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. Muscle membrane integrity in Duchenne muscular dystrophy: recent advances in copolymer-based muscle membrane stabilizers. Before 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. This form of membrane remodeling maintains lipid homeostasis and plasma membrane functionality. Calcium-activated exocytosis reduces membrane tension and promotes spontaneous repair driven by lipid disorder for injuries hundreds of nanometers in diameter. Many of the sphingolipids also contain a glycosidically bound carbohydrate moiety causing formation of the glycosphingolipids. Survival from bacterial pore-forming toxins utilizes both exocytic and endocytic responses. . Leikina E, Defour A, Melikov K, Van der Meulen JH, Nagaraju K, Bhuvanendran S, Jaiswal JK (2015). 2022 Dec 1;11(1):38. doi: 10.1186/s13619-022-00141-8. 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. Delivery of membrane (i.e. An actin-dependent annexin complex mediates plasma membrane repair in muscle. We use cookies to give you the best browsing experience. Lipids act as signaling molecules through their ability to directly bind or otherwise alter the activity or localization of target proteins (Figure 2B, ,C).C). For example, a scallop prevents structural failure from fracture because its shell is comprised of two materials of varying stiffness. Use the force: membrane tension as an organizer of cell shape and motility. Demonbreun AR, Quattrocelli M, Barefield DY, Allen MV, Swanson KE, & McNally EM (2016). PIP2 also accumulates at the site of membrane injury (Demonbreun et al., 2016; Vaughan et al., 2014). Cheng JP, Mendoza-Topaz C, Howard G, Chadwick J, Shvets E, Cowburn AS, Nichols BJ (2015). 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 role of lipids during plasma membrane repair goes far beyond a passive role in vesicle-mediated delivery of membrane lipids. They break down excess or worn-out cell parts. Elife. The poor repair of these patient cells can be mirrored in healthy cells by increasing their membrane lipid mobility through the removal of cholesterol or by addition of a glucocorticoid (prednisone) (Heier et al., 2013; Sreetama et al., 2018). Calcium can activate proteins directly, and ultimately is the initiator of many downstream repair pathways. J.K.J. 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. This cell membrane provides a protective barrier around the cell and regulates which materials can pass in or out. If you break a bone, your body immediately begins producing new cells to heal the damage. A decrease in membrane tension precedes successful cell-membrane repair. Alkaloid molecules protect plants from bacterial infections. (B) Phospholipid biosynthesis depends on multiple inputs from metabolism (glycerol-3-phosphate) and extracellular import (choline and ethanolamine). Sezgin E, Levental I, Mayor S, & Eggeling C (2017). Sphingomyelin also confers different properties to the plasma membrane than the phospholipids, not least due to its preferential association with sterols (Ramstedt & Slotte, 2006). One such mechanism for this may be mediated by the protein MG53. Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. Lee I-H, Kai H, Carlson L-A, Groves JT, & Hurley JH (2015). Shao S, Liao X, Xie F, Deng S, Liu X, Ristaniemi T, & Liu B (2018). Marg A, Schoewel V, Timmel T, Schulze A, Shah C, Daumke O, & Spuler S (2012). 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). 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. For example, replacement of a cylindrical lipid (e.g. Calcium entry after plasma membrane injury is required for repair. 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. These examples of organizational heterogeneity, along with the differences among the lipids that comprise the plasma membrane confer a variety of structural and signaling properties to the plasma membrane and allow the plasma membrane to mount and sustain localized signaling despite being fully interconnected and fluid. 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)). Epub 2017 Jun 26. Phosphatidic acid regulation of PIPKI is critical for actin cytoskeletal reorganization. Unlike Annexin 5 that forms a lattice structure at the wound edge (Bouter et al., 2011), Annexins A4 and A6 work together to mediate constriction of the wounded edges of the plasma membrane, aiding in the closure of the wound (Boye et al., 2017). Cambridge (MA): Harvard Stem Cell Institute; 2008. Local oxidation at the site of membrane injury activates MG53 oligomerization (Cai et al., 2009), which may locally increase membrane rigidity. It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. Such a role of CLIC/GEEC-mediated endocytosis in membrane remodeling is also supported by the observation that CLIC/GEEC is immediately activated in response to decreased membrane tension and has the capacity to turn over large amounts of plasma membrane (Thottacherry et al., 2018). (A) Plasma membrane phospholipids are generated from biosynthetic pathways, which rely on formation of the molecule diacylglycerol (DAG) or cytidine diphosphate diacylglycerol (CDP-DAG) from phosphatidic acid (PA). Bookshelf Boye TL, Maeda K, Pezeshkian W, Snder SL, Haeger SC, Gerke V, Nylandsted J. 