells is by the activity of PI(4)P-5 kinase (PI5K) (Kolay, Basu, & Raghu, 2016). Thus, while increase in lipid mobility following plasma membrane injury is associated with successful repair, excessive lipid mobility leading to membrane instability is detrimental to the repair process. This lipid binds ALIX and is capable of budding vesicles away from the cytosol (Matsuo et al., 2004). The cell membrane is an extremely pliable structure composed primarily of two layers of phospholipids (a "bilayer"). Necrosis is a progressive failure of essential metabolic and structural cell components usually in the cytoplasm. ESCRT machinery is required for plasma membrane repair. Cells respond to mechanical stress by rapid disassembly of caveolae. Arp2/3-mediated F-actin formation controls regulated exocytosis in vivo. 8600 Rockville Pike 2023 Feb 28;24(5):4647. doi: 10.3390/ijms24054647. This Goldilocks principle applies to several aspects of lipid involvement in the repair process. 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. The signal to activate recruitment of MG53 to injury sites is not clear, but may relate to its role as a ubiquitin ligase to target substrate(s) damaged as a consequence of the membrane injury. Yasuda S, Townsend D, Michele DE, Favre EG, Day SM, & Metzger JM (2005). Plasma membrane lipids are routinely interconverted as a means to maintain lipid homeostasis and for lipid-mediated signaling. 2018 Apr 23;28(8):R392-R397. It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. 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). 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. calcium, which when constantly increased, induces apoptosis. Would you like email updates of new search results? Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Clementi E. (2009). and transmitted securely. doi: 10.3791/50848. For example, caveolae are the site for assembling membrane repair proteins such as EHD2 and MG53 (Cai et al., 2009; Daumke et al., 2007; Marg et al., 2012). PTRF presumably contributes to the translocation of MG53 to the injury-site, where MG53 is also able to bind PS and become activated in an oxidation-dependent manner (Cai et al., 2009). Repair of injured cells is tied closely to tissue repair and regeneration, as shown by studies demonstrating release of inflammatory mediators, including small molecules, peptides and proteins that signal to cells in the inflammatory and regenerative systems to initiate a tissue level reparative response. doi: 10.1042/BSR20220765. 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. Calise S, Blescia S, Cencetti F, Bernacchioni C, Donati C, & Bruni P (2012). Gushchina LV, Bhattacharya S, McElhanon KE, Choi JH, Manring H, Beck EX, Weisleder N. (2017). A different model for plasma membrane repair began to emerge when mammalian cells injured mechanically or by SLO pores were found to undergo massive endocytosis, after Ca 2+ -triggered exocytosis of lysosomes ( Figure 1 C). Plasma membrane wounding and repair in pulmonary diseases, American Journal of Physiology-Lung Cellular and Molecular Physiology, Membrane repair: mechanisms and pathophysiology. Different cell-intrinsic PM repair mechanisms have been reported, including membrane fusion and replacement strategies (via exocytosis-mediated repair), removal of damaged membranes (by. 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). 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). In this way, lipids play an important role in polarizing the cellular response to an injury. Gauthier NC, Masters TA, & Sheetz MP (2012). Temporary increase in plasma membrane tension coordinates the activation of exocytosis and contraction during cell spreading. official website and that any information you provide is encrypted Living systems do this using structures or waterproof materials to prevent or slow liquid movement. Small GTPases, such as Rho family members, associate with biological membranes via lipid modifications (ten Klooster & Hordijk, 2007); however, selectivity for the plasma membrane is regulated through the polybasic domain comprised of a cluster of positively charged amino acids (Do Heo et al., 2006; Maxwell, Zhou, & Hancock, 2018). Cells are the basic building blocks of all living systems, so cellular processes dictate how physiological processes occur within those systems. 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. The role of lipids during plasma membrane repair goes far beyond a passive role in vesicle-mediated delivery of membrane lipids. Mitochondrial fragmentation and ROS signaling in wound response and repair. Why does our body heal itself? However, ceramide formation also changes membrane dynamics by forming rigid microdomains and potentially by displacing cholesterol from lipid rafts (London, 2004). Instead, distinct inter- and intra-leaflet heterogeneity exists. Disclaimer. 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. Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis, Lipid peroxidation induces cholesterol domain formation in model membranes. These examples illustrate the far-reaching consequence of lipid movement on structural stability of the plasma membrane and its ability to successfully repair. Plasma membrane lipids can be grouped into three classes glycerophospholipids, sphingolipids, and sterols. Trends Cell Biol. Int J Mol Sci. Unauthorized use of these marks is strictly prohibited. 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. MG53 (40) shows diffuse enrichment at injury sites within 2 s of membrane injury in a calcium-independent manner (150). In the subsequent sections, we will discuss how this is achieved and utilized by the cell. 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. Disclaimer. Phospholipids in particular show inter-leaflet heterogeneity. 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). Newer pharmacological approaches for antioxidant neuroprotection in traumatic brain injury. Limiting the spread of lipid hydroperoxides may also explain the beneficial effect of vitamin E treatment on plasma membrane repair (Howard, McNeil, & McNeil, 2011; Labazi et al., 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). Living systems must maintain a proper liquid balance, which is especially difficult in dry conditions. Would you like email updates of new search results? For example, venomous snakes store precursor molecules to instantly synthesize a suite of toxins via enzyme-mediated cascades. In mammalian cells, lipids formed upon the phosphate and glycerol (e.g. Intriguingly, PA preferentially binds the Rho family member Rac1, resulting in nanocluster formation (Maxwell et al., 2018). Another role identified for lysosomal fusion in membrane repair is the secretion of the lipid modifying enzyme acid sphingomyelinase (ASM) (Defour et al., 2014; Tam et al., 2010). Caveolae protect endothelial cells from membrane rupture during increased cardiac output. Examples of self-repairing cells. These domains decrease the local fluidity in the membrane relative to the regions comprised primarily of phospholipids. Regulation of Rac1 translocation and activation by membrane domains and their boundaries, Stressing caveolae new role in cell mechanics, Membrane cytoskeleton: PIP2 pulls the strings, The FluidMosaic Model of Membrane Structure: Still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years, Biochimica et Biophysica Acta (BBA)-Biomembranes. Vaughan EM, You J-S, Yu H-YE, Lasek A, Vitale N, Hornberger TA, & Bement WM (2014). Lateral movement, rotation, and flipping of lipids between the leaflets of the plasma membrane are the physical changes that work together to allow the fluid membrane to adapt to the changes in membrane tension (Nicolson, 2014) (Figure 2C). Many organisms and tissues display the ability to heal and regenerate as needed for normal physiology and as a result of pathogenesis. If the damage is beyond repair, the cell will normally send itself into apoptosis, ensuring that it will not pass on its damaged DNA. 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. Plataki M, Lee YD, Rasmussen DL, & Hubmayr RD (2011). 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). Here we will discuss the current knowledge of how lipids facilitate plasma membrane repair by regulating membrane structure and signaling to coordinate the repair response, and will briefly note how lipid involvement extends beyond plasma membrane repair to the tissue repair response. The long held dogma in the cardiac biology community was that these cells do not . Houang EM, Haman KJ, Filareto A, Perlingeiro RC, Bates FS, Lowe DA, & Metzger JM (2015). 2022 Aug 4;11:e80778. 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. 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. We use cookies to give you the best browsing experience. Of potential interest in this regard is the unconventional phospholipid lysobisphosphatidic acid (LBPA), which is found on endolysosomes. However, these repair activities can also be observed at the single-cell level. Bookshelf One such mechanism is addition of more membrane via vesicle fusion (Fig 1B ). An official website of the United States government. Plasma membrane repair in health and disease. Alkaloid molecules protect plants from bacterial infections. 