how does a cell membrane repair itself

2023 Apr 4;122(7):1355-1363. doi: 10.1016/j.bpj.2023.03.001. 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. This site needs JavaScript to work properly. doi: 10.1016/j.cub.2017.12.034. Following injury, lysosomes are known to fuse with the damaged membrane and may deposit LBPA at the site of injury, which would in turn facilitate ALIX-mediated vesicle shedding. Van Meer G, Voelker DR, & Feigenson GW (2008). How does the cell membrane self heal? However, these repair activities can also be observed at the single-cell level. 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. 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. 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. Sezgin E, Levental I, Mayor S, & Eggeling C (2017). National Library of Medicine 8600 Rockville Pike 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. Careers. Spaeth C, Fan J, Spaeth E, Robison T, Wilcott R, & Bittner G (2012). Int J Mol Sci. Microfluidic guillotine reveals multiple timescales and mechanical modes of wound response in Stentor coeruleus. The precise role of EHD2 in membrane repair is not known, although it is known as a membrane shaping protein that may be involved in membrane fusion (Campelo, Fabrikant, McMahon, & Kozlov, 2010). 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). official website and that any information you provide is encrypted Calcium also initiates lipid signaling after plasma membrane injury by activating phospholipases, such as phospholipase C (PLC). Annexin-A5 assembled into two-dimensional arrays promotes cell membrane repair. Amongst other causes, this can be due to physical, chemical, infectious, biological, nutritional or immunological factors. 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). 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. Influx of calcium from the extracellular space, as well as locally increased oxidation, both trigger lipid signaling that is required for repair. MG53 nucleates assembly of cell membrane repair machinery. This phase represents restoration of the barrier function of the plasma membrane; however, cells must still undergo a membrane remodeling phase due to the presence of cytoskeletal as well as other repair proteins and lipids that accumulate during the repair process. Membrane damage: Damage to the cell membrane disturbs the state of cell electrolytes, e.g. 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. Houang EM, Haman KJ, Filareto A, Perlingeiro RC, Bates FS, Lowe DA, & Metzger JM (2015). Epub 2012 Jul 9. This mechanism is particularly intriguing in light of the redox-sensitive nature of MG53. 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. For example, when inserted into a region abundant in phospholipids, cholesterol has a rigidifying effect; however, the opposite can be true with sphingolipids. Defour A, Van der Meulen JH, Bhat R, Bigot A, Bashir R, Nagaraju K, & Jaiswal JK (2014). calcium, which when constantly increased, induces apoptosis. The plasma membrane forms the physical barrier between the cytoplasm and extracellular space, allowing for biochemical reactions necessary for life to occur. 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). Epub 2017 Jun 26. It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. The role of lipids during plasma membrane repair goes far beyond a passive role in vesicle-mediated delivery of membrane lipids. These roles of lipids in plasma membrane repair include both a structural role and a signaling role. Alteration in this response inhibits the subsequent stages, tissue regeneration and remodeling, leading to increased tissue scarring. 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). As a library, NLM provides access to scientific literature. The lipids in the membrane control the function of the membrane - keeping some products inside and some outside. The signaling lipid PS is interesting in this regard due to its localization to the wound edge after injury. Schematic representation of the structural features of the protein families implicated in membrane repair. Before The https:// ensures that you are connecting to the Endogenous mechanisms of repair in healthy cells appear to mimic the beneficial effect provided by poloxamer 188 by allowing for transient increases in lipid mobility while restricting fluidity increase to a relatively small spatial or temporal window. 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). As dysferlin may only be detected at injury sites with antibodies recognizing COOH-terminal epitopes, and not several antibodies to NH. When the cell is under stress, and the amount of ROS increases, the number of methionine "errors" is ramped up tenfold, allowing new proteins to be even more resistant to attack. Temporary increase in plasma membrane tension coordinates the activation of exocytosis and contraction during cell spreading. 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). 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). Gurtner GC, Werner S, Barrandon Y, & Longaker MT (2008). Phospholipids and sphingolipids are connected by the head group choline, found on both PC and sphingomyelin (SM). Cai C, Masumiya H, Weisleder N, Matsuda N, Nishi M, Hwang M, Zhao X. Analysis of Dysferlin Direct Interactions with Putative Repair Proteins Links Apoptotic Signaling to Ca. F-actin accumulation is also responsible for providing support to the newly resealed membrane, restoring tension, and preventing subsequent 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). FOIA Int J Mol Sci. Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis, Lipid peroxidation induces cholesterol domain formation in model membranes. 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). There are many differences between cancer cells and normal cells in noncancerous (benign) or cancerous (malignant) tumors. Healing, Examples of self-repairing cells. Presence of PS at the free membrane wound edge helps directs the annexin proteins to this site in a calcium-dependent manner, where they perform vital functions required for stabilization and shaping of the repairing membrane (see Section 3.3). Riazifar M, Pone EJ, Ltvall J, & Zhao W (2017). While intracellular MG53 is a redox-sensitive protein capable of facilitating vesicle aggregation, it is proposed to have multiple functions during membrane repair. Why does our body heal itself? The chemical structure of the cell membrane makes it remarkably flexible, the ideal boundary for rapidly growing and dividing cells. Trends Cell Biol. 