(D) The lipid make-up of the plasma membrane constantly changes. The chemical structure of the cell membrane makes it remarkably flexible, the ideal boundary for rapidly growing and dividing cells. VBP15, a novel antiinflammatory and membranestabilizer, improves muscular dystrophy without side effects, Cellular mechanisms and signals that coordinate plasma membrane repair. While intracellular MG53 is a redox-sensitive protein capable of facilitating vesicle aggregation, it is proposed to have multiple functions during membrane repair. For example, replacement of a cylindrical lipid (e.g. Corrotte M, Almeida PE, Tam C, Castro-Gomes T, Fernandes MC, Millis BA, Maugel TK. The https:// ensures that you are connecting to the Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. How skin heals is a good example of the role of cellular processes. This cytoskeletal assembly is regulated by Rho GTPase activity, which triggers F-actin accumulation at the site of injury. Biosci Rep. 2023 Feb 27;43(2):BSR20220765. Epub 2023 Mar 3. 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. Radiation Effects on Cells & DNA | Let's Talk Science (2017). In bacterial and plant cells, a cell wall is attached to the plasma membrane on its outside surface. Bacterial pore-forming, What might membrane injury to muscle fibers look like? This is due to its protein-binding ability, resulting in protein translocation to the cholesterol-rich regions of plasma membrane (Sheng et al., 2012; Van Meer et al., 2008). Zuzek A, Fan JD, Spaeth CS, & Bittner GD (2013). Rayens NT, Cook KJ, McKinley SA, Payne CK. Elife. 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. 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). 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. 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. Analysis of Dysferlin Direct Interactions with Putative Repair Proteins Links Apoptotic Signaling to Ca. Recombinant MG53 protein modulates therapeutic cell membrane repair in treatment of muscular dystrophy. 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. Yasuda S, Townsend D, Michele DE, Favre EG, Day SM, & Metzger JM (2005). Careers. Jaiswal JK, Lauritzen SP, Scheffer L, Sakaguchi M, Bunkenborg J, Simon SM, Nylandsted J (2014). 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. C-terminal di-arginine motif of Cdc42 protein is essential for binding to phosphatidylinositol 4, 5-bisphosphate-containing membranes and inducing cellular transformation, Plasma membraneCortical cytoskeleton interactions: A cell biology approach with biophysical considerations, Control of diverse subcellular processes by a single multi-functional lipid phosphatidylinositol 4, 5-bisphosphate [PI (4, 5) P2], The structural role of cholesterol in cell membranes: from condensed bilayers to lipid rafts. We here review what is known about the cellular and molecular mechanisms of membrane repair, with particular emphasis on the relevance of repair as it relates to disease pathologies. Gazzerro E, Sotgia F, Bruno C, Lisanti MP, & Minetti C (2010). This allows small GTPases, such as Rac1 and Cdc42 to preferentially bind the negatively charged PIP2 and PIP3 (Johnson, Erickson, & Cerione, 2012; Maxwell et al., 2018; Remorino et al., 2017). Tailored protection against plasmalemmal injury by annexins with different Ca2+ sensitivities, Sphingolipids and the formation of sterol-enriched ordered membrane domains, Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. 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. Membrane Damage - an overview | ScienceDirect Topics 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. SM utilizes the ceramide (Cer) backbone and can be used to generate the signaling lipid sphingosine-1-phosphate (S1P). 14.2: Cell Damage and Tissue Repair - Chemistry LibreTexts Phosphatidylinositol is found in many cell types and tissues, but is particularly abundant in the brain. diacylglycerol - DAG) backbone are called glycerophospholipids (referred to as phospholipids hereafter) and make up the majority of the plasma membrane. Each month, well bring you a selection of compelling updates to this ever-growing library of biological strategies and innovations. sharing sensitive information, make sure youre on a federal doi: 10.3791/50848. Dysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair. This results in the replacement of half of the body's adipocytes in 8 years. Thottacherry JJ, Kosmalska AJ, Kumar A, Vishen AS, Elosegui-Artola A, Pradhan S, Chaudhary N (2018). Das S, Yin T, Yang Q, Zhang J, Wu YI, & Yu J (2015). Local oxidation at the site of membrane injury activates MG53 oligomerization (Cai et al., 2009), which may locally increase membrane rigidity. Moissoglu K, Kiessling V, Wan C, Hoffman BD, Norambuena A, Tamm LK, & Schwartz MA (2014). 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. ESCRT assembly for membrane shedding is activated by the calcium-dependent ALG-2 protein, which then recruits its interacting partner ALIX leading to subsequent recruitment of the remaining complex members (Scheffer et al., 2014). The role of lipids during plasma membrane repair goes far beyond a passive role in vesicle-mediated delivery of membrane lipids. The fatty membranes of cells are capable of self-repair using a mechanism that involves calcium-dependent exocytosis. Presence of LBPA at the plasma membrane through vesicle fusion could allow for ALIX recruitment and ESCRT assembly (Bissig et al., 2013); however, the presence of LBPA at membrane wound sites has not been directly observed. These phospholipids are important for the formation of other molecules that are involved in cell signaling and help to bind proteins and carbohydrates to the outer cell membrane. 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). This raises the intriguing possibility that MG53 may affect plasma membrane structural properties. (2013). Structural and signaling role of lipids in plasma membrane repair Class Mammalia (breast): Bats, cats, whales, horses, humans. PC), with a conical shaped, charged phospholipid (e.g. An official website of the United States government. High force impact or stress can cause materials that comprise living systems to separate into two or more pieces (called fracturing) or to break or burst suddenly (called rupturing). In some cases, these forces are benign, such as membrane protrusion driven by cortical actin polymerization (Pontes, Monzo, & Gauthier, 2017). What is cell membrane integrity? - Studybuff Modular, cascade-like transcriptional program of regeneration in, R01 GM113602/GM/NIGMS NIH HHS/United States. McNeil AK, Rescher U, Gerke V, & McNeil PL (2006). These same processes also work to dynamically control membrane fluidity by regulating the distribution of phospholipids, sphingolipids, and cholesterol in the membrane. 