Another critical shared feature is a set of highly-specialized teeth. Cell death occurs mainly by two methods: necrosis and apoptosis. However, these repair activities can also be observed at the single-cell level. Zuzek A, Fan JD, Spaeth CS, & Bittner GD (2013). 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. Multiplexed molecular descriptors of pressure ulcers defined by imaging mass spectrometry, Targeting and localized signalling by small GTPases. Evidence suggests these pores are removed both by endosomal degradative pathways (123, 164, 280) and exosomal shedding (14, 118, 136). This helps to remodel the newly repaired plasma membrane (Middel et al., 2016), but may also serve to potentiate tissue inflammation. Scar/WAVE has Rac GTPase-independent functions during cell wound repair. Below we describe the biochemical signaling role of lipids in facilitating plasma membrane repair. Analysis of Dysferlin Direct Interactions with Putative Repair Proteins Links Apoptotic Signaling to Ca. 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. Thus, local lipid peroxidation may provide transient membrane stabilization, while mechanisms such as redox-dependent MG53 binding may limit the spread of lipid peroxides. Despite the many different types of tissue, there is a common repair program involved in tissue repair. Disruption of the cell plasma membrane is a commonplace occurrence in many mechanically challenging, biological environments. Plasma membrane lipids and proteins interact with the extracellular matrix (ECM) and the cortical actin network, both of which provide sources of tension that support the structure of the membrane. Bacterial pore-forming toxins oligomerize and insert in the plasma membrane of target cells forming a diffusible pore. Their localization and function in response to injury is controlled by the patterning of anionic lipids such as PS, which is present at the wound edge and is a known binding partner of annexins (Gerke, Creutz, & Moss, 2005). A decrease in membrane tension precedes successful cell-membrane 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. In mammalian cells, lipids formed upon the phosphate and glycerol (e.g. How does the cell membrane self heal? diacylglycerol - DAG) backbone are called glycerophospholipids (referred to as phospholipids hereafter) and make up the majority of the plasma membrane. "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. Bi G-Q, Alderton JM, & Steinhardt RA (1995). Muscle membrane integrity in Duchenne muscular dystrophy: recent advances in copolymer-based muscle membrane stabilizers. It has since become evident that in addition to resealing, remodeling of the plasma membrane through vesicle fusion (exocytosis), vesicle internalization (endocytosis), and shedding (ectocytosis) also contribute to the repair process (reviewed in (Horn & Jaiswal, 2018)). Lateral movement, rotation, and flipping of lipids between the leaflets of the plasma membrane are the physical changes that work together to allow the fluid membrane to adapt to the changes in membrane tension (Nicolson, 2014) (Figure 2C). (2009). Rather than these roles being separated from each other, they overlap significantly such that one can easily be an extension of the other. Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Clementi E. (2009). Therefore, injury-triggered protein-lipid interactions that result in modified lipids generates signaling that allows for changes in activity and localization of plasma membrane repair machinery. The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. In this review, we will focus on the role of lipids during plasma membrane repair by discussing their functions as both structural and signaling molecules. Vaughan EM, You J-S, Yu H-YE, Lasek A, Vitale N, Hornberger TA, & Bement WM (2014). Epub 2023 Mar 3. 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). 