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. Role of phosphatidylinositol 4, 5-bisphosphate in regulating EHD2 plasma membrane localization. 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). Houang EM, Sham YY, Bates FS, & Metzger JM (2018). Saarikangas J, Zhao H, & Lappalainen P (2010). Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. 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. 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). (2017). 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). Following this, accumulation of Annexin 4 and Annexin 6 results in folding and inward contraction of the injured membrane, respectively (Boye et al., 2017). 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. 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. PIP2 accumulation was observed as early as 4 seconds in mouse myofibers; however, it continued to accumulate even 1 minute post-injury suggesting a role in the later stages of repair (Demonbreun et al., 2016). and transmitted securely. 2022 May 15;23(10):5525. doi: 10.3390/ijms23105525. 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). Lysosome fusion is required for the process of repair (Reddy, Caler, & Andrews, 2001). Mammals make up less than 1% of all animals on earth, but they include some of the most well-known species. How does the cell membrane self heal? 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. The primary plasma membrane sphingolipid in mammalian cells is sphingomyelin, which utilizes a ceramide backbone (Merrill Jr, 2008). Epub 2023 Mar 3. Rac1, a Rho family GTPase required for repair (Verboon & Parkhurst, 2015), forms nanoclusters at sites enriched in PA and PIP3, whose roles in regulating Rac1 appear to be non-overlapping (Maxwell et al., 2018). "Knowledge of how single cells repair and regenerate themselves underpins our mechanistic understanding of cell biology and could guide treatments for conditions involving cellular damage." These examples illustrate the ability of cells to heal wounds and regenerate missing structures. When a crack moves from the scallops stiff material to the less stiff one, the latter reduces the force at the tip of the crack, thereby stopping it from spreadingfarther. The calcium influx, Survival from bacterial pore-forming toxins, Survival from bacterial pore-forming toxins utilizes both exocytic and endocytic responses. Jimenez AJ, Maiuri P, Lafaurie-Janvore J, Divoux S, Piel M, & Perez F (2014). 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). sharing sensitive information, make sure youre on a federal The calcium influx of a membrane injury activates vesicular exocytosis and homo- and heterotypic fusion of cytoplasmic vesicles. 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). Inflammatory exudates provide insights into the regulation of the first stage of wound repair inflammation. Thus, it is clear that there is a need to acknowledge the role of lipids as an active participant in the processes of both cell and tissue repair. Another critical shared feature is a set of highly-specialized teeth. 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)). Neurite transection produces cytosolic oxidation, which enhances plasmalemmal repair. When a cell's DNA is damaged, it will typically detect the damage and try to repair it. 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. 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). Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion, Demonbreun AR, & McNally EM (2016). 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. Membrane lipids: where they are and how they behave. This involves a series of distinct, but mutually dependent stages including inflammation, regeneration, and remodeling of the tissue (Gurtner, Werner, Barrandon, & Longaker, 2008). "Self-repair: Our bodies are packages within packages. Thus, local lipid peroxidation may provide transient membrane stabilization, while mechanisms such as redox-dependent MG53 binding may limit the spread of lipid peroxides. 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). Local oxidation at the site of membrane injury activates MG53 oligomerization (Cai et al., 2009), which may locally increase membrane rigidity. Horn A, Van der Meulen JH, Defour A, Hogarth M, Sreetama SC, Reed A, Jaiswal JK. However, shear force on the membrane increases the kinetic energy required for lipid mixing (i.e. Dysferlin is not detected at injury sites until 10 s postinjury, a delay we attribute to an intermediary step involving calpain cleavage. Bi G-Q, Alderton JM, & Steinhardt RA (1995). 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. Drescher DG, Drescher MJ, Selvakumar D, Annam NP. Careers, Unable to load your collection due to an error. To regulate the composition of plasma membrane lipids, cells utilize vesicle trafficking, which can add lipids (by exocytosis) or remove lipids (by endocytosis) from the plasma membrane. Palmitate-mediated disruption of the endoplasmic reticulum decreases intracellular vesicle motility. Many of the sphingolipids also contain a glycosidically bound carbohydrate moiety causing formation of the glycosphingolipids. 