how does a cell membrane repair itself

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). 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 The wounded cell can survive if a rapid repair respons Membrane Repair: Mechanisms and Pathophysiology 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). Senju Y, Kalimeri M, Koskela EV, Somerharju P, Zhao H, Vattulainen I, & Lappalainen P (2017). A decrease in membrane tension precedes successful cell-membrane repair. Dysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair. They break down excess or worn-out cell parts. Here we will discuss the current knowledge of how lipids facilitate plasma membrane repair by regulating membrane structure and signaling to coordinate the repair response, and will briefly note how lipid involvement extends beyond plasma membrane repair to the tissue repair response. 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. 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. Simone LC, Caplan S, & Naslavsky N (2013). However, these repair activities can also be observed at the single-cell level. Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis. Cell damage. Andrews NW, Almeida PE, & Corrotte M (2014). Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding? Weisleder N, Takizawa N, Lin P, Wang X, Cao C, Zhang Y, Chen P-J (2012). 2021 Apr 2;19(1):63. doi: 10.1186/s12915-021-00970-0. This remodeling is likely provided by processes described previously: membrane endocytosis (Section 3.1) and membrane shedding (Section 4.1). sharing sensitive information, make sure youre on a federal MG53 nucleates assembly of cell membrane repair machinery. Cell walls provide structural support for the cell. Water is essential to life. 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). Repair of muscle fibers lacking the dysferlin protein, which results in reduced membrane stability, is improved by the presence of extracellular (oxidized) MG53 protein, suggesting that this protein can act on the outer leaflet of the plasma membrane to improve plasma membrane in diseased cells. Despite the many different types of tissue, there is a common repair program involved in tissue repair. 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). Spatiotemporal dynamics of actin remodeling and endomembrane trafficking in alveolar epithelial type I cell wound healing. An actin-dependent annexin complex mediates plasma membrane repair in muscle. Thus, each of these lipids contributes significantly to the organization, structure, and function of the plasma membrane as a whole. 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. The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. Structure and Composition of the Cell Membrane. Cell Calcium. Similar to the changes in tension described above, the fluidity of the plasma membrane is also dynamic after injury. 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. government site. The https:// ensures that you are connecting to the In addition to working on their own, lipids also interact with proteins to coordinate these processes. Glycerol-3-phosphate is used to generate PA as well as PG through the intermediate phosphatidylglycerol phosphate (PGP). How skin heals is a good example of the role of cellular processes. This preferential association between different lipids results in an important feature of the plasma membrane its transverse and lateral heterogeneity. There are mechanisms that allow some products to enter or leave the cell either actively or passively. Why does our body heal itself? Sphingomyelin also confers different properties to the plasma membrane than the phospholipids, not least due to its preferential association with sterols (Ramstedt & Slotte, 2006). Inclusion in an NLM database does not imply endorsement of, or agreement with, FOIA Spaeth C, Fan J, Spaeth E, Robison T, Wilcott R, & Bittner G (2012). HHS Vulnerability Disclosure, Help 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). Unauthorized use of these marks is strictly prohibited. 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. Shao S, Liao X, Xie F, Deng S, Liu X, Ristaniemi T, & Liu B (2018). The basement membrane of the basal cells attaches via hemidesmosomes to the underlying Bowman's layer, while anchoring fibrils pass through . What might membrane injury to muscle fibers look like? When the plasma membrane of eukaryotic cells is mechanically injured, Ca 2+ influx triggers a rapid repair process that involves exocytosis (Reddy et al., 2001; McNeil, 2002; McNeil et al., 2003).Although the precise repair mechanism is still unknown, current hypotheses propose that resealing is directly mediated by the delivery of intracellular membrane to the cell surface. Muscle fibers are subject to huge variations in membrane tension, due to their contractile activity. Zhang KS, Blauch LR, Huang W, Marshall WF, Tang SKY. Int J Mol Sci. In response to an injury, a sudden change in hydrostatic pressure and local disassembly of the cortical cytoskeleton causes a rapid drop in membrane tension (Jaiswal et al., 2014; Miyake, McNeil, Suzuki, Tsunoda, & Sugai, 2001; Togo et al., 2000). In the subsequent sections, we will discuss how this is achieved and utilized by the cell. 