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). How does the cell membrane self heal? Dysferlin is not detected at injury sites until 10 s postinjury, a delay we attribute to an intermediary step involving calpain cleavage. 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). Cell damage can be reversible or irreversible. 2021 Apr 2;19(1):63. doi: 10.1186/s12915-021-00970-0. However, in addition to this role, restoring membrane tension is another role that has been proposed for endocytosis after the membrane is resealed following a pore forming toxin injury (Skalman, Holst, Larsson, & Lundmark, 2018). 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. Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling. The Importance of Pore-Forming Toxins in Multiple Organ Injury and Dysfunction. See this image and copyright information in PMC. As she describes, a lesion is followed by a Ca2+-dependent movement of vesicles to the plasma membrane. Further, PE and PC head groups can be cleaved and replaced with serine to produce PS (Oropeza, 2017). Furthermore, exposure of the plasma membrane hydrophobic core as a result of reduced lipid packing provides the opportunity for injury-triggered lipid signaling through the binding of cholesterol (see Section 4). Andrews NW, Almeida PE, & Corrotte M (2014). The lipids in the membrane control the function of the membrane - keeping some products inside and some outside. Careers. Disclaimer. A lysosome is a membrane-bound cell organelle that contains digestive enzymes. Drescher DG, Drescher MJ, Selvakumar D, Annam NP. 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). Disruption of the cell plasma membrane is a commonplace occurrence in many mechanically challenging, biological environments. Annexin A1 deficiency does not affect myofiber repair but delays regeneration of injured muscles. 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). By clicking the Accept button you agree to the terms of our privacy policy. Bacterial pore-forming toxins oligomerize and insert in the plasma membrane of target cells forming a diffusible pore. For example, membrane shedding is a known mechanism of plasma membrane repair, which functions to limit the lateral expansion of the wound area (Andrews, Almeida, & Corrotte, 2014; Horn & Jaiswal, 2018). 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. Heier CR, Damsker JM, Yu Q, Dillingham BC, Huynh T, Van der Meulen JH, Scheffer L. (2013). Different cell-intrinsic PM repair mechanisms have been reported, including membrane fusion and replacement strategies (via exocytosis-mediated repair), removal of damaged membranes (by. They consist of a variety of lipid mediators derived from the omega-3 essential fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and include lipoxins, resolvins and protectins. One model explaining membrane injury in dystrophin-deficient muscle fibers proposes that an initial injury causes a local influx of calcium and a local region of hypercontraction. Annexins are a class of calcium-sensitive proteins that rapidly accumulate at the site of a membrane injury (Potez et al., 2011). 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. Additionally, in contrast to PS, which recruits proteins directly involved in repair, DAG appears to recruit signaling proteins such as protein kinase C (PKC) (Vaughan et al., 2014; Zuzek, Fan, Spaeth, & Bittner, 2013). The physical properties of the plasma membrane are governed in large part by the effect of lipid interactions at the population level. This site needs JavaScript to work properly. Remorino A, De Beco S, Cayrac F, Di Federico F, Cornilleau G, Gautreau A, Coppey M (2017). 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). As MG53 interacts with the plasma membrane in a cholesterol-dependent manner ((Zhu et al., 2012); see Section 4), its extracellular role may involve a mode of action similar to poloxamer 188, where it inserts within membranes in a disordered lipid environment. Role of LBPA and Alix in multivesicular liposome formation and endosome organization, Rac1 nanoscale organization on the plasma membrane is driven by lipid binding specificity encoded in the membrane anchor. Phospholipid signalling through phospholipase D and phosphatidic acid. Translocation of existing lipid species to the site of injury provides a mechanism to recruit and activate protein machinery. cell, in biology, the basic membrane-bound unit that contains the fundamental molecules of life and of which all living things are composed. 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. Membrane lipids: where they are and how they behave. The common eastern firefly produces light through a chemical reaction that energizes a molecule so it can release aphoton. Similar to PLC, phospholipase D (PLD) activity is also increased after injury and is required for repair (Arun et al., 2013). This is especially important for membrane signaling functions as the liquid-ordered domains often serve to aggregate membrane-associated proteins (Cebecauer et al., 2018). 