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. McNeil AK, Rescher U, Gerke V, & McNeil PL (2006). 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. Self-repairing cells: How single cells heal membrane ruptures and restore lost structures Many organisms and tissues display the ability to heal and regenerate as needed for normal physiology and as a result of pathogenesis. 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. 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. Scattered throughout the bloodstream are lens-shaped structures that serve to plug thewound. As described above, damage to the plasma membrane transiently increases the mobility of individual lipids. In a similar manner, PS signaling may be involved in the early recruitment of other membrane repair proteins such as dysferlin (McDade et al., 2014; Middel et al., 2016) and MG53 (Cai et al., 2009). Similar to the changes in tension described above, the fluidity of the plasma membrane is also dynamic after injury. Clipboard, Search History, and several other advanced features are temporarily unavailable. FRET biosensor allows spatiotemporal observation of shear stress-induced polar RhoGDI activation. Cong X, Hubmayr RD, Li C, & Zhao X (2017). Weisleder N, Takizawa N, Lin P, Wang X, Cao C, Zhang Y, Chen P-J (2012). Similar inter-leaflet heterogeneity exists among sphingolipids, with the glycosphingolipids maintained exclusively in the outer leaflet. Rapid Changes to Endomembrane System of Infected Root Nodule Cells to Adapt to Unusual Lifestyle. Spiders turn liquid into a strong, stretchy fiber by squeezing it through a small space that helps protein molecules to connect with eachother. When a cell's DNA is damaged, it will typically detect the damage and try to repair it. 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. 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. Campelo F, Fabrikant G, McMahon HT, & Kozlov MM (2010). Accumulation of GRAF1 at the repair site occurs 2 minutes after injury, supporting its potential role in membrane remodeling following resealing. (A) The plasma membrane is a fluid-mosaic of lipids, including glycerophospholipids, sphingolipids, and cholesterol, as well as plasma membrane-associated proteins. An organelle (think of it as a cell's internal organ) is a membrane bound structure found within a cell. This form of membrane remodeling maintains lipid homeostasis and plasma membrane functionality. "Self-repair: Our bodies are packages within packages. PTRF Anchors MG53 to Cell Injury Site for Initiation of Membrane Repair. Plasma membrane damage needs to be rapidly repaired to avoid cell death. and transmitted securely. This helps to remodel the newly repaired plasma membrane (Middel et al., 2016), but may also serve to potentiate tissue inflammation. Gradients of Rac1 nanoclusters support spatial patterns of Rac1 signaling. While much attention has been paid to the involvement of proteins in the membrane repair pathway, the role of lipids in facilitating plasma membrane repair remains poorly studied. However, these repair activities can also be observed at the single-cell level. For example, when humans receive a cut, they must limit blood loss. In mammalian cells, lipids formed upon the phosphate and glycerol (e.g. These enzymes initiate signaling through the generation of new lipid species, providing an added spatial, as well as a temporal component to lipid signaling, helping to more precisely coordinate the repair response. and transmitted securely. This is called apoptosis. The second stage of tissue repair, regeneration, makes use of signaling by different lipids, one of which is sphingolipid. Godin LM, Vergen J, Prakash Y, Pagano RE, & Hubmayr RD (2011). 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. Glycerol-3-phosphate is used to generate PA as well as PG through the intermediate phosphatidylglycerol phosphate (PGP). Further, PA is implicated in processes critical to the success of membrane repair such as vesicle fusion with the plasma membrane and GTPase signaling (Cazzolli et al., 2006; Zhang & Du, 2009). In response to increased stress on the plasma membrane, caveolae have been proposed to act as mechanosensors, buffering membrane tension in response to mechanical stress (Cheng et al., 2015; Sinha et al., 2011). government site. 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. While this mechanism outlines how ESCRT proteins assemble, the lipid signaling that determines the appropriate spatial localization relative to the membrane injury in order to limit wound expansion has not been elucidated. Bethesda, MD 20894, Web Policies sharing sensitive information, make sure youre on a federal A cartoon depicting the potential role of dysferlin-mediated vesicle fusion in membrane repair. Demonbreun AR, Quattrocelli M, Barefield DY, Allen MV, Swanson KE, & McNally EM (2016). It is unclear what role, if any, that IP3 may have in repair, but its role in calcium signaling and the fact that injured cells secrete IP3 for hours post-injury (Lamb et al., 1997) suggest a possible signaling role in repair that may extend beyond the process of membrane resealing, which needs further investigation. All RightsReserved. 