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. However, all cells are susceptible to plasma membrane damage, which results in the mixture of the intracellular fluid and extracellular milieu and can result in death if the damage is not rapidly repaired. Similar to the changes in tension described above, the fluidity of the plasma membrane is also dynamic after injury. Before Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair, Involvement of lipid peroxidation in CNS injury, Focal adhesions, stress fibers and mechanical tension. This may allow these lipids and proteins to interact with new partners that were unavailable due to spatial segregation prior to injury. This Review presents current understanding in wound healing and regeneration as two distinct aspects of cellular self-repair by examining a few model organisms that have displayed robust repair capacity, including Xenopus oocytes, Chlamydomonas, and Stentor coeruleus Although many open questions remain, elucidating how cells repair themselves is important for our mechanistic understanding of cell biology. Cholesterol modulates cell signaling and protein networking by specifically interacting with PDZ domain-containing scaffold proteins. lipids) is one of the roles proposed for lysosome-mediated repair (Andrews et al., 2014; McNeil, 2002). Howard AC, McNeil AK, & McNeil PL (2011). Van Meer G, Voelker DR, & Feigenson GW (2008). 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. Rapid Changes to Endomembrane System of Infected Root Nodule Cells to Adapt to Unusual Lifestyle. 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. Slabodnick M, Prevo B, Gross P, Sheung J, Marshall W. J Vis Exp. Role of phosphatidylinositol 4, 5-bisphosphate in regulating EHD2 plasma membrane localization. McNeil AK, Rescher U, Gerke V, & McNeil PL (2006). Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion, Demonbreun AR, & McNally EM (2016). Lipids also interact with plasma membrane localized proteins to regulate membrane tension and fluidity. Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling. However, whether caveolae facilitate repair by buffering membrane tension remains unclear because, unlike the capacity of CLIC/GEEC endocytosis, caveolae make up a small portion (as small as 0.03%) of the membrane area and are not found ubiquitously in all cells (Gauthier et al., 2012; Sinha et al., 2011). Accumulation of GRAF1 at the repair site occurs 2 minutes after injury, supporting its potential role in membrane remodeling following resealing. 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). With larger injuries, the opposing force of membrane tension exceeds the resealing forces of lipid disorder at the edges of the disruption, negating the driving forces of spontaneous membrane resealing. Epub 2012 Jul 9. Muscle fibers are subject to huge variations in membrane tension, due to their contractile activity. When cells have DNA damage but fail to undergo apoptosis, they may be on the road to cancer. Houang EM, Sham YY, Bates FS, & Metzger JM (2018). Ligeti E, Dagher M-C, Hernandez SE, Koleske AJ, & Settleman J (2004). official website and that any information you provide is encrypted The physical properties of the plasma membrane are governed in large part by the effect of lipid interactions at the population level. 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. Healing, Examples of self-repairing cells. 2023 Apr 4;122(7):1355-1363. doi: 10.1016/j.bpj.2023.03.001. Modular, cascade-like transcriptional program of regeneration in, R01 GM113602/GM/NIGMS NIH HHS/United States. It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. J Cell Biol. Lee I-H, Kai H, Carlson L-A, Groves JT, & Hurley JH (2015). The plasma membrane is a dynamic barrier that separates the cell interior from the extracellular space (Figure 2C). SM utilizes the ceramide (Cer) backbone and can be used to generate the signaling lipid sphingosine-1-phosphate (S1P). Bethesda, MD 20894, Web Policies (B) The plasma membrane is not a homogenous mixture of proteins and lipids (as in A). 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). These observations on PIP2 kinetics line up remarkably well with the accumulation of F-actin at the injury site, which begins around 30 seconds after injury and extends for several minutes (Godin, Vergen, Prakash, Pagano, & Hubmayr, 2011; Horn et al., 2017). 2021 Apr 2;19(1):63. doi: 10.1186/s12915-021-00970-0. 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. This study showed that shear force on the membrane, as experienced by cells during mechanical injury, facilitated increased PLD activity through the process of lipid mixing. While lipids are often ascribed a metabolic role as energy storage molecules, they also play important structural and signaling roles in the cell. High force impact or stress can cause materials that comprise living systems to separate into two or more pieces (called fracturing) or to break or burst suddenly (called rupturing). Imagine a polymer wrapper that would heal when ripped during use, but would eventually decompose when placed in a compost heap. (Biomimicry Guild unpublished report). Gurtner GC, Werner S, Barrandon Y, & Longaker MT (2008). See this image and copyright information in PMC. Myofiber injury in zebrafish was found to cause rapid loss of PIP2, followed by restoration to pre-injury levels by 30 seconds post-injury (Middel et al., 2016).
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