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. Stem cell medicine brings a new paradigm to modern medicine which has relied heavily on medicine or surgery. the contents by NLM or the National Institutes of Health. Dysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair. Lipids also react to the changing biochemical environment to become signaling molecules that determine the spatiotemporal dynamics of protein activation (Eyster, 2007) (Figure 1B). Live tracking of inter-organ communication by endogenous exosomes in vivo. This is especially important for membrane signaling functions as the liquid-ordered domains often serve to aggregate membrane-associated proteins (Cebecauer et al., 2018). Slabodnick M, Prevo B, Gross P, Sheung J, Marshall W. J Vis Exp. Transient change in lipid mobility can have many effects on plasma membrane function related to both structure and signaling, and deciphering which of these are beneficial for repair requires further studies. For example, the cytoskeletal proteins interact with membrane lipids to supply the cortical tension that regulates the global shape of the plasma membrane and produces cell movement (Cebecauer et al., 2018; Sezgin et al., 2017). Houang EM, Haman KJ, Filareto A, Perlingeiro RC, Bates FS, Lowe DA, & Metzger JM (2015). Cells are the basic building blocks of all living systems, so cellular processes dictate how physiological processes occur within those systems. Labazi M, McNeil AK, Kurtz T, Lee TC, Pegg RB, Angeli JPF, McNeil PL (2015). These lipids also exist at the boundary of lipid-ordered domains, such as lipid rafts, indicating that GTPases are targeted to these regions where protein accumulation at the membrane is common (Moissoglu et al., 2014), increasing their relative signaling capacity. 2008 Nov;18(11):552-9. doi: 10.1016/j.tcb.2008.09.001. When cells have DNA damage but fail to undergo apoptosis, they may be on the road to cancer. Use the force: membrane tension as an organizer of cell shape and motility. doi: 10.3791/50848. Phospholipids in particular show inter-leaflet heterogeneity. Cong X, Hubmayr RD, Li C, & Zhao X (2017). Temporary increase in plasma membrane tension coordinates the activation of exocytosis and contraction during cell spreading. Plasma Membrane (Cell Membrane) - Genome.gov Physico-chemical and biological considerations for membrane wound evolution and repair in animal cells. Structural and signaling role of lipids in plasma membrane repair 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). Lee I-H, Kai H, Carlson L-A, Groves JT, & Hurley JH (2015). (2017). Heier CR, Damsker JM, Yu Q, Dillingham BC, Huynh T, Van der Meulen JH, Scheffer L. (2013). Stem cell therapy in pain medicine - PMC - National Center for These domains decrease the local fluidity in the membrane relative to the regions comprised primarily of phospholipids. 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). It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. Sinha B, Kster D, Ruez R, Gonnord P, Bastiani M, Abankwa D, Johannes L (2011). As a library, NLM provides access to scientific literature. doi: 10.7554/eLife.80778. Palmitate-mediated disruption of the endoplasmic reticulum decreases intracellular vesicle motility. Lenhart KC, ONeill TJ, Cheng Z, Dee R, Demonbreun AR, Li J, Taylor JM (2015). Definition. Jimenez AJ, Maiuri P, Lafaurie-Janvore J, Divoux S, Piel M, & Perez F (2014). 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). All RightsReserved. Elife. 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. Viral infection controlled by a calcium-dependent lipid-binding module in ALIX. Proc Natl Acad Sci U S A. When a cell's DNA is damaged, it will typically detect the damage and try to repair it. 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. These examples illustrate the far-reaching consequence of lipid movement on structural stability of the plasma membrane and its ability to successfully repair. 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). 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). Similar to PLC, phospholipase D (PLD) activity is also increased after injury and is required for repair (Arun et al., 2013). In addition to working on their own, lipids also interact with proteins to coordinate these processes. Int J Mol Sci. The common eastern firefly produces light through a chemical reaction that energizes a molecule so it can release aphoton. Bookshelf Water is essential to life. 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. 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. Howard AC, McNeil AK, & McNeil PL (2011). Riazifar M, Pone EJ, Ltvall J, & Zhao W (2017). Use of lipidomics during epidermal wound repair identified that several of the plasma membrane lipids discussed above are enriched during wound repair. The variety of possible phospholipid interconversions, such as these, allows the cell to rapidly change the lipid composition of the plasma membrane. To do so, they must control the movement of liquids across their boundaries. Careers. 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. 