GRAF1 deficiency blunts sarcolemmal injury repair and exacerbates cardiac and skeletal muscle pathology in dystrophin-deficient mice. Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling. For example, when inserted into a region abundant in phospholipids, cholesterol has a rigidifying effect; however, the opposite can be true with sphingolipids. The lipids in the membrane control the function of the membrane - keeping some products inside and some outside. They may be used to destroy invading viruses and bacteria. National Library of Medicine 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). The plasma membrane is semi-permeable, allowing the cell to communicate with and utilize resources from its surrounding environment. Intriguingly, PA preferentially binds the Rho family member Rac1, resulting in nanocluster formation (Maxwell et al., 2018). If the cell is damaged beyond repair, lysosomes can help it to self-destruct in a process called programmed . Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis. Additional structural changes the plasma membrane must adopt for repair include molding the shape of the membrane to limit wound expansion as well as pulling in the membrane edges to close the wound. Despite the many different types of tissue, there is a common repair program involved in tissue repair. Rather than these roles being separated from each other, they overlap significantly such that one can easily be an extension of the other. Jimenez AJ, Maiuri P, Lafaurie-Janvore J, Divoux S, Piel M, & Perez F (2014). 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). 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). 8600 Rockville Pike 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. 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 . Corrotte M, Almeida PE, Tam C, Castro-Gomes T, Fernandes MC, Millis BA, Maugel TK. These remodeling events actively promote plasma membrane repair; however, they also act as extensions of the repair response and may continue long after successful resealing in order to restore the plasma membrane to its pre-injury state. Careers. Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Clementi E. (2009). EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription. 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. See this image and copyright information in PMC. Enzymes that generate lipid signaling after plasma membrane injury (in red) include the phospholipases C and D (PLC and PLD), phosphatidyloinositol kinases (PI5K and PI3K), and sphingomyelinase (SMase). 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). For example, a scallop prevents structural failure from fracture because its shell is comprised of two materials of varying stiffness. 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. All RightsReserved. The site is secure. 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). Cong X, Hubmayr RD, Li C, & Zhao X (2017). 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). Eukaryotic cells have been shown to utilize calcium-activated exocytosis to reduce membrane tension and promote repair via lipid-disorder driven attractions. Plataki M, Lee YD, Rasmussen DL, & Hubmayr RD (2011). 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. (B) Phospholipid biosynthesis depends on multiple inputs from metabolism (glycerol-3-phosphate) and extracellular import (choline and ethanolamine). In order to provide a cell with energy, these molecules have to pass across the cell membrane, which functions as a barrier but not an impassable one. 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. The plasma membrane forms the physical barrier between the cytoplasm and extracellular space, allowing for biochemical reactions necessary for life to occur. Sezgin E, Levental I, Mayor S, & Eggeling C (2017). Wound closure is mediated in part by the interactions of the cortical actin cytoskeleton with the plasma membrane. 2022 Aug 23;13(1):4950. doi: 10.1038/s41467-022-31277-5. Muscle membrane integrity in Duchenne muscular dystrophy: recent advances in copolymer-based muscle membrane stabilizers. In: StemBook [Internet]. At each of these levels the structural and signaling aspects of lipids are critical for the cell to mount an efficient response to plasma membrane injury. While tension acts at the level of an entire membrane, the physical properties of the individual lipids and lipid domains dynamically guide the local changes required for adapting to the change in tension. "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. 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). 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). When cells have DNA damage but fail to undergo apoptosis, they may be on the road to cancer. This allows for the movement and patterning of lipids into signaling domains, changing the spatial arrangement of proteins that selectively interact with a particular lipid species. While the structural importance of plasma membrane cholesterol is well appreciated, it can also play a role in signaling. 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). Spiders turn liquid into a strong, stretchy fiber by squeezing it through a small space that helps protein molecules to connect with eachother. 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). 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. This preferential association between different lipids results in an important feature of the plasma membrane its transverse and lateral heterogeneity. 