Dysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair. Activated calpains cleave dysferlin within a motif specifically encoded by alternately spliced exon 40a (230). Physico-chemical and biological considerations for membrane wound evolution and repair in animal cells. Collective evidence reveals membrane repair employs primitive yet robust molecular machinery, such as vesicle fusion and contractile rings, processes evolutionarily honed for simplicity and success. An official website of the United States government. "Think of a . The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. BMC Biol. Accessibility eCollection 2021. Lenhart KC, ONeill TJ, Cheng Z, Dee R, Demonbreun AR, Li J, Taylor JM (2015). Bacterial pore-forming toxins oligomerize and insert in the plasma membrane of target cells forming a diffusible pore. Bethesda, MD 20894, Web Policies FOIA the contents by NLM or the National Institutes of Health. 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. EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription. Different cell-intrinsic PM repair mechanisms have been reported, including membrane fusion and replacement strategies (via exocytosis-mediated repair), removal of damaged membranes (by. Mechanical feedback between membrane tension and dynamics. PS) in the inner leaflet, causes the plasma membrane to attain an overall outward curvature. Boye TL, Maeda K, Pezeshkian W, Snder SL, Haeger SC, Gerke V, Nylandsted J. 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). 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. J Cell Biol. This may allow these lipids and proteins to interact with new partners that were unavailable due to spatial segregation prior to injury. Modular, cascade-like transcriptional program of regeneration in, R01 GM113602/GM/NIGMS NIH HHS/United States. With an abundance of uncharged (zwitterionic) lipids and smaller amounts of neutral and anionic glycosphingolipids in the outer leaflet, and the negatively charged phosphatidylserine, phosphatidic acid and phosphatidylinositol within the inner leaflet, there exists a charge differential between the two plasma membrane leaflets (Steck & Lange, 2018; Zachowski, 1993). Injury to the plasma membrane also changes the biochemical environment within the cell. Membrane injury causes a local influx of calcium and activation of calpains. This allows local and functional diversity between the two leaflets as well as various parts of the single contiguous plasma membrane (Figure 2B). While being a mostly non-polar molecule, owing to its steroid backbone and hydrocarbon chain, cholesterol does possess a hydroxyl group opposite the hydrocarbon chain. Liquids, mostly water, make up 70 to 90% of all living systems, and the loss of even a small percentage can mean the difference between life and death. Further, the addition of new membrane by increased calcium-triggered exocytosis also decreases membrane tension and is required for plasma membrane repair (Togo et al., 2000). Cells (whether entire unicellular organisms or parts of multicellular living systems) grow, metabolize nutrients (that is, chemically transform them), produce proteins and enzymes, replicate, and move. Please enable it to take advantage of the complete set of features! The chemical structure of the cell membrane makes it remarkably flexible, the ideal boundary for rapidly growing and dividing cells. Just like cells have membranes to hold everything in, these mini-organs are also bound in a double layer of phospholipids to insulate their little compartments within the larger cells. Intriguingly, PIP2 is needed for PLD activity suggesting the possibility that a feed-forward loop leads to increasing PIP2 concentrations as repair progresses ultimately facilitating the necessary build-up of F-actin (Figure 1B). One signaling function of lipids is the recruitment of peripheral membrane proteins to the plasma membrane. HHS Vulnerability Disclosure, Help While small injuries to the plasma membrane (on the nanometer scale) can be spontaneously resealed due to the line tension imposed by plasma membrane lipids alone (McNeil & Terasaki, 2001), larger membrane injuries (on the micron scale) require a series of coordinated mechanisms to undergo repair. Cai C, Masumiya H, Weisleder N, Matsuda N, Nishi M, Hwang M, Zhao X. Glycerol-3-phosphate is used to generate PA as well as PG through the intermediate phosphatidylglycerol phosphate (PGP). Plasma membrane repair relies on the coordinated activity of repair machinery, which carries out vesicle fusion to the membrane, membrane shedding, and polymerization of F-actin at the site of repair (Horn & Jaiswal, 2018). 8600 Rockville Pike 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). The cell membrane is an extremely pliable structure composed primarily of two layers of phospholipids (a "bilayer"). Recombinant MG53 protein modulates therapeutic cell membrane repair in treatment of muscular dystrophy. 