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). MG53 nucleates assembly of cell membrane repair machinery. Inflammatory exudates provide insights into the regulation of the first stage of wound repair inflammation. Gazzerro E, Sotgia F, Bruno C, Lisanti MP, & Minetti C (2010). 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. Accumulation of PS at the site of membrane injury allows it to act as a damage sensor, marking a key site for the recruitment of repair proteins such as annexins (Boye et al., 2017). Int J Mol Sci. Heier CR, Damsker JM, Yu Q, Dillingham BC, Huynh T, Van der Meulen JH, Scheffer L. (2013). 2023 Feb 28;24(5):4647. doi: 10.3390/ijms24054647. Negative membrane curvature catalyzes nucleation of endosomal sorting complex required for transport (ESCRT)-III assembly. Middel V, Zhou L, Takamiya M, Beil T, Shahid M, Roostalu U, Nienhaus GU (2016). Moissoglu K, Kiessling V, Wan C, Hoffman BD, Norambuena A, Tamm LK, & Schwartz MA (2014). Unlike sharks or alligators, for example, whose teeth are generally all the same size and shape, mammals have differently shaped teeth in different areas of the jaws to target specific foods or foraging strategies. This process is more efficient when GTPases and their regulatory proteins (which are themselves regulated by lipids) are clustered (Ligeti, Dagher, Hernandez, Koleske, & Settleman, 2004). 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). Role of phosphatidylinositol 4, 5-bisphosphate in regulating EHD2 plasma membrane localization. (C) Plasma membrane is dynamic and individual lipids have the capacity to move laterally within a leaflet (shown in pink) and between the leaflets (shown in blue). This is notable because it is hypothesized that a beneficial role of decreasing membrane fluidity is preventing the spread of harmful lipid hydroperoxides, which likely form in the oxidative environment near the site of injury (Braughler & Hall, 1992; Hall, Wang, Miller, Cebak, & Hill, 2018). GRAF1 deficiency blunts sarcolemmal injury repair and exacerbates cardiac and skeletal muscle pathology in dystrophin-deficient mice. The organization of lipids within the membrane also affects the structure of underlying cortical cytoskeleton. Howard AC, McNeil AK, & McNeil PL (2011). Microfluidic guillotine for single-cell wound repair studies. Scheffer LL, Sreetama SC, Sharma N, Medikayala S, Brown KJ, Defour A, & Jaiswal JK (2014). Calise S, Blescia S, Cencetti F, Bernacchioni C, Donati C, & Bruni P (2012). However, these repair activities can also be observed at the single-cell level. Ligeti E, Dagher M-C, Hernandez SE, Koleske AJ, & Settleman J (2004). It also holds the potential for new applications and therapeutic approaches for treating human disease. The cell membrane is an extremely pliable structure composed primarily of two layers of phospholipids (a "bilayer"). Thus, local lipid peroxidation may provide transient membrane stabilization, while mechanisms such as redox-dependent MG53 binding may limit the spread of lipid peroxides. During the G1 stage, the cell prepares for division by increasing its mass. Many of the sphingolipids also contain a glycosidically bound carbohydrate moiety causing formation of the glycosphingolipids. Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding? 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). Muscle fibers are subject to huge variations in membrane tension, due to their contractile activity. 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). This dissociation has the effect of allowing Rho GTPase translocation to the membrane where it can interact with signaling lipids. These same processes also work to dynamically control membrane fluidity by regulating the distribution of phospholipids, sphingolipids, and cholesterol in the membrane. Unauthorized use of these marks is strictly prohibited. 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. With their calcium and lipid affinities spanning a wide spectrum, annexins accumulate slightly differently from each other at the site of injury and perform different functions to facilitate repair of the wounded plasma membrane (see Section 4.1). The chemical structure of the cell membrane makes it remarkably flexible, the ideal boundary for rapidly growing and dividing cells. 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). 