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. The site is secure. Scar/WAVE has Rac GTPase-independent functions during cell wound repair. However, lipid signaling also helps to coordinate downstream repair pathways that result in the membrane trafficking and cytoskeletal reorganization required for repair. The plasma membrane is semi-permeable, allowing the cell to communicate with and utilize resources from its surrounding environment. Lipid-soluble molecules and some small molecules can permeate the membrane, but the lipid bilayer effectively repels the many large . Stem cell extracellular vesicles: extended messages of regeneration, Annual review of pharmacology and toxicology. Spiders turn liquid into a strong, stretchy fiber by squeezing it through a small space that helps protein molecules to connect with eachother. These mediators promote wound resolution by acting upon the immune and endothelial cells and help to control the duration and nature of the immune and phagocytic cell infiltration at the injury site (Serhan, 2014). In mammalian cells, lipids formed upon the phosphate and glycerol (e.g. The membrane phosphoinositides, and PIP2 in particular, play an important role in regulating the interaction of F-actin with the plasma membrane (Kapus & Janmey, 2013; Saarikangas, Zhao, & Lappalainen, 2010). Membrane injury causes a local influx of calcium and activation of calpains. Wound closure is mediated in part by the interactions of the cortical actin cytoskeleton with the plasma membrane. The .gov means its official. Structure and Composition of the Cell Membrane. Ceramide microdomains formed by the activity of extracellular acid sphingomyelinase near the site of injury could appear on the extracellular leaflet (resulting in endocytosis) or the inner leaflet either by selective flipping across the membrane bilayer (Pollet et al., 2018) or through diffusion of sphingomyelinase through the wounded area to act on inner leaflet sphingomyelin found proximal to the wound edge. Epub 2008 Oct 9. . Activated calpains cleave dysferlin within a motif specifically encoded by alternately spliced exon 40a (230). In mammalian cells the majority of cellular cholesterol is found in the plasma membrane, where it can make up to 50% of lipid content (Van Meer, Voelker, & Feigenson, 2008). Cebecauer M, Amaro M, Jurkiewicz P, Sarmento M. J. o., achl R, Cwiklik L, & Hof M (2018). Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, Donati MA (1998). 8600 Rockville Pike PC), with a conical shaped, charged phospholipid (e.g. 2008 Mar 10;180(5):905-14. doi: 10.1083/jcb.200708010. Like the exterior walls of a house, the . Muscle fibers have a, Schematic representation of the structural, Schematic representation of the structural features of the protein families implicated in membrane, A cartoon depicting the potential role of dysferlin-mediated vesicle fusion in membrane repair., MeSH Plasma membrane lipids can be grouped into three classes glycerophospholipids, sphingolipids, and sterols. Not only is the composition and organization of the plasma membrane in constant flux, the membrane itself also must interact with forces being applied to it from all directions. doi: 10.3791/50848. Other cells acquire specialized functions as they mature. The major differences between normal cells and cancer cells relate to growth, communication, cell repair and death, "stickiness" and spread, appearance, maturation, evasion of the immune system, function and blood supply . 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. Bacterial pore-forming, What might membrane injury to muscle fibers look like? 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). Thus, caveolae may serve a signaling function during membrane repair (see Section 4). Labazi M, McNeil AK, Kurtz T, Lee TC, Pegg RB, Angeli JPF, McNeil PL (2015). Spatiotemporal dynamics of actin remodeling and endomembrane trafficking in alveolar epithelial type I cell wound healing. The lipids in the membrane are fluid, and therefore in motion, and are constantly adapting to the changing environment. Shed microvesicles containing streptolysin-O have been shown to also contain annexins A1 and A6 (219). Bethesda, MD 20894, Web Policies Being the most abundant component of the plasma membrane, lipids are also essential player in the process of plasma membrane repair; however, much of the research committed to identifying the mechanisms of plasma membrane repair has focused on the proteins associated with plasma membrane repair (Cooper & McNeil, 2015). We will highlight how lipids respond to injury and facilitate repair both at the level of individual molecules and at the bulk level by collectively altering the plasma membrane form and function. Dysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair. 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). 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. PMC The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. This remodeling is likely provided by processes described previously: membrane endocytosis (Section 3.1) and membrane shedding (Section 4.1). Sarcolemmal repair is a slow process and includes EHD2, Effect of oxidative stress on membrane structure: small-angle X-ray diffraction analysis. (B) The plasma membrane is not a homogenous mixture of proteins and lipids (as in A). In this way, lipids play an important role in polarizing the cellular response to an injury. 2022 Aug 4;11:e80778. Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis. Plasma membrane damage needs to be rapidly repaired to avoid cell death. FOIA Calcium has been identified as the key trigger to activate an effective membrane repair response that utilizes exocytosis and endocytosis to repair a membrane tear, or remove a membrane pore. and transmitted securely. The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. Arp2/3-mediated F-actin formation controls regulated exocytosis in vivo. Plasma membrane lipids are routinely interconverted as a means to maintain lipid homeostasis and for lipid-mediated signaling. Despite the many different types of tissue, there is a common repair program involved in tissue repair. The tight packing, along with the preference of cholesterol to intercalate the acyl chains of sphingomyelin creates the liquid-ordered membrane domains, such as the so-called lipid rafts (Van Meer et al., 2008) (Figure 2C). As these features change dynamically, tension forces experienced by the plasma membrane are not static and the cells ability to respond to them appropriately allows for essential functions such as change in morphology, movement, adhering to new substrates, cell division, and membrane fusion. In addition to their structural role, and often as an extension of it, lipids also provide a signaling function that facilitates plasma membrane repair. Here the sugar (oligosaccharide) moiety faces the extracellular space interacting with other cells and extracellular ligands required for processes such as signaling, cell adhesion or intercellular interactions.

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