This raises the intriguing possibility that MG53 may affect plasma membrane structural properties. 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). PIP2 also accumulates at the site of membrane injury (Demonbreun et al., 2016; Vaughan et al., 2014). Wound closure is mediated in part by the interactions of the cortical actin cytoskeleton with the plasma membrane. However, whether caveolae facilitate repair by buffering membrane tension remains unclear because, unlike the capacity of CLIC/GEEC endocytosis, caveolae make up a small portion (as small as 0.03%) of the membrane area and are not found ubiquitously in all cells (Gauthier et al., 2012; Sinha et al., 2011). Indeed, mechanical injury of healthy cells transiently increases the mobile fraction of plasma membrane lipids by as much as 9% (Sreetama et al., 2018). The site is secure. Corrotte M, Almeida PE, Tam C, Castro-Gomes T, Fernandes MC, Millis BA, Maugel TK. These cells cooperate with other specialized cells and become the building blocks of large multicellular . Andrews NW, Almeida PE, & Corrotte M (2014). A surprise arrived when heart muscle cells were analyzed. The nanoclusters appear to form specifically at the boundary of ordered raft domains and disordered domains where signaling lipids such as PIP3 and PIP2 are found. Verweij FJ, Revenu C, Arras G, Dingli F, Loew D, Pegtel DM, Zimmermann P (2019). The fluidity of the membrane is determined in part by its composition, with cholesterol and sphingolipid-rich regions being less fluid than those areas comprised primarily of phospholipids. Unauthorized use of these marks is strictly prohibited. Lipids also interact with plasma membrane localized proteins to regulate membrane tension and fluidity. Many of the sphingolipids also contain a glycosidically bound carbohydrate moiety causing formation of the glycosphingolipids. Membrane lipids: where they are and how they behave. In addition to allowing for the lateral translocation of membrane lipids, injury-triggered increase in membrane fluidity also results in reduced lipid packing. This cytoskeletal assembly is regulated by Rho GTPase activity, which triggers F-actin accumulation at the site of injury. 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. PIP2 dynamics after plasma membrane injury support a role for PIP2 in actin assembly during repair as its accumulation near the site of injury is generally delayed. Prior to increase in shear force, PLD associates with lipid rafts, physically segregated from its activator PIP2 and its substrate PC (Petersen et al., 2016). Injury to the plasma membrane also changes the biochemical environment within the cell. Sezgin E, Levental I, Mayor S, & Eggeling C (2017). 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 . Cell wounding activates phospholipase D in primary mouse keratinocytes. calcium, which when constantly increased, induces apoptosis. Mammals make up less than 1% of all animals on earth, but they include some of the most well-known species. 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 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. Recombinant MG53 protein modulates therapeutic cell membrane repair in treatment of muscular dystrophy. Lethal Injury (Cell Death) In many situations, the damage to a cell may be so severe that the cell cannot survive. EVs are known to be generated in response to plasma membrane injury of single cells, and this is required for successful repair (Jimenez et al., 2014; Scheffer et al., 2014). Calcium can activate proteins directly, and ultimately is the initiator of many downstream repair pathways. See this image and copyright information in PMC. 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). 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. 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. The goal of signaling during plasma membrane repair is to generate a polarized response such that the repair machinery can be spatially and temporally localized and activated at the repair site. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. (B) The plasma membrane is not a homogenous mixture of proteins and lipids (as in A). Amongst other causes, this can be due to physical, chemical, infectious, biological, nutritional or immunological factors. This mechanism is particularly intriguing in light of the redox-sensitive nature of MG53. Cebecauer M, Amaro M, Jurkiewicz P, Sarmento M. J. o., achl R, Cwiklik L, & Hof M (2018). Curr Biol. Of potential interest in this regard is the unconventional phospholipid lysobisphosphatidic acid (LBPA), which is found on endolysosomes. 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. Ribosome damage: Damage to ribosomal and cellular proteins such as protein misfolding, Leading to apoptotic enzyme activation. The reduction in membrane tension is likely due directly to the addition of phospholipids to reduced lipid packing, as well as due in part to the cytoskeletal remodeling associated with vesicular transport at the plasma membrane. 