Living systems do this using structures or waterproof materials to prevent or slow liquid movement. This homeostatic process of vesicle fusion that maintains the plasma membrane at rest also enables plasma membrane repair through regulated fusion of vesicles triggered by calcium influx following plasma membrane injury (Horn & Jaiswal, 2018; McNeil & Steinhardt, 2003). In fact, cells are able to perform hundreds, even thousands, of chemical transformations at the same time under life-friendly conditions (ambient temperature and pressure in an aqueous environment). Proc Natl Acad Sci U S A. 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). While PC exists in both the inner and outer leaflet of the plasma membrane, the charged phospholipids PE, PI, and PS are almost exclusively maintained within the inner leaflet (Nicolson, 2014; van Meer, 1989). Miyake K, McNeil PL, Suzuki K, Tsunoda R, & Sugai N (2001). Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis, Lipid peroxidation induces cholesterol domain formation in model membranes. 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. 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. Phospholipids in particular show inter-leaflet heterogeneity. 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). If you break a bone, your body immediately begins producing new cells to heal the damage. Glycerol-3-phosphate is used to generate PA as well as PG through the intermediate phosphatidylglycerol phosphate (PGP). 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). EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription. Calcium also initiates lipid signaling after plasma membrane injury by activating phospholipases, such as phospholipase C (PLC). The antioxidant requirement for plasma membrane repair in skeletal muscle. Verweij FJ, Revenu C, Arras G, Dingli F, Loew D, Pegtel DM, Zimmermann P (2019). Spontaneous resealing of plasma membrane, Spontaneous resealing of plasma membrane injuries in the nanometer range is opposed by, Calcium-activated exocytosis reduces membrane tension, Calcium-activated exocytosis reduces membrane tension and promotes spontaneous repair driven by lipid disorder, Very large plasma membrane disruptions (micron diameter) require membrane patching. 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). This process is more efficient when GTPases and their regulatory proteins (which are themselves regulated by lipids) are clustered (Ligeti, Dagher, Hernandez, Koleske, & Settleman, 2004). The plasma membrane, also called the cell membrane, is the membrane found in all cells that separates the interior of the cell from the outside environment. PTRF Anchors MG53 to Cell Injury Site for Initiation of Membrane Repair. Transient and local lipid peroxidation may affect membrane stabilization as peroxidation of polyunsaturated fatty acids changes head group separation and acyl chain interdigitation, increasing their molecular volume and causing formation of distinct cholesterol domains in the membrane, which increases the membrane rigidity (Jacob & Mason, 2005; Mason, Walter, & Mason, 1997). Nakamura M, Hui J, Stjepi V, Parkhurst SM. Boye TL, Maeda K, Pezeshkian W, Snder SL, Haeger SC, Gerke V, Nylandsted J. Corrotte M, Almeida PE, Tam C, Castro-Gomes T, Fernandes MC, Millis BA, Maugel TK. Muscle fibers have a complex plasma membrane network with a repeating register of deep plasma membrane invaginations called the t-tubule network. 8600 Rockville Pike Torrino S, Shen W-W, Blouin CM, Mani SK, de Lesegno CV, Bost P, Chambon V (2018). 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. Cells respond to mechanical stress by rapid disassembly of caveolae. and transmitted securely. EHD2 localization at caveolae results from its affinity for phosphatidylinositol 4,5-bisphosphate (PIP2), which is enriched around the caveolae boundary (Parton & Del Pozo, 2013; Simone, Caplan, & Naslavsky, 2013). (2017). Bethesda, MD 20894, Web Policies Cambridge (MA): Harvard Stem Cell Institute; 2008. Regulation of the actin cytoskeleton-plasma membrane interplay by phosphoinositides. National Library of Medicine 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. Skalman LN, Holst MR, Larsson E, & Lundmark R (2018). The plasma membrane is semi-permeable, allowing the cell to communicate with and utilize resources from its surrounding environment. This dissociation has the effect of allowing Rho GTPase translocation to the membrane where it can interact with signaling lipids. During the S stage, the cell A surprise arrived when heart muscle cells were analyzed. This involves a series of distinct, but mutually dependent stages including inflammation, regeneration, and remodeling of the tissue (Gurtner, Werner, Barrandon, & Longaker, 2008). Copyright 2015 the American Physiological Society. Do Heo W, Inoue T, Park WS, Kim ML, Park BO, Wandless TJ, & Meyer T (2006). 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. While lipids are often ascribed a metabolic role as energy storage molecules, they also play important structural and signaling roles in the cell. Calcium entry after plasma membrane injury is required for repair. Zhang KS, Blauch LR, Huang W, Marshall WF, Tang SKY. While intracellular MG53 is a redox-sensitive protein capable of facilitating vesicle aggregation, it is proposed to have multiple functions during membrane repair. Calcium-activated exocytosis reduces membrane tension and promotes spontaneous repair driven by lipid disorder for injuries hundreds of nanometers in diameter. Sreetama SC, Chandra G, Van der Meulen JH, Ahmad MM, Suzuki P, Bhuvanendran S, Jaiswal JK (2018). The mystery of membrane organization: composition, regulation and roles of lipid rafts. Mechanistically, the process of membrane shedding is mediated by the endosomal sorting complexes required for transport (ESCRT) proteins (Jimenez et al., 2014; Scheffer et al., 2014). Phospholipid signalling through phospholipase D and phosphatidic acid. Federal government websites often end in .gov or .mil. The common eastern firefly produces light through a chemical reaction that energizes a molecule so it can release aphoton. For example, the dynamic arrangement of lipids in the plasma membrane as discussed above, and the electrostatic or chemical changes in lipids due to enzymatic activity of lipid modifying enzymes rapidly affect lipids themselves as well as the target proteins in the plasma membrane (Figure 2B, ,C).C). 