increased lipid fluidity described in Section 3) and allows for the membrane associated PLD to diffuse outward from lipid rafts and interact with PIP2 in order to metabolize PC. 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). 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. Alterations in Phosphatidylcholine Metabolism of StretchInjured Cultured Rat Astrocytes. While lipids are often ascribed a metabolic role as energy storage molecules, they also play important structural and signaling roles in the cell. 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 Defour A, Van der Meulen JH, Bhat R, Bigot A, Bashir R, Nagaraju K, & Jaiswal JK (2014). "Self-repair: Our bodies are packages within packages. 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. Cell before mitosis showing the location of the centrioles, microtubules, nuclear membrane, nucleolus, and DNA (Let's Talk Science using an image by Aldona via iStockphoto). Zuzek A, Fan JD, Spaeth CS, & Bittner GD (2013). The physical properties of the plasma membrane are governed in large part by the effect of lipid interactions at the population level. During the G1 stage, the cell prepares for division by increasing its mass. 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. The radiation could prevent the DNA from replicating correctly. 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). These phospholipids are derived from glycerol-3-phosphate, itself a product of cellular metabolism that is enzymatically modified into phosphatidic acid (PA). Simone LC, Caplan S, & Naslavsky N (2013). The mystery of membrane organization: composition, regulation and roles of lipid rafts. Demonbreun AR, Quattrocelli M, Barefield DY, Allen MV, Swanson KE, & McNally EM (2016). Membrane damage: Damage to the cell membrane disturbs the state of cell electrolytes, e.g. McNeil AK, Rescher U, Gerke V, & McNeil PL (2006). Unlike phospholipids and sphingolipids, which are structurally analogous, cholesterol is composed of a steroid backbone that results in a planar and more rigid molecule. The plasma membrane has a unique lipid composition that helps distinguish its structural and functional properties from the other internal membrane-bound compartments. 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. Horn A, Van der Meulen JH, Defour A, Hogarth M, Sreetama SC, Reed A, Jaiswal JK. 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. While reassembly of the cortical cytoskeleton in the minutes following injury is known to restore membrane tension (described in Section 3.3), membrane remodeling also contributes to increasing tension. They may be used to destroy invading viruses and bacteria. 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. lipids) is one of the roles proposed for lysosome-mediated repair (Andrews et al., 2014; McNeil, 2002). Please enable it to take advantage of the complete set of features! 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). In. An actin-dependent annexin complex mediates plasma membrane repair in muscle. Gradients of Rac1 nanoclusters support spatial patterns of Rac1 signaling. PMC 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). Membrane-stabilizing copolymers confer marked protection to dystrophic skeletal muscle in vivo, Molecular Therapy-Methods & Clinical Development. A decrease in membrane tension precedes successful cell-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). 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). 2021 Apr 2;19(1):63. doi: 10.1186/s12915-021-00970-0. If the damage is beyond repair, the cell will normally send itself into apoptosis, ensuring that it will not pass on its damaged DNA. Accumulation of GRAF1 at the repair site occurs 2 minutes after injury, supporting its potential role in membrane remodeling following resealing. 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. Scheffer LL, Sreetama SC, Sharma N, Medikayala S, Brown KJ, Defour A, & Jaiswal JK (2014). HHS Vulnerability Disclosure, Help official website and that any information you provide is encrypted Given their integral role in forming the structural backbone of the membrane, lipids are ideally placed to act as damage sensors, initiating early signaling that sets the stage for subsequent repair machinery. and transmitted securely. Copyright 2017, American Association for the Advancement of Science. This study showed that shear force on the membrane, as experienced by cells during mechanical injury, facilitated increased PLD activity through the process of lipid mixing. 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). 