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. Spatial arrangement of lipids is also known to regulate Rho family GTPase activity (see Section 4.3). While PA mediates targeting to the membrane, Rac1 activity depends on PIP3, suggesting multiple roles for signaling lipids in GTPase activity after repair. (2017). Cell damage. 2023 Apr 4;122(7):1355-1363. doi: 10.1016/j.bpj.2023.03.001. (2009). Interestingly, several methods for PIP2 micro-domain formation may allow for this to occur after plasma membrane injury. Subsequent insult(s) of eccentric stretch result in a more severe wound and global hypercontraction, producing fiber retraction within the muscle bundle (53). The primary plasma membrane sphingolipid in mammalian cells is sphingomyelin, which utilizes a ceramide backbone (Merrill Jr, 2008). It can also be produced by methylation of existing PE, while PE can be produced by the decarboxylation of PS. 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). The antioxidant requirement for plasma membrane repair in skeletal muscle. 2013 Dec 19;(82):e50848. 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. 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. This cell membrane provides a protective barrier around the cell and regulates which materials can pass in or out. 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). Membrane-stabilizing copolymers confer marked protection to dystrophic skeletal muscle in vivo, Molecular Therapy-Methods & Clinical Development. Clipboard, Search History, and several other advanced features are temporarily unavailable. Inherent plasticity and microfracture toughening mechanisms work together to prevent antlers from breaking. Membrane damage: Damage to the cell membrane disturbs the state of cell electrolytes, e.g. Biophys J. Disruption of the cell plasma membrane is a commonplace occurrence in many mechanically challenging, biological environments. 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. Rapid actin-cytoskeletondependent recruitment of plasma membranederived dysferlin at wounds is critical for muscle membrane repair. Another role identified for lysosomal fusion in membrane repair is the secretion of the lipid modifying enzyme acid sphingomyelinase (ASM) (Defour et al., 2014; Tam et al., 2010). How does the cell membrane self heal? Plasma membrane lipids containing the alkanoamine sphingosine are called sphingolipids. The radiation could prevent the DNA from replicating correctly. 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). Similar to the changes in tension described above, the fluidity of the plasma membrane is also dynamic after injury. Bacterial pore-forming toxins oligomerize and insert in the plasma membrane of target cells forming a diffusible pore. As structural components of the plasma membrane, lipids are responsible for contributing to membrane tension, rigidity, and overall shape. 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. Other cells acquire specialized functions as they mature. 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. 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. This lipid binds ALIX and is capable of budding vesicles away from the cytosol (Matsuo et al., 2004). 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 physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. government site. Cebecauer M, Amaro M, Jurkiewicz P, Sarmento M. J. o., achl R, Cwiklik L, & Hof M (2018). 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. Cellular organelles and structure (article) | Khan Academy 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. The second stage of tissue repair, regeneration, makes use of signaling by different lipids, one of which is sphingolipid. One model explaining membrane injury in dystrophin-deficient muscle fibers proposes that an initial injury causes a local influx of calcium and a local region of hypercontraction. 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. Cells defend themselves from viruses, bacteria with armor of protein Before In general, PIP2 is a positive regulator of F-actin polymerization and the presence of PIP2 increases the stability of the actin cytoskeletonplasma membrane interface. Thus, caveolae may serve a signaling function during membrane repair (see Section 4). 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). Please enable it to take advantage of the complete set of features! Palmitate-mediated disruption of the endoplasmic reticulum decreases intracellular vesicle motility. HHS Vulnerability Disclosure, Help Why does our body heal itself? Similar inter-leaflet heterogeneity exists among sphingolipids, with the glycosphingolipids maintained exclusively in the outer leaflet. 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. The wounded cell can survive if a rapid repair respons Membrane Repair: Mechanisms and Pathophysiology Amongst other causes, this can be due to physical, chemical, infectious, biological, nutritional or immunological factors. Scheffer LL, Sreetama SC, Sharma N, Medikayala S, Brown KJ, Defour A, & Jaiswal JK (2014). sharing sensitive information, make sure youre on a federal Int J Mol Sci. Poloxamer 188 facilitates the repair of alveolus resident cells in ventilator-injured lungs, American journal of respiratory and critical care medicine. 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. McDade JR, Archambeau A, & Michele DE (2014). Similar benefits have been attributed to membrane stabilizing copolymers such as poloxamer 188, that improved repair after physiological mechanical injury (Plataki, Lee, Rasmussen, & Hubmayr, 2011), and injury to dystrophic cells (Houang et al., 2015; Yasuda et al., 2005). 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). However, to successfully repair the cell also needs to restore the barrier function of the resealed membrane. These examples illustrate the far-reaching consequence of lipid movement on structural stability of the plasma membrane and its ability to successfully repair. 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. Each of these lipids contributes their own qualities that affect the structural and signaling characteristics of the plasma membrane (Nicolson, 2014). and transmitted securely. 2023 Feb 28;24(5):4707. doi: 10.3390/ijms24054707. As lipids comprise the bulk of the plasma membrane, the acts of injury, resealing, and remodeling all directly impinge upon the plasma membrane lipids. Importantly, sequestration of cholesterol alone increased PLD activity, supporting the idea that transient increase in lipid fluidity after membrane injury may be required for PLD-mediated signaling. Indeed, mechanical injury of healthy cells transiently increases the mobile fraction of plasma membrane lipids by as much as 9% (Sreetama et al., 2018). 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.