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. Scheffer LL, Sreetama SC, Sharma N, Medikayala S, Brown KJ, Defour A, & Jaiswal JK (2014). Similar to PLC, phospholipase D (PLD) activity is also increased after injury and is required for repair (Arun et al., 2013). Bookshelf Cell Regen. These same processes also work to dynamically control membrane fluidity by regulating the distribution of phospholipids, sphingolipids, and cholesterol in the membrane. (2017). Treatment with Recombinant Human MG53 Protein Increases Membrane Integrity in a Mouse Model of Limb Girdle Muscular Dystrophy 2B. PS) in the inner leaflet, causes the plasma membrane to attain an overall outward curvature. Microfluidic guillotine for single-cell wound repair studies. (B) The plasma membrane is not a homogenous mixture of proteins and lipids (as in A). The lipids in the membrane are fluid, and therefore in motion, and are constantly adapting to the changing environment. 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 .gov means its official. Further, PE and PC head groups can be cleaved and replaced with serine to produce PS (Oropeza, 2017). Mechanism of Ca 2+-triggered ESCRT assembly and regulation of cell membrane repair. Cell walls provide structural support for the cell. 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). Shed microvesicles containing streptolysin-O have been shown to also contain annexins A1 and A6 (219). While lipids are often ascribed a metabolic role as energy storage molecules, they also play important structural and signaling roles in the cell. Lethal Injury (Cell Death) In many situations, the damage to a cell may be so severe that the cell cannot survive. 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 basement membrane of the basal cells attaches via hemidesmosomes to the underlying Bowman's layer, while anchoring fibrils pass through . One such mechanism for this may be mediated by the protein MG53. A decrease in membrane tension precedes successful cell-membrane repair. The tension forces acting on the plasma membrane are generally applied by three sources: the difference in hydrostatic pressure between the cell interior and extracellular space, the cortical cytoskeletal network, and the extracellular matrix to which the cell is attached (Gauthier, Masters, & Sheetz, 2012; Kozlov & Chernomordik, 2015) (Figure 2B). By clicking the Accept button you agree to the terms of our privacy policy. This structural arrangement is important for the organization of cholesterol in biological membranes as it results in the hydroxyl group associating with the neighboring lipid head groups and water, while the majority of the cholesterol molecule resides within the hydrophobic core of the membrane. Myofiber injury in zebrafish was found to cause rapid loss of PIP2, followed by restoration to pre-injury levels by 30 seconds post-injury (Middel et al., 2016). 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). Please enable it to take advantage of the complete set of features! This raises the intriguing possibility that MG53 may affect plasma membrane structural properties. Bomal E, Grandgeorge P, Yeo RJ, Candau N, Reis PM, Frauenrath H. Nat Commun. 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). What's found inside a cell. Lipids also interact with plasma membrane localized proteins to regulate membrane tension and fluidity. Heier CR, Damsker JM, Yu Q, Dillingham BC, Huynh T, Van der Meulen JH, Scheffer L. (2013). Phospholipid signalling through phospholipase D and phosphatidic acid. Hall ED, Wang JA, Miller DM, Cebak JE, & Hill RL (2018). Temporary increase in plasma membrane tension coordinates the activation of exocytosis and contraction during cell spreading. This cell membrane provides a protective barrier around the cell and regulates which materials can pass in or out. Damage control: cellular mechanisms of plasma membrane repair. Weisleder N, Takizawa N, Lin P, Wang X, Cao C, Zhang Y, Chen P-J (2012). HHS Vulnerability Disclosure, Help Healing of a punctured, The regeneration and reorganization of the oral apparatus (green) of, Wound healing studies in model cells such as. PI5K activity is itself driven by regulators of membrane repair including Rho GTPases (Gilmore & Burridge, 1996) and PLD (Roach et al., 2012). Verweij FJ, Revenu C, Arras G, Dingli F, Loew D, Pegtel DM, Zimmermann P (2019). In this review, we have discussed how lipids working at the individual as well as at the population level facilitate the proper orchestration of the repair response. The cell membrane is an extremely pliable structure composed primarily of two layers of phospholipids (a "bilayer"). Repair of injured cells is tied closely to tissue repair and regeneration, as shown by studies demonstrating release of inflammatory mediators, including small molecules, peptides and proteins that signal to cells in the inflammatory and regenerative systems to initiate a tissue level reparative response. Scattered throughout the bloodstream are lens-shaped structures that serve to plug thewound. In some cases, these forces are benign, such as membrane protrusion driven by cortical actin polymerization (Pontes, Monzo, & Gauthier, 2017). Daumke O, Lundmark R, Vallis Y, Martens S, Butler PJG, & McMahon HT (2007). 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. sharing sensitive information, make sure youre on a federal Thottacherry JJ, Kosmalska AJ, Kumar A, Vishen AS, Elosegui-Artola A, Pradhan S, Chaudhary N (2018). When a cell's DNA is damaged, it will typically detect the damage and try to repair it. Idone V, Tam C, Goss JW, Toomre D, Pypaert M, Andrews NW. The primary method for PIP2 formation in cells is by the activity of PI(4)P-5 kinase (PI5K) (Kolay, Basu, & Raghu, 2016). The mystery of membrane organization: composition, regulation and roles of lipid rafts. Injury to the plasma membrane also changes the biochemical environment within the cell. The https:// ensures that you are connecting to the 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).
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