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 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. Ribosome damage: Damage to ribosomal and cellular proteins such as protein misfolding, Leading to apoptotic enzyme activation. The variety of possible phospholipid interconversions, such as these, allows the cell to rapidly change the lipid composition of the plasma membrane. Palmitate-mediated disruption of the endoplasmic reticulum decreases intracellular vesicle motility. These observations suggest that lipids are not bystanders during the repair process, but are instead actively involved in organizing the playing field on which repair machinery operates. Every cell has a fatty membrane that self-assembles when placed in water, then reassembles when a breach occurs. Each of these provides another mechanism for generating specific membrane lipids acutely in parallel to biosynthetic inputs. Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion, Demonbreun AR, & McNally EM (2016). Calcium entry after plasma membrane injury is required for repair. During regeneration, sphingolipids such as sphingosine 1-phosphate (S1P) are known for their growth promoting effect on tissue resident stem cells (Calise et al., 2012; Nojima, Freeman, Gulbins, & Lentsch, 2015). Acid sphingomyelinase activity triggers microparticle release from glial cells. The publisher's final edited version of this article is available at, Lipids, plasma membrane, membrane injury, tissue repair. 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. Jaiswal JK, Lauritzen SP, Scheffer L, Sakaguchi M, Bunkenborg J, Simon SM, Nylandsted J (2014). In addition to PA, PG is another lipid product of PLD activity relevant to membrane repair, and its synthesis has been implicated in the process of membrane repair and repair of epithelial wounds (Arun et al., 2013; Piazza & Marmer, 2007). Stem cells in animal models of regeneration. In addition to regulating the patterning and activity of Rho family GTPases, lipids also have a more direct role in regulating F-actin association with the plasma membrane. The plasma membrane is semi-permeable, allowing the cell to communicate with and utilize resources from its surrounding environment. FOIA 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). government site. Without adequate remodeling, the plasma membrane protein and lipid composition would change dramatically, particularly after repeat injuries, and no longer function as in its pre-injury state. Disruption of the cell plasma membrane is a commonplace occurrence in many mechanically challenging, biological environments. (D) The lipid make-up of the plasma membrane constantly changes. Why does our body heal itself? Careers. Thus, the signaling role of lipids affects membrane structure and how the wound is eventually resealed and remodeled, returning the plasma membrane to homeostasis. Yet the membrane is also a formidable barrier, allowing some dissolved substances, or solutes, to pass while blocking others. At the population level, the composition of lipids in a membrane can result in formation of signaling platforms that can change the properties of an entire membrane, enabling the cell to finely tune tension, shape, and rigidity. Each of these lipids contributes their own qualities that affect the structural and signaling characteristics of the plasma membrane (Nicolson, 2014). It also works extracellularly to improve repair of injured muscle and other cells (Gushchina et al., 2017; Weisleder et al., 2012). Self-repair: Our bodies are packages within packages. The physical properties of the plasma membrane are governed in large part by the effect of lipid interactions at the population level. However, all cells are susceptible to plasma membrane damage, which results in the mixture of the intracellular fluid and extracellular milieu and can result in death if the damage is not rapidly repaired. The structural role of lipids described above illustrates how their ability to modify the biophysical properties of the plasma membrane is beneficial for resealing. 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). 