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). Alterations in Phosphatidylcholine Metabolism of StretchInjured Cultured Rat Astrocytes. For example, when inserted into a region abundant in phospholipids, cholesterol has a rigidifying effect; however, the opposite can be true with sphingolipids. Calcium can activate proteins directly, and ultimately is the initiator of many downstream repair pathways. 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). Interestingly, several methods for PIP2 micro-domain formation may allow for this to occur after plasma membrane injury. However, shear force on the membrane increases the kinetic energy required for lipid mixing (i.e. Labazi M, McNeil AK, Kurtz T, Lee TC, Pegg RB, Angeli JPF, McNeil PL (2015). The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. Sarcolemmal repair is a slow process and includes EHD2, Effect of oxidative stress on membrane structure: small-angle X-ray diffraction analysis. 2008 Mar 10;180(5):905-14. doi: 10.1083/jcb.200708010. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Before Blauch LR, Gai Y, Khor JW, Sood P, Marshall WF, Tang SKY. Lipids contribute to cellular physiology at both an individual and population level. Annexins can physically manipulate the injured plasma membrane by stabilizing, folding, and contracting in order to facilitate repair (Gerke et al., 2005; Jaiswal & Nylandsted, 2015). In some cases, these forces are benign, such as membrane protrusion driven by cortical actin polymerization (Pontes, Monzo, & Gauthier, 2017). Every cell has a fatty membrane that self-assembles when placed in water, then reassembles when a breach occurs. We use cookies to give you the best browsing experience. An official website of the United States government. However, ceramide formation also changes membrane dynamics by forming rigid microdomains and potentially by displacing cholesterol from lipid rafts (London, 2004). Role of phosphatidylinositol 4, 5-bisphosphate in regulating EHD2 plasma membrane localization. Bethesda, MD 20894, Web Policies 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. The long held dogma in the cardiac biology community was that these cells do not . 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). While PA mediates targeting to the membrane, Rac1 activity depends on PIP3, suggesting multiple roles for signaling lipids in GTPase activity after repair. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. 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. SM utilizes the ceramide (Cer) backbone and can be used to generate the signaling lipid sphingosine-1-phosphate (S1P). Quantification of membrane tension after injury to fibroblasts demonstrated that a minimum tension force was reached by approximately 30 seconds post-injury, but tension was fully restored by 80 seconds post-injury (Togo et al., 2000). 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). An organelle (think of it as a cell's internal organ) is a membrane bound structure found within a cell. 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. Gurtner GC, Werner S, Barrandon Y, & Longaker MT (2008). In order to balance any decrease in membrane tension, such as that caused by exocytosis, cells routinely utilize endocytosis, which reduces the membrane area and results in increased tension (Dai & Sheetz, 1995). Tran DT, Masedunskas A, Weigert R, & Ten Hagen KG (2015). Further, PE and PC head groups can be cleaved and replaced with serine to produce PS (Oropeza, 2017). 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). Live tracking of inter-organ communication by endogenous exosomes in vivo. 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). 2022 Dec 14;10(12):3256. doi: 10.3390/biomedicines10123256. Tools. By clicking the Accept button you agree to the terms of our privacy policy. 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. Cai C, Masumiya H, Weisleder N, Matsuda N, Nishi M, Hwang M, Zhao X. Accumulation of GRAF1 at the repair site occurs 2 minutes after injury, supporting its potential role in membrane remodeling following resealing. Dysferlin is not detected at injury sites until 10 s postinjury, a delay we attribute to an intermediary step involving calpain cleavage. Annexin A1 deficiency does not affect myofiber repair but delays regeneration of injured muscles. Accessibility 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. Taverna D, Nanney LB, Pollins AC, Sindona G, & Caprioli R (2011). 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. 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. 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). Phosphatidylinositol is found in many cell types and tissues, but is particularly abundant in the brain. 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. 