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). 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). While initial loss of cortical actin aids in repair by allowing physical access for vesicles to fuse with the plasma membrane, the accumulation of F-actin at the injury site in the minutes following injury, is also required to provide structural support to the repairing/repaired membrane and prevent additional injury due to membrane fragility (Demonbreun et al., 2016; Horn et al., 2017; Jaiswal et al., 2014; McDade, Archambeau, & Michele, 2014; Miyake et al., 2001). The common eastern firefly produces light through a chemical reaction that energizes a molecule so it can release aphoton. This signaling function may occur due to the activity of the repair protein EHD2, which accumulates at the site of membrane injury and is thought to play a role in shaping membrane dynamics (Daumke et al., 2007; Demonbreun et al., 2016; Marg et al., 2012). Newer pharmacological approaches for antioxidant neuroprotection in traumatic brain injury. 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). The radiation could damage the DNA so badly that the cell dies. 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). The plasma membrane forms the physical barrier between the cytoplasm and extracellular space, allowing for biochemical reactions necessary for life to occur. Changing the head group attached to the DAG backbone creates different phospholipid species, which include phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), and PA (Oropeza, 2017) (Figure 1B). The goal of signaling during plasma membrane repair is to generate a polarized response such that the repair machinery can be spatially and temporally localized and activated at the repair site. PA is itself generated primarily from glycerol-3-phosphate, which is a product of glycolysis. The plasma membrane has a unique lipid composition that helps distinguish its structural and functional properties from the other internal membrane-bound compartments. The radiation could damage the cell's DNA, but the DNA repairs itself. Potez S, Luginbhl M, Monastyrskaya K, Hostettler A, Draeger A, & Babiychuk EB (2011). 2008 Mar 10;180(5):905-14. doi: 10.1083/jcb.200708010. 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). Dysferlin is not detected at injury sites until 10 s postinjury, a delay we attribute to an intermediary step involving calpain cleavage. Definition. 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). Repeated eccentric exercise in healthy subjects (i.e., stepping down for 20 min) is known to induce damage so severe that muscle fibers degenerate over the following days and weeks (91, 131, 199). Plasma membrane damage needs to be rapidly repaired to avoid cell death. Remorino A, De Beco S, Cayrac F, Di Federico F, Cornilleau G, Gautreau A, Coppey M (2017). Membrane lipids: where they are and how they behave. During the repair of sarcolemmal lesions, macrophages recognize exposed phosphatidylserine at the site of . Membrane tension: A challenging but universal physical parameter in cell biology, Paper presented at the Seminars in cell & developmental biology. Lipid domaindependent regulation of single-cell wound repair, Rho family GTPases bring a familiar ring to cell wound repair. Cell damage (also known as cell injury) is a variety of changes of stress that a cell suffers due to external as well as internal environmental changes. Structurally, the conical ceramide molecule results in negative membrane curvature associated with rapid nucleation of ESCRT complex proteins (Lee, Kai, Carlson, Groves, & Hurley, 2015). Phospholipid signalling through phospholipase D and phosphatidic acid. If the cell is damaged beyond repair, lysosomes can help it to self-destruct in a process called programmed . diacylglycerol - DAG) backbone are called glycerophospholipids (referred to as phospholipids hereafter) and make up the majority of the plasma membrane. Similar inter-leaflet heterogeneity exists among sphingolipids, with the glycosphingolipids maintained exclusively in the outer leaflet. (D) The lipid make-up of the plasma membrane constantly changes. Unable to load your collection due to an error, Unable to load your delegates due to an error, Examples of self-repairing cells. lipids) is one of the roles proposed for lysosome-mediated repair (Andrews et al., 2014; McNeil, 2002). 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. Membrane repair is a conserved physiologic process in multiple tissues Organ Type of mechanical force Principal cells stressed Cell wounding 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. GTPases are molecular switches that require the cycling of nucleotides to remain active. Because membrane tension limits the ability of cellular membranes to self-seal, cellular mechanisms that reduce membrane tension can promote membrane sealing. 