2022 Dec 1;11(1):38. doi: 10.1186/s13619-022-00141-8. They break down excess or worn-out cell parts. diacylglycerol - DAG) backbone are called glycerophospholipids (referred to as phospholipids hereafter) and make up the majority of the plasma membrane. Schematic representation of the structural features of the protein families implicated in membrane repair. This involves a series of distinct, but mutually dependent stages including inflammation, regeneration, and remodeling of the tissue (Gurtner, Werner, Barrandon, & Longaker, 2008). Cells as part of multicellular systems rarely act alone, instead having ways to signal to start and complete simple to quite complex interactions. While initial depolymerization of the local F-actin network is thought to assist with vesicle fusion and membrane shedding, delayed accumulation of F-actin may facilitate repair either by working in coordination with myosin to pull the wounded membrane edges toward each other or by providing a barrier and stabilizing function for the newly formed membrane. Despite the many different types of tissue, there is a common repair program involved in tissue repair. This is especially important in sensing membrane damage. For example, PIP2 interacts with actin-associated proteins, resulting in a local strengthening of the plasma membrane-cytoskeleton interface. Examples of self-repairing cells. During the repair of sarcolemmal lesions, macrophages recognize exposed phosphatidylserine at the site of . Translocation of existing lipid species to the site of injury provides a mechanism to recruit and activate protein machinery. In this way, lipids play an important role in polarizing the cellular response to an injury. 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. The site is secure. 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. Mammals make up less than 1% of all animals on earth, but they include some of the most well-known species. 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). Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair, Involvement of lipid peroxidation in CNS injury, Focal adhesions, stress fibers and mechanical tension. 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). This can limit the expansion of the wound area itself. Shao S, Liao X, Xie F, Deng S, Liu X, Ristaniemi T, & Liu B (2018). PMC 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). When cells have DNA damage but fail to undergo apoptosis, they may be on the road to cancer. 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). 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). Cell walls provide structural support for the cell. The https:// ensures that you are connecting to the Lysosomes are involved with various cell processes. To do so, they must control the movement of liquids across their boundaries. As muscle fibers have strong interfiber connections, muscle injuries may manifest both as shearing of the membrane from increased membrane tension and strain, as well as ripping of plasma membrane regions from fiber retraction or hypercontraction. Damage control: cellular mechanisms of plasma membrane repair. Drescher DG, Drescher MJ, Selvakumar D, Annam NP. 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). . This relies upon the coordinated action of the machinery that polarizes the repair response to the site of injury, resulting in resealing of the damaged membrane and subsequent remodeling to return the injured plasma membrane to its pre-injury state. In addition to working on their own, lipids also interact with proteins to coordinate these processes. Epub 2008 Mar 3. Epub 2012 Jul 9. While membrane stabilization at the time of injury appears to improve membrane repair, a chronically rigid plasma membrane may inhibit the beneficial effects of transient lipid mobility after injury. These observations align well with the observed kinetics of membrane resealing, which suggests that plasma membrane wounds can be resealed within 30 seconds; however, restoration of membrane tension shortly afterward is required for successful membrane remodeling and completion of the repair process. 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). A single cell is often a complete organism in itself, such as a bacterium or yeast. Viral infection controlled by a calcium-dependent lipid-binding module in ALIX. Disclaimer. Interphase has three stages: G1, S and G2. Cambridge (MA): Harvard Stem Cell Institute; 2008. 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). The role of lipids during plasma membrane repair goes far beyond a passive role in vesicle-mediated delivery of membrane lipids. Plataki M, Lee YD, Rasmussen DL, & Hubmayr RD (2011). 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. 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). 8600 Rockville Pike 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). This results in the replacement of half of the body's adipocytes in 8 years. "Think of a . 2021 Sep 29;9:753625. doi: 10.3389/fcell.2021.753625. 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. Senju Y, Kalimeri M, Koskela EV, Somerharju P, Zhao H, Vattulainen I, & Lappalainen P (2017). A surprise arrived when heart muscle cells were analyzed. Analysis of Dysferlin Direct Interactions with Putative Repair Proteins Links Apoptotic Signaling to Ca. , convoy commander brief example, estes park police department,
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