2021 Sep 29;9:753625. doi: 10.3389/fcell.2021.753625. Phospholipid signalling through phospholipase D and phosphatidic acid. When cells have DNA damage but fail to undergo apoptosis, they may be on the road to cancer. Jimenez AJ, Maiuri P, Lafaurie-Janvore J, Divoux S, Piel M, & Perez F (2014). J Cell Biol. Would you like email updates of new search results? Van Meer G, Voelker DR, & Feigenson GW (2008). From PA, cells generate DAG, or cytidine diphosphate-DAG (CDP-DAG), which serve as inputs into the phospholipid biosynthetic pathways (Figure 1A, ,B).B). Please enable it to take advantage of the complete set of features! Copyright 2015 the American Physiological Society. 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. Moissoglu K, Kiessling V, Wan C, Hoffman BD, Norambuena A, Tamm LK, & Schwartz MA (2014). The primary method for PIP2 formation in cells is by the activity of PI(4)P-5 kinase (PI5K) (Kolay, Basu, & Raghu, 2016). Membrane tension: A challenging but universal physical parameter in cell biology, Paper presented at the Seminars in cell & developmental biology. 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. Lysosomes are involved with various cell processes. Due to the differences in the three-dimensional conformations of membrane lipids, a change in their distribution changes the lipid packing density in a given lipid domain. doi: 10.1042/BSR20220765. Another critical shared feature is a set of highly-specialized teeth. 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). Bacterial pore-forming, What might membrane injury to muscle fibers look like? Plasma membrane lipids are routinely interconverted as a means to maintain lipid homeostasis and for lipid-mediated signaling. For example, when humans receive a cut, they must limit blood loss. The plasma membrane itself forms the barrier responsible for the hydrostatic pressure experienced by the cell, while the cortical actin cytoskeleton, focal adhesions, and extracellular matrix regulate the structural tension (Burridge & Guilluy, 2016; Gauthier et al., 2012). 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. Membrane damage: Damage to the cell membrane disturbs the state of cell electrolytes, e.g. "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. The variety of possible phospholipid interconversions, such as these, allows the cell to rapidly change the lipid composition of the plasma membrane. Bissig C, Lenoir M, Velluz M-C, Kufareva I, Abagyan R, Overduin M, & Gruenberg J (2013). PTRF Anchors MG53 to Cell Injury Site for Initiation of Membrane Repair. Calise S, Blescia S, Cencetti F, Bernacchioni C, Donati C, & Bruni P (2012). Shed microvesicles containing streptolysin-O have been shown to also contain annexins A1 and A6 (219). 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). 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). Because membrane tension limits the ability of cellular membranes to self-seal, cellular mechanisms that reduce membrane tension can promote membrane sealing. 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). Careers. Zuzek A, Fan JD, Spaeth CS, & Bittner GD (2013). This may allow these lipids and proteins to interact with new partners that were unavailable due to spatial segregation prior to injury. 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). Injury to the plasma membrane also changes the biochemical environment within the cell. eCollection 2021. 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). Horn A, Van der Meulen JH, Defour A, Hogarth M, Sreetama SC, Reed A, Jaiswal JK. PLD-mediated activation of PI5K relies on the formation of PA, which itself is able to determine the spatial localization of PI5K as well as cause its activation (Roach et al., 2012). A lysosome is a membrane-bound cell organelle that contains digestive enzymes. Other cells acquire specialized functions as they mature. Similar to PLC, phospholipase D (PLD) activity is also increased after injury and is required for repair (Arun et al., 2013). To do so, they must control the movement of liquids across their boundaries. Many of the sphingolipids also contain a glycosidically bound carbohydrate moiety causing formation of the glycosphingolipids. VBP15, a novel antiinflammatory and membranestabilizer, improves muscular dystrophy without side effects, Cellular mechanisms and signals that coordinate plasma membrane repair. Plasma membrane lipids can be grouped into three classes glycerophospholipids, sphingolipids, and sterols. calcium, which when constantly increased, induces apoptosis. Plasma membrane lipids help with successful repair by being part of the affected entity that also works to sense membrane injury, providing spatial and temporal cues to trigger signaling for downstream repair pathways, and ultimately being the benefactor of the successful wound repair response. 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. The plasma membrane has a unique lipid composition that helps distinguish its structural and functional properties from the other internal membrane-bound compartments.

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