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). Given their ability to traverse away from the site of synthesis (Verweij et al., 2019), the EVs generated during plasma membrane injury may activate both local and distant tissue regeneration responses needed for repair. Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. 2022 Aug 4;11:e80778. 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)). Bissig C, Lenoir M, Velluz M-C, Kufareva I, Abagyan R, Overduin M, & Gruenberg J (2013). Calcium entry after plasma membrane injury is required for repair. When a cell's DNA is damaged, it will typically detect the damage and try to repair it. Many organisms and tissues display the ability to heal and regenerate as needed for normal physiology and as a result of pathogenesis. Dr. Norma Andrews overviews the mechanisms of cellular plasma membrane repair. Calcium can activate proteins directly, and ultimately is the initiator of many downstream repair pathways. Horn A, Van der Meulen JH, Defour A, Hogarth M, Sreetama SC, Reed A, Jaiswal JK. 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). Gauthier NC, Fardin MA, Roca-Cusachs P, & Sheetz MP (2011). Another role of plasma membrane lipids in wound detection is that of mechanosensing provided by lipid microdomains, such as caveolae, by way of sensing injury-triggered alteration in membrane stress (see Section 3.1). The long held dogma in the cardiac biology community was that these cells do not . This raises the intriguing possibility that MG53 may affect plasma membrane structural properties. This process, facilitated by the dysferlin-mediated release of acid sphingomyelinase (Defour et al., 2014) creates microdomains of ceramide from sphingomyelin. For example, a scallop prevents structural failure from fracture because its shell is comprised of two materials of varying stiffness. 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 nanoclusters appear to form specifically at the boundary of ordered raft domains and disordered domains where signaling lipids such as PIP3 and PIP2 are found. Clipboard, Search History, and several other advanced features are temporarily unavailable. 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). Copyright 2015 the American Physiological Society. 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. 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. Instead, there exists distinct inter- and intra-leaflet heterogeneity of lipids. This Goldilocks principle applies to several aspects of lipid involvement in the repair process. The plasma membrane consists of a lipid bilayer that is semipermeable. For example, the cytoskeletal proteins interact with membrane lipids to supply the cortical tension that regulates the global shape of the plasma membrane and produces cell movement (Cebecauer et al., 2018; Sezgin et al., 2017). 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. Two-way traffic on the road to plasma membrane repair. Gradients of Rac1 nanoclusters support spatial patterns of Rac1 signaling. Examples of self-repairing cells. This is especially important for membrane signaling functions as the liquid-ordered domains often serve to aggregate membrane-associated proteins (Cebecauer et al., 2018). The fatty membranes of cells are capable of self-repair using a mechanism that involves calcium-dependent exocytosis. These phospholipids are derived from glycerol-3-phosphate, itself a product of cellular metabolism that is enzymatically modified into phosphatidic acid (PA). Another critical shared feature is a set of highly-specialized teeth. 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). The structural role of lipids may extend into the signaling role, which can then impact back on the structural characteristics of the repairing membrane by changing the composition or distribution of individual lipids. Calcium-regulated exocytosis is required for cell membrane resealing. Spatiotemporal dynamics of actin remodeling and endomembrane trafficking in alveolar epithelial type I cell wound healing. 2023 Feb 28;24(5):4647. doi: 10.3390/ijms24054647. The MG53 binding protein PTRF (cavin-1) binds cholesterol in response to membrane injury (Zhu et al., 2012). government site. Bouter A, Gounou C, Brat R, Tan S, Gallois B, Granier T, Brisson AR. 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. 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. . Das S, Yin T, Yang Q, Zhang J, Wu YI, & Yu J (2015). Sterols, or steroid alcohols, are a third type of plasma membrane lipid, with cholesterol being the predominant form found in mammalian cells.
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