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). Rather than these roles being separated from each other, they overlap significantly such that one can easily be an extension of the other. The membrane patch may serve only temporarily as a surface barrier replacement that is subsequently remodeled and removed via exocytic and/or endocytic machinery. Lysosomes are involved with various cell processes. 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. Sheng R, Chen Y, Gee HY, Stec E, Melowic HR, Blatner NR, Fujiwara TK (2012). Use of lipidomics during epidermal wound repair identified that several of the plasma membrane lipids discussed above are enriched during wound repair. Epub 2015 Oct 19. Miyake K, McNeil PL, Suzuki K, Tsunoda R, & Sugai N (2001). 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. Plataki M, Lee YD, Rasmussen DL, & Hubmayr RD (2011). (2013). A surprise arrived when heart muscle cells were analyzed. Johnson JL, Erickson JW, & Cerione RA (2012). 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 plasma membrane is semi-permeable, allowing the cell to communicate with and utilize resources from its surrounding environment. Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis, Lipid peroxidation induces cholesterol domain formation in model membranes. This cytoskeletal assembly is regulated by Rho GTPase activity, which triggers F-actin accumulation at the site of injury. Plasma membrane wounding and repair in pulmonary diseases, American Journal of Physiology-Lung Cellular and Molecular Physiology, Membrane repair: mechanisms and pathophysiology. Caveolae protect endothelial cells from membrane rupture during increased cardiac output. As described above, damage to the plasma membrane transiently increases the mobility of individual lipids. Roach AN, Wang Z, Wu P, Zhang F, Chan RB, Yonekubo Y, Du G (2012). Gradients of Rac1 nanoclusters support spatial patterns of Rac1 signaling. The organization of lipids within the membrane also affects the structure of underlying cortical cytoskeleton. eCollection 2021. the contents by NLM or the National Institutes of Health. Simone LC, Caplan S, & Naslavsky N (2013). Plasma membrane lipids containing the alkanoamine sphingosine are called sphingolipids. Membrane tension: A challenging but universal physical parameter in cell biology, Paper presented at the Seminars in cell & developmental biology. It can also be produced by methylation of existing PE, while PE can be produced by the decarboxylation of PS. What's found inside a cell. Direct lipid modification of proteins, such as GTPases, provides another method to regulate protein localization and activity (Casey, 1995). The primary plasma membrane sphingolipid in mammalian cells is sphingomyelin, which utilizes a ceramide backbone (Merrill Jr, 2008). Potez S, Luginbhl M, Monastyrskaya K, Hostettler A, Draeger A, & Babiychuk EB (2011). HHS Vulnerability Disclosure, Help These phospholipids are derived from glycerol-3-phosphate, itself a product of cellular metabolism that is enzymatically modified into phosphatidic acid (PA). National Library of Medicine Membrane injury causes a local influx of calcium and activation of calpains. 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. Cebecauer M, Amaro M, Jurkiewicz P, Sarmento M. J. o., achl R, Cwiklik L, & Hof M (2018). This is called apoptosis. PTRF Anchors MG53 to Cell Injury Site for Initiation of Membrane Repair. Instead, there exists distinct inter- and intra-leaflet heterogeneity of lipids. Another endogenous mechanism of acutely decreasing membrane lipid mobility after injury involves the lipid species ceramide, the formation of which causes endocytosis in response to membrane injury through the activity of extracellular acid sphingomyelinase (Tam et al., 2010). Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D, Conversion of phosphatidylcholine to phosphatidylglycerol with phospholipase D and glycerol, Journal of the American Oil Chemists Society. doi: 10.1042/BSR20220765. doi: 10.1016/j.cub.2017.12.034. 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. Lenhart KC, ONeill TJ, Cheng Z, Dee R, Demonbreun AR, Li J, Taylor JM (2015). While the structural importance of plasma membrane cholesterol is well appreciated, it can also play a role in signaling. Copolymers such as poloxamer 188 avoid this potential issue by only stabilizing the plasma membrane once lipid packing density is sufficiently reduced, such as after an injury. Bookshelf Idone V, Tam C, Goss JW, Toomre D, Pypaert M, Andrews NW. As structural components of the plasma membrane, lipids are responsible for contributing to membrane tension, rigidity, and overall shape. FOIA 'Resealing' is the emergency response required for cell . The plasma membrane is a dynamic barrier that separates the cell interior from the extracellular space (Figure 2C). Ligeti E, Dagher M-C, Hernandez SE, Koleske AJ, & Settleman J (2004). Subsequent insult(s) of eccentric stretch result in a more severe wound and global hypercontraction, producing fiber retraction within the muscle bundle (53). 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). Spaeth C, Fan J, Spaeth E, Robison T, Wilcott R, & Bittner G (2012). 