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). diacylglycerol - DAG) backbone are called glycerophospholipids (referred to as phospholipids hereafter) and make up the majority of the plasma membrane. It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. The cell membrane is an extremely pliable structure composed primarily of two layers of phospholipids (a "bilayer"). The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). This is due to their lack of integration into the membrane under normal lipid packing conditions. This site needs JavaScript to work properly. Direct lipid modification of proteins, such as GTPases, provides another method to regulate protein localization and activity (Casey, 1995). Lipids contribute to cellular physiology at both an individual and population level. Do Heo W, Inoue T, Park WS, Kim ML, Park BO, Wandless TJ, & Meyer T (2006). This is called apoptosis. Using these dating methods, it was inferred that fat cells (adipocytes) replace at a rate of 86% per year (BNID 103455). 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. This remodeling is likely provided by processes described previously: membrane endocytosis (Section 3.1) and membrane shedding (Section 4.1). 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). As dysferlin may only be detected at injury sites with antibodies recognizing COOH-terminal epitopes, and not several antibodies to NH. Thus, while increase in lipid mobility following plasma membrane injury is associated with successful repair, excessive lipid mobility leading to membrane instability is detrimental to the repair process. Gradients of Rac1 nanoclusters support spatial patterns of Rac1 signaling. This is achieved in part through the activity of lipid modifying enzymes, such as phospholipases, which are activated by the changing biochemical environment after injury. 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. Nakamura M, Hui J, Stjepi V, Parkhurst SM. When a cell's DNA is damaged, it will typically detect the damage and try to repair it. Thus, caveolae may serve a signaling function during membrane repair (see Section 4). As she describes, a lesion is followed by a Ca2+-dependent movement of vesicles to the plasma membrane. The lipids in the membrane control the function of the membrane - keeping some products inside and some outside. Caveolinopathies: from the biology of caveolin-3 to human diseases, Annexins: linking Ca 2+ signalling to membrane dynamics, Regulation of vinculin binding to talin and actin by phosphatidyl-inositol-45-bisphosphate. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Ligeti E, Dagher M-C, Hernandez SE, Koleske AJ, & Settleman J (2004). If you break a bone, your body immediately begins producing new cells to heal the damage. 2008 Mar 10;180(5):905-14. doi: 10.1083/jcb.200708010. 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). When cells have DNA damage but fail to undergo apoptosis, they may be on the road to cancer. The radiation could prevent the DNA from replicating correctly. A cartoon depicting the potential role of dysferlin-mediated vesicle fusion in membrane repair. 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). Membrane stabilization by modified steroid offers a potential therapy for muscular dystrophy due to dysferlin deficit, Transverse distribution of plasma membrane bilayer cholesterol: Picking sides. Careers. Epub 2008 Oct 9. 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. Horn A, Van der Meulen JH, Defour A, Hogarth M, Sreetama SC, Reed A, Jaiswal JK. A lysosome is a membrane-bound cell organelle that contains digestive enzymes. 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. 2022 May 15;23(10):5525. doi: 10.3390/ijms23105525. Remorino A, De Beco S, Cayrac F, Di Federico F, Cornilleau G, Gautreau A, Coppey M (2017). Saarikangas J, Zhao H, & Lappalainen P (2010). The chemical structure of the cell membrane makes it remarkably flexible, the ideal boundary for rapidly growing and dividing cells. 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. 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). Bethesda, MD 20894, Web Policies 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). 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. They include glycerophosphocholines, glycerophosphoglycerols, glycerophosphoinositols, as well as triacylglycerols (Taverna, Nanney, Pollins, Sindona, & Caprioli, 2011). Exocytic fusion reduces membrane tension, and vesicle-vesicle fusion events provide a patch as a replacement for the membrane barrier missing at the disruption site. Acid sphingomyelinase activity triggers microparticle release from glial cells. The plasma membrane separates the extracellular environment from the cell interior, where biochemical reactions necessary for life occur. 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). The plasma membrane is a dynamic barrier that separates the cell interior from the extracellular space (Figure 2C). 