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). 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). A lysosome is a membrane-bound cell organelle that contains digestive enzymes. Once membrane tension is restored, the poloxamer compound is forced out of the outer membrane leaflet (Houang, Sham, Bates, & Metzger, 2018). For example, when humans receive a cut, they must limit blood loss. Healing, Examples of self-repairing cells. As discussed above, sphingolipids in the plasma membrane are an important regulator of plasma membrane repair. 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). Mechanism of Ca 2+-triggered ESCRT assembly and regulation of cell membrane repair. There are mechanisms that allow some products to enter or leave the cell either actively or passively. 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. 2023 Feb 28;24(5):4707. doi: 10.3390/ijms24054707. We have briefly discussed how such an integral role of lipids in plasma membrane repair also extends into tissue-level repair and restoration of organ function. Thottacherry JJ, Kosmalska AJ, Kumar A, Vishen AS, Elosegui-Artola A, Pradhan S, Chaudhary N (2018). We here review what is known about the cellular and molecular mechanisms of membrane repair, with particular emphasis on the relevance of repair as it relates to disease pathologies. Epub 2012 Jul 9. It can also be produced by methylation of existing PE, while PE can be produced by the decarboxylation of PS. The site is secure. 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). These roles of lipids in plasma membrane repair include both a structural role and a signaling role. Failure or delay in these processes, as in chronic inflammatory conditions and conditions of regenerative deficit would lead to aberrant tissue remodeling resulting in fibrotic or adipogenic replacement of the lost tissue. This is in part achieved through the activity of lipid modifying enzymes, such as kinases, phosphatases, and phospholipases. 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. 2013 Dec 19;(82):e50848. This remodeling is likely provided by processes described previously: membrane endocytosis (Section 3.1) and membrane shedding (Section 4.1). 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. 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. 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. PC), with a conical shaped, charged phospholipid (e.g. This helps to remodel the newly repaired plasma membrane (Middel et al., 2016), but may also serve to potentiate tissue inflammation. Microfluidic guillotine reveals multiple timescales and mechanical modes of wound response in Stentor coeruleus. Plasma membrane repair in health and disease. Mechanistic principles underlying regulation of the actin cytoskeleton by phosphoinositides, Regulation of actin dynamics by PI (4, 5) P2 in cell migration and endocytosis, Pro-resolving lipid mediators are leads for resolution physiology. Modeling membrane shaping by proteins: Focus on EHD2 and NBAR domains. Healing of a punctured Xenopus oocyte, where the dark, The regeneration and reorganization of the oral apparatus (green) of Stentor coeruleus ., Wound healing studies in model cells such as Xenopus oocytes and muscle cells, Evidence that oral regeneration in Stentor can be triggered by the loss of, MeSH In addition to their structural role in shaping the physical properties of the plasma membrane, lipids also play an important signaling role in maintaining plasma membrane integrity. The plasma membrane is a dynamic barrier that separates the cell interior from the extracellular space (Figure 2C). In addition to their structural role, and often as an extension of it, lipids also provide a signaling function that facilitates plasma membrane repair. Gushchina LV, Bhattacharya S, McElhanon KE, Choi JH, Manring H, Beck EX, Weisleder N. (2017). 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). Other cells acquire specialized functions as they mature. Int J Mol Sci. 2023 Apr 4;122(7):1355-1363. doi: 10.1016/j.bpj.2023.03.001. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Similar to PLC, phospholipase D (PLD) activity is also increased after injury and is required for repair (Arun et al., 2013). Similar to the changes in tension described above, the fluidity of the plasma membrane is also dynamic after injury. Their localization and function in response to injury is controlled by the patterning of anionic lipids such as PS, which is present at the wound edge and is a known binding partner of annexins (Gerke, Creutz, & Moss, 2005). Federal government websites often end in .gov or .mil. Rather than these roles being separated from each other, they overlap significantly such that one can easily be an extension of the other. These examples illustrate the far-reaching consequence of lipid movement on structural stability of the plasma membrane and its ability to successfully repair. 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). official website and that any information you provide is encrypted If the cell is damaged beyond repair, lysosomes can help it to self-destruct in a process called programmed . PMC 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. Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Clementi E. (2009). This site needs JavaScript to work properly. Evidence suggests these pores are removed both by endosomal degradative pathways (123, 164, 280) and exosomal shedding (14, 118, 136). Furthermore, individual lipids may be modified by proteins, which generate new lipid species that can change membrane structural properties (red, Cer) or be used for signaling (purple, DAG). To do so, they must control the movement of liquids across their boundaries. Accumulation of GRAF1 at the repair site occurs 2 minutes after injury, supporting its potential role in membrane remodeling following resealing. As she describes, a lesion is followed by a Ca2+-dependent movement of vesicles to the plasma membrane. Living systems must maintain a proper liquid balance, which is especially difficult in dry conditions. GRAF1 deficiency blunts sarcolemmal injury repair and exacerbates cardiac and skeletal muscle pathology in dystrophin-deficient mice. Each of these pathways that facilitate repair through membrane remodeling also alter the local composition and distribution of plasma membrane lipids in healthy cells (van Meer, 1989) (Figure 2D). Lethal Injury (Cell Death) In many situations, the damage to a cell may be so severe that the cell cannot survive. It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. This suggests the possibility that caveolae could act as mechanosensors that facilitate adaptation to membrane injury through gene transcription, although this remains to be explored. Mechanical feedback between membrane tension and dynamics. Arp2/3-mediated F-actin formation controls regulated exocytosis in vivo. Gradients of Rac1 nanoclusters support spatial patterns of Rac1 signaling. Thus, electrostatic interaction with signaling lipids helps to facilitate GTPase localization, which is a critical feature that determines the efficiency and magnitude of the downstream response (Das et al., 2015; Yogurtcu & Johnson, 2018). One such mechanism for this may be mediated by the protein MG53. However, these repair activities can also be observed at the single-cell level. Bookshelf The radiation could damage the cell's DNA, but the DNA repairs itself. Promotion of plasma membrane repair by vitamin E. Idone V, Tam C, Goss JW, Toomre D, Pypaert M, & Andrews NW (2008). Membrane-stabilizing copolymers confer marked protection to dystrophic skeletal muscle in vivo, Molecular Therapy-Methods & Clinical Development. In addition to regulating the patterning and activity of Rho family GTPases, lipids also have a more direct role in regulating F-actin association with the plasma membrane. 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. Campelo F, Fabrikant G, McMahon HT, & Kozlov MM (2010). While much attention has been paid to the involvement of proteins in the membrane repair pathway, the role of lipids in facilitating plasma membrane repair remains poorly studied. . Direct lipid modification of proteins, such as GTPases, provides another method to regulate protein localization and activity (Casey, 1995). 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. Leikina E, Defour A, Melikov K, Van der Meulen JH, Nagaraju K, Bhuvanendran S, Jaiswal JK (2015). 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). The plasma membrane consists of a lipid bilayer that is semipermeable. PIP2 also accumulates at the site of membrane injury (Demonbreun et al., 2016; Vaughan et al., 2014). This may allow these lipids and proteins to interact with new partners that were unavailable due to spatial segregation prior to injury. 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). The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. In general, PIP2 is a positive regulator of F-actin polymerization and the presence of PIP2 increases the stability of the actin cytoskeletonplasma membrane interface. 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). FOIA 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). If the damage is beyond repair, the cell will normally send itself into apoptosis, ensuring that it will not pass on its damaged DNA. Andrews NW, Almeida PE, & Corrotte M (2014). F-actin accumulation is also responsible for providing support to the newly resealed membrane, restoring tension, and preventing subsequent injury. Bennett APS, de la Torre-Escudero E, Dermott SSE, Threadgold LT, Hanna REB, Robinson MW. 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. 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). Cong X, Hubmayr RD, Li C, & Zhao X (2017). "Think of a . While PA mediates targeting to the membrane, Rac1 activity depends on PIP3, suggesting multiple roles for signaling lipids in GTPase activity after repair. Clipboard, Search History, and several other advanced features are temporarily unavailable. Togo T, Krasieva TB, & Steinhardt RA (2000). Necrosis is a progressive failure of essential metabolic and structural cell components usually in the cytoplasm. PS) in the inner leaflet, causes the plasma membrane to attain an overall outward curvature. Bouter A, Gounou C, Brat R, Tan S, Gallois B, Granier T, Brisson AR. A decrease in membrane tension precedes successful cell-membrane repair. Local oxidation at the site of membrane injury activates MG53 oligomerization (Cai et al., 2009), which may locally increase membrane rigidity. Different cell-intrinsic PM repair mechanisms have been reported, including membrane fusion and replacement strategies (via exocytosis-mediated repair), removal of damaged membranes (by. 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. This mechanism is particularly intriguing in light of the redox-sensitive nature of MG53. Poloxamer 188 facilitates the repair of alveolus resident cells in ventilator-injured lungs, American journal of respiratory and critical care medicine. Thus, local lipid peroxidation may provide transient membrane stabilization, while mechanisms such as redox-dependent MG53 binding may limit the spread of lipid peroxides. 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). 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 know first-hand some of the characteristics that make mammals unique, like having hair, being able to sweat, and producing milk through mammary glands. Dr. Norma Andrews overviews the mechanisms of cellular plasma membrane repair.
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