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. Recombinant MG53 protein modulates therapeutic cell membrane repair in treatment of muscular dystrophy. Plataki M, Lee YD, Rasmussen DL, & Hubmayr RD (2011). Endocytosis also occurs in response to plasma membrane injury and has been described as a mechanism for membrane resealing (Idone et al., 2008). cell, in biology, the basic membrane-bound unit that contains the fundamental molecules of life and of which all living things are composed. Physico-chemical and biological considerations for membrane wound evolution and repair in animal cells. Viral infection controlled by a calcium-dependent lipid-binding module in ALIX. diacylglycerol - DAG) backbone are called glycerophospholipids (referred to as phospholipids hereafter) and make up the majority of the plasma membrane. A lysosome is a membrane-bound cell organelle that contains digestive enzymes. Before 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. Calcium also initiates lipid signaling after plasma membrane injury by activating phospholipases, such as phospholipase C (PLC). One of the roles of lipid mobility may be to allow for the movement of individual lipids to form microdomains near the site of injury, which has been shown to be important for repair (Vaughan et al., 2014), perhaps by facilitating lipid-mediated signaling. Do Heo W, Inoue T, Park WS, Kim ML, Park BO, Wandless TJ, & Meyer T (2006). Bookshelf 2008 Mar 10;180(5):905-14. doi: 10.1083/jcb.200708010. After an injury, the biophysical properties of the plasma membrane, and the individual lipids themselves, are altered, eliciting changes to membrane rigidity and fluidity. Weisleder N, Takizawa N, Lin P, Wang X, Cao C, Zhang Y, Chen P-J (2012). 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. Cong X, Hubmayr RD, Li C, & Zhao X (2017). The Biomimicry Institute empowers people to create nature-inspired solutions for a healthy planet. 2021 The Biomimicry Institute. Diz-Muoz A, Fletcher DA, & Weiner OD (2013). Many of the sphingolipids also contain a glycosidically bound carbohydrate moiety causing formation of the glycosphingolipids. 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. 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. Gazzerro E, Sotgia F, Bruno C, Lisanti MP, & Minetti C (2010). There also exists lateral heterogeneity of lipid composition within each leaflet, which is demonstrated by the formation of lipid microdomains, such as the sphingomyelin and cholesterol-rich domains that exist interspersed among the phospholipids throughout the plasma membrane (Cebecauer et al., 2018; Sezgin, Levental, Mayor, & Eggeling, 2017) (Figure 2B). The role of lipids during plasma membrane repair goes far beyond a passive role in vesicle-mediated delivery of membrane lipids. These same processes also work to dynamically control membrane fluidity by regulating the distribution of phospholipids, sphingolipids, and cholesterol in the membrane. As described above, damage to the plasma membrane transiently increases the mobility of individual lipids. Bethesda, MD 20894, Web Policies Direct lipid modification of proteins, such as GTPases, provides another method to regulate protein localization and activity (Casey, 1995). 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). This allows local and functional diversity between the two leaflets as well as various parts of the single contiguous plasma membrane (Figure 2B). This raises the intriguing possibility that MG53 may affect plasma membrane structural properties. Lysosomes are involved with various cell processes. Of potential interest in this regard is the unconventional phospholipid lysobisphosphatidic acid (LBPA), which is found on endolysosomes. Phospholipids in particular show inter-leaflet heterogeneity. The Importance of Pore-Forming Toxins in Multiple Organ Injury and Dysfunction. Requirement for annexin A1 in plasma membrane repair, Repairing a torn cell surface: make way, lysosomes to the rescue, Plasma membrane disruption: repair, prevention, adaptation, Annual review of cell and developmental biology, Coping with the inevitable: how cells repair a torn surface membrane, Biochemistry of lipids, lipoproteins and membranes. How does the cell membrane self heal? Mechanochemical feedback control of dynamin independent endocytosis modulates membrane tension in adherent cells, Long-term Potentiation of Wound-induced Exocytosis and Plasma Membrane Repair Is Dependant on cAMP-response Element-mediated Transcription via a Protein Kinase C-and p38 MAPK-dependent Pathway. Annexins are a class of calcium-sensitive proteins that rapidly accumulate at the site of a membrane injury (Potez et al., 2011). Structure and Composition of the Cell Membrane. Each of these provides another mechanism for generating specific membrane lipids acutely in parallel to biosynthetic inputs. Modeling membrane shaping by proteins: Focus on EHD2 and NBAR domains. The plasma membrane is not a homogenous mixture of the different lipids described above (Figure 2A). Taverna D, Nanney LB, Pollins AC, Sindona G, & Caprioli R (2011). PMC The membrane patch may serve only temporarily as a surface barrier replacement that is subsequently remodeled and removed via exocytic and/or endocytic machinery. Int J Mol Sci. 