8600 Rockville Pike 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. National Library of Medicine 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. While a common thread in lipid signaling is the modification of a target protein, either directly or indirectly, the numerous mechanisms lipids use to achieve this outcome allows for a great diversity of signaling. To achieve these tasks, cells employ signaling networks, which respond to the changing microenvironment after injury and activate the diverse plasma membrane repair mechanisms with precise control in time and space. 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. Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding? Influx of calcium, increase in oxidation, and change in tension on the plasma membrane due to injury all trigger changes in lipid structure and behavior to initiate signaling. 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. Intriguingly, PA preferentially binds the Rho family member Rac1, resulting in nanocluster formation (Maxwell et al., 2018). Spatial arrangement of lipids is also known to regulate Rho family GTPase activity (see Section 4.3). Palmitate-mediated disruption of the endoplasmic reticulum decreases intracellular vesicle motility. A cartoon depicting the potential role of dysferlin-mediated vesicle fusion in membrane repair. The chemical structure of the cell membrane makes it remarkably flexible, the ideal boundary for rapidly growing and dividing cells. Proc Natl Acad Sci U S A. Healing of a punctured, The regeneration and reorganization of the oral apparatus (green) of, Wound healing studies in model cells such as. Scattered throughout the bloodstream are lens-shaped structures that serve to plug thewound. Individual lipids can serve as signaling molecules on their own or through binding proteins, and chemical changes to a single lipid can initiate change in local membrane composition. Tailored protection against plasmalemmal injury by annexins with different Ca2+ sensitivities, Sphingolipids and the formation of sterol-enriched ordered membrane domains, Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. F-actin accumulation is also responsible for providing support to the newly resealed membrane, restoring tension, and preventing subsequent injury. Biophys J. PMC These cells cooperate with other specialized cells and become the building blocks of large multicellular . Cazzolli R, Shemon AN, Fang MQ, & Hughes WE (2006). The .gov means its official. The signaling lipid PS is interesting in this regard due to its localization to the wound edge after injury. Instead, distinct inter- and intra-leaflet heterogeneity exists. 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). 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. 2008 Dec 31. While intracellular MG53 is a redox-sensitive protein capable of facilitating vesicle aggregation, it is proposed to have multiple functions during membrane repair. Diz-Muoz A, Fletcher DA, & Weiner OD (2013). Clipboard, Search History, and several other advanced features are temporarily unavailable. Each of these lipids contributes their own qualities that affect the structural and signaling characteristics of the plasma membrane (Nicolson, 2014). Van Meer G, Voelker DR, & Feigenson GW (2008). Structure and Composition of the Cell Membrane. For an injury to a phospholipid bilayer alone (. Houang EM, Haman KJ, Filareto A, Perlingeiro RC, Bates FS, Lowe DA, & Metzger JM (2015). Negative membrane curvature catalyzes nucleation of endosomal sorting complex required for transport (ESCRT)-III assembly. This allows local and functional diversity between the two leaflets as well as various parts of the single contiguous plasma membrane (Figure 2B). While no defined roles for PA after membrane injury are known, PA has been observed to rapidly appear at the wound edge (Vaughan et al., 2014), which fits with the fast (650 s) timescale of PA generation by PLD (Petersen et al., 2016). 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. BMC Biol. FRET biosensor allows spatiotemporal observation of shear stress-induced polar RhoGDI activation. In order to provide a cell with energy, these molecules have to pass across the cell membrane, which functions as a barrier but not an impassable one. 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). 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). 2021 Sep 29;9:753625. doi: 10.3389/fcell.2021.753625. (2017). government site. Epub 2023 Mar 3. While lipids are often ascribed a metabolic role as energy storage molecules, they also play important structural and signaling roles in the cell. 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. National Library of Medicine Das S, Yin T, Yang Q, Zhang J, Wu YI, & Yu J (2015). In addition to their structural role, and often as an extension of it, lipids also provide a signaling function that facilitates plasma membrane repair. 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. Federal government websites often end in .gov or .mil. For example, venomous snakes store precursor molecules to instantly synthesize a suite of toxins via enzyme-mediated cascades. 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).
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