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. As structural components of the plasma membrane, lipids are responsible for contributing to membrane tension, rigidity, and overall shape. Unlike phospholipids and sphingolipids, which are structurally analogous, cholesterol is composed of a steroid backbone that results in a planar and more rigid molecule. Tools. Federal government websites often end in .gov or .mil. One dead cell is not a big problem. The plasma membrane separates the extracellular environment from the cell interior, where biochemical reactions necessary for life occur. These roles of lipids in plasma membrane repair include both a structural role and a signaling role. 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. Calise S, Blescia S, Cencetti F, Bernacchioni C, Donati C, & Bruni P (2012). Necrosis is a progressive failure of essential metabolic and structural cell components usually in the cytoplasm. Unauthorized use of these marks is strictly prohibited. PI5K activity is itself driven by regulators of membrane repair including Rho GTPases (Gilmore & Burridge, 1996) and PLD (Roach et al., 2012). Similar inter-leaflet heterogeneity exists among sphingolipids, with the glycosphingolipids maintained exclusively in the outer leaflet. During the G1 stage, the cell prepares for division by increasing its mass. PTRF Anchors MG53 to Cell Injury Site for Initiation of Membrane Repair. 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. Acid sphingomyelinase activity triggers microparticle release from glial cells. What feature of a cell membrane allows it to repair itself quickly? During the S stage, the cell . Sealing of transected neurites of rat B104 cells requires a diacylglycerol PKC-dependent pathway and a PKA-dependent pathway, Sezgin, Levental, Mayor, & Eggeling, 2017, Gauthier, Fardin, Roca-Cusachs, & Sheetz, 2011, Miyake, McNeil, Suzuki, Tsunoda, & Sugai, 2001, Skalman, Holst, Larsson, & Lundmark, 2018, Gazzerro, Sotgia, Bruno, Lisanti, & Minetti, 2010, Petersen, Chung, Nayebosadri, & Hansen, 2016, Lee, Kai, Carlson, Groves, & Hurley, 2015, Campelo, Fabrikant, McMahon, & Kozlov, 2010, Lamb, Harper, McKinney, Rzigalinski, & Ellis, 1997, Ligeti, Dagher, Hernandez, Koleske, & Settleman, 2004, Tran, Masedunskas, Weigert, & Ten Hagen, 2015, Godin, Vergen, Prakash, Pagano, & Hubmayr, 2011, Gurtner, Werner, Barrandon, & Longaker, 2008, Taverna, Nanney, Pollins, Sindona, & Caprioli, 2011, Nojima, Freeman, Gulbins, & Lentsch, 2015. The mystery of membrane organization: composition, regulation and roles of lipid rafts. Cambridge (MA): Harvard Stem Cell Institute; 2008. Lipid domaindependent regulation of single-cell wound repair, Rho family GTPases bring a familiar ring to cell wound repair. Ribosome damage: Damage to ribosomal and cellular proteins such as protein misfolding, Leading to apoptotic enzyme activation. This is in part achieved through the activity of lipid modifying enzymes, such as kinases, phosphatases, and phospholipases. 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. The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. For example, when inserted into a region abundant in phospholipids, cholesterol has a rigidifying effect; however, the opposite can be true with sphingolipids. Careers, Unable to load your collection due to an error. Zhang KS, Blauch LR, Huang W, Marshall WF, Tang SKY. This is due to their lack of integration into the membrane under normal lipid packing conditions. Following this, accumulation of Annexin 4 and Annexin 6 results in folding and inward contraction of the injured membrane, respectively (Boye et al., 2017). 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. These phospholipids are derived from glycerol-3-phosphate, itself a product of cellular metabolism that is enzymatically modified into phosphatidic acid (PA). Inclusion in an NLM database does not imply endorsement of, or agreement with, How Phospholipids Help Hold a Cell Together - ThoughtCo 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. 