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). Not only is the composition and organization of the plasma membrane in constant flux, the membrane itself also must interact with forces being applied to it from all directions. A cartoon depicting the potential role of dysferlin-mediated vesicle fusion in membrane repair. Lipids act as signaling molecules through their ability to directly bind or otherwise alter the activity or localization of target proteins (Figure 2B, ,C).C). Given their ability to traverse away from the site of synthesis (Verweij et al., 2019), the EVs generated during plasma membrane injury may activate both local and distant tissue regeneration responses needed for repair. Another critical shared feature is a set of highly-specialized teeth. Different cell-intrinsic PM repair mechanisms have been reported, including membrane fusion and replacement strategies (via exocytosis-mediated repair), removal of damaged membranes (by. As she describes, a lesion is followed by a Ca2+-dependent movement of vesicles to the plasma membrane. Very large plasma membrane disruptions (micron diameter) require membrane patching. Despite the many different types of tissue, there is a common repair program involved in tissue repair. . An official website of the United States government. 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). Cell Regen. Live tracking of inter-organ communication by endogenous exosomes in vivo. Spiders turn liquid into a strong, stretchy fiber by squeezing it through a small space that helps protein molecules to connect with eachother. Temporary increase in plasma membrane tension coordinates the activation of exocytosis and contraction during cell spreading. In fact, cells are able to perform hundreds, even thousands, of chemical transformations at the same time under life-friendly conditions (ambient temperature and pressure in an aqueous environment). 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, 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). In this case, cholesterol actually increases the fluidity among these lipids, which prevents them from forming a gel-like phase that is incompatible with the overall fluid nature of the plasma membrane (Krause & Regen, 2014). Every cell has a fatty membrane that self-assembles when placed in water, then reassembles when a breach occurs. Many organisms and tissues display the ability to heal and regenerate as needed for normal physiology and as a result of pathogenesis. All RightsReserved. Middel V, Zhou L, Takamiya M, Beil T, Shahid M, Roostalu U, Nienhaus GU (2016). 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. Two-way traffic on the road to plasma membrane repair. The structural role of lipids described above illustrates how their ability to modify the biophysical properties of the plasma membrane is beneficial for resealing. National Library of Medicine The second stage of tissue repair, regeneration, makes use of signaling by different lipids, one of which is sphingolipid. Hall ED, Wang JA, Miller DM, Cebak JE, & Hill RL (2018). Instead, distinct inter- and intra-leaflet heterogeneity exists. Matsuo H, Chevallier J, Mayran N, Le Blanc I, Ferguson C, Faur J, Sadoul R (2004). 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. 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). Togo T, Krasieva TB, & Steinhardt RA (2000). Because membrane tension limits the ability of cellular membranes to self-seal, cellular mechanisms that reduce membrane tension can promote membrane sealing. 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. . PA is itself generated primarily from glycerol-3-phosphate, which is a product of glycolysis. BMC Biol. official website and that any information you provide is encrypted The https:// ensures that you are connecting to the 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). Daumke O, Lundmark R, Vallis Y, Martens S, Butler PJG, & McMahon HT (2007). 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). Johnson JL, Erickson JW, & Cerione RA (2012). Formation of these outward budding vesicles at the plasma membrane is associated with an increase in cytosolic calcium and oxidation, as well as the disruption of the actin cytoskeletonplasma membrane interface (Pollet, Conrard, Cloos, & Tyteca, 2018), and each of these occurs locally in the immediate aftermath of membrane injury (Andrews et al., 2014; Horn & Jaiswal, 2018). Remorino A, De Beco S, Cayrac F, Di Federico F, Cornilleau G, Gautreau A, Coppey M (2017). VBP15, a novel antiinflammatory and membranestabilizer, improves muscular dystrophy without side effects, Cellular mechanisms and signals that coordinate plasma membrane repair. 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. Rayens NT, Cook KJ, McKinley SA, Payne CK. While often considered to be a passive resident of the plasma membrane, there is ample evidence to support a more active role of lipids in the process of plasma membrane repair as well as tissue repair. The chemical structure of the cell membrane makes it remarkably flexible, the ideal boundary for rapidly growing and dividing cells. These structural changes to lipids are both necessary for repair and potentially pathogenic if left uncorrected (Sreetama et al., 2018). Before Calcium can activate proteins directly, and ultimately is the initiator of many downstream repair pathways. Role of phosphatidylinositol 4, 5-bisphosphate in regulating EHD2 plasma membrane localization. PTRF Anchors MG53 to Cell Injury Site for Initiation of Membrane Repair. Rapid Changes to Endomembrane System of Infected Root Nodule Cells to Adapt to Unusual Lifestyle. Thus, the signaling role of lipids affects membrane structure and how the wound is eventually resealed and remodeled, returning the plasma membrane to homeostasis. Class Mammalia (breast): Bats, cats, whales, horses, humans. Phospholipids and sphingolipids are connected by the head group choline, found on both PC and sphingomyelin (SM). Houang EM, Haman KJ, Filareto A, Perlingeiro RC, Bates FS, Lowe DA, & Metzger JM (2015). The calcium influx of a membrane injury activates vesicular exocytosis and homo- and heterotypic fusion of cytoplasmic vesicles. Moissoglu K, Kiessling V, Wan C, Hoffman BD, Norambuena A, Tamm LK, & Schwartz MA (2014). 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). How does the cell membrane self heal? 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. For example, a scallop prevents structural failure from fracture because its shell is comprised of two materials of varying stiffness. The radiation could damage the cell's DNA, but the DNA repairs itself. Clipboard, Search History, and several other advanced features are temporarily unavailable. For example, caveolae are the site for assembling membrane repair proteins such as EHD2 and MG53 (Cai et al., 2009; Daumke et al., 2007; Marg et al., 2012). 2022 May 15;23(10):5525. doi: 10.3390/ijms23105525. Spaeth C, Fan J, Spaeth E, Robison T, Wilcott R, & Bittner G (2012). 2018 Apr 23;28(8):R392-R397. 2023 Apr 4;122(7):1355-1363. doi: 10.1016/j.bpj.2023.03.001. (2017). 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. Newer pharmacological approaches for antioxidant neuroprotection in traumatic brain injury. Acid sphingomyelinase activity triggers microparticle release from glial cells. Cai C, Masumiya H, Weisleder N, Matsuda N, Nishi M, Hwang M, Zhao X. In addition to working on their own, lipids also interact with proteins to coordinate these processes. Int J Mol Sci. Careers. 8600 Rockville Pike A single cell is often a complete organism in itself, such as a bacterium or yeast. Membrane injury causes a local influx of calcium and activation of calpains. Houang EM, Sham YY, Bates FS, & Metzger JM (2018). Shao S, Liao X, Xie F, Deng S, Liu X, Ristaniemi T, & Liu B (2018). 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). 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). Interphase has three stages: G1, S and G2. This Goldilocks principle applies to several aspects of lipid involvement in the repair process. 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). What's found inside a cell. Translocation of existing lipid species to the site of injury provides a mechanism to recruit and activate protein machinery. Influx of calcium, increase in oxidation, and change in tension on the plasma membrane due to injury all trigger changes in lipid structure and behavior to initiate signaling.
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