2012 Sep-Oct;52(3-4):191-5. doi: 10.1016/j.ceca.2012.06.003. Unlike phospholipids and sphingolipids, which are structurally analogous, cholesterol is composed of a steroid backbone that results in a planar and more rigid molecule. While the local accumulation of proteins such as annexins acts to stabilize the structurally unstable membrane after injury, remodeling of the membrane itself can achieve a similar outcome. This allows local and functional diversity between the two leaflets as well as various parts of the single contiguous plasma membrane (Figure 2B). For example, when inserted into a region abundant in phospholipids, cholesterol has a rigidifying effect; however, the opposite can be true with sphingolipids. PA is itself generated primarily from glycerol-3-phosphate, which is a product of glycolysis. 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). Taverna D, Nanney LB, Pollins AC, Sindona G, & Caprioli R (2011). Small GTPases, such as Rho family members, associate with biological membranes via lipid modifications (ten Klooster & Hordijk, 2007); however, selectivity for the plasma membrane is regulated through the polybasic domain comprised of a cluster of positively charged amino acids (Do Heo et al., 2006; Maxwell, Zhou, & Hancock, 2018). If the cell is damaged beyond repair, lysosomes can help it to self-destruct in a process called programmed . Just like cells have membranes to hold everything in, these mini-organs are also bound in a double layer of phospholipids to insulate their little compartments within the larger cells. Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding? 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). 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). Eukaryotic cells have been shown to utilize calcium-activated exocytosis to reduce membrane tension and promote repair via lipid-disorder driven attractions. If the damage is beyond repair, the cell will normally send itself into apoptosis, ensuring that it will not pass on its damaged DNA. ESCRT machinery is required for plasma membrane repair. Bookshelf 2022 Aug 23;13(1):4950. doi: 10.1038/s41467-022-31277-5. Trends Cell Biol. 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. Within a single leaflet, lateral heterogeneity is found in the form of lipid microdomains, such as the cholesterol and sphingolipid-rich domains that serve as signaling platforms to accumulate plasma membrane-associated proteins. 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. Similarly, peak PIP2 accumulation at the injury site occurred 45 seconds post-injury in Xenopus oocytes (Vaughan et al., 2014). Interphase has three stages: G1, S and G2. Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. Sheng R, Chen Y, Gee HY, Stec E, Melowic HR, Blatner NR, Fujiwara TK (2012). 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. Cell death occurs mainly by two methods: necrosis and apoptosis. An official website of the United States government. 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). 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. This cell membrane provides a protective barrier around the cell and regulates which materials can pass in or out. J.K.J. 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). 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). 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). 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 plasma membrane repair to occur successfully, the cell must possess a means to sense that injury has occurred, coordinate the change in activity and localization of repair machinery, and ultimately close the wounded area. Please enable it to take advantage of the complete set of features! Lysosomes are involved with various cell processes. Lipids also react to the changing biochemical environment to become signaling molecules that determine the spatiotemporal dynamics of protein activation (Eyster, 2007) (Figure 1B). The https:// ensures that you are connecting to the government site. 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. After an injury, the biophysical properties of the plasma membrane, and the individual lipids themselves, are altered, eliciting changes to membrane rigidity and fluidity. This is in part achieved through the activity of lipid modifying enzymes, such as kinases, phosphatases, and phospholipases. 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. The lipids in the membrane are fluid, and therefore in motion, and are constantly adapting to the changing environment. The lipid-mediated cytoskeletal rearrangement described above provides the cell with a mechanism to close the wounded site and add structural support to the newly resealed membrane. Biosci Rep. 2023 Feb 27;43(2):BSR20220765. sharing sensitive information, make sure youre on a federal government site. 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).
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