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). Bethesda, MD 20894, Web Policies A cartoon depicting the potential role of dysferlin-mediated vesicle fusion in membrane repair. Int J Mol Sci. Defour A, Van der Meulen JH, Bhat R, Bigot A, Bashir R, Nagaraju K, & Jaiswal JK (2014). Charged phospholipids such as PIP2, PS, and PE are almost exclusively found on the inner leaflet, while the glycosphingolipids are only found on the outer leaflet. Caveolae internalization repairs wounded cells and muscle fibers, Regulation of endocytosis, exocytosis, and shape by membrane tension, Paper presented at the Cold Spring Harbor symposia on quantitative biology. Lysosome fusion is required for the process of repair (Reddy, Caler, & Andrews, 2001). Repair of muscle fibers lacking the dysferlin protein, which results in reduced membrane stability, is improved by the presence of extracellular (oxidized) MG53 protein, suggesting that this protein can act on the outer leaflet of the plasma membrane to improve plasma membrane in diseased cells. This process is itself facilitated by mechanisms that regulate membrane tension, in particular the re-establishment of the actin cortex. It remains possible that caveolar endocytosis does help partially balance membrane tension, but another possibility is that they serve as mechanosensitive platforms during membrane repair. Careers. 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. This can limit the expansion of the wound area itself. Phospholipid signalling through phospholipase D and phosphatidic acid. The primary plasma membrane sphingolipid in mammalian cells is sphingomyelin, which utilizes a ceramide backbone (Merrill Jr, 2008). Nojima H, Freeman CM, Gulbins E, & Lentsch AB (2015). The https:// ensures that you are connecting to the We use cookies to give you the best browsing experience. This dissociation has the effect of allowing Rho GTPase translocation to the membrane where it can interact with signaling lipids. Spiders turn liquid into a strong, stretchy fiber by squeezing it through a small space that helps protein molecules to connect with eachother. In: StemBook [Internet]. Plasma membrane repair in health and disease. Neurite transection produces cytosolic oxidation, which enhances plasmalemmal repair. Inositol is bound to the phosphate group in this phospholipid. The physical properties of the plasma membrane are governed in large part by the effect of lipid interactions at the population level. These structural changes to lipids are both necessary for repair and potentially pathogenic if left uncorrected (Sreetama et al., 2018). After an injury, the biophysical properties of the plasma membrane, and the individual lipids themselves, are altered, eliciting changes to membrane rigidity and fluidity. 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. The site is secure. Lipids contribute to cellular physiology at both an individual and population level. 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). sharing sensitive information, make sure youre on a federal Plasma membrane integrity in health and disease: significance and 2015 Sep;45:2-9. doi: 10.1016/j.semcdb.2015.09.023. During the repair of sarcolemmal lesions, macrophages recognize exposed phosphatidylserine at the site of . Accessibility Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. Spatiotemporal dynamics of actin remodeling and endomembrane trafficking in alveolar epithelial type I cell wound healing. 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 allows local and functional diversity between the two leaflets as well as various parts of the single contiguous plasma membrane (Figure 2B). While initial loss of cortical actin aids in repair by allowing physical access for vesicles to fuse with the plasma membrane, the accumulation of F-actin at the injury site in the minutes following injury, is also required to provide structural support to the repairing/repaired membrane and prevent additional injury due to membrane fragility (Demonbreun et al., 2016; Horn et al., 2017; Jaiswal et al., 2014; McDade, Archambeau, & Michele, 2014; Miyake et al., 2001). The antioxidant requirement for plasma membrane repair in skeletal muscle. Using these dating methods, it was inferred that fat cells (adipocytes) replace at a rate of 86% per year (BNID 103455). By studying how the Trypanosoma cruzi parasite enters the cell, Andrews' laboratory discovered that an increase of intracellular calcium was triggering lysosomal . 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. Thus, DAG acts as a scaffold that initiates and coordinates downstream signaling pathways within a tight spatial and temporal window rather than as a marker of membrane injury for fast-acting structural proteins. Further, the addition of new membrane by increased calcium-triggered exocytosis also decreases membrane tension and is required for plasma membrane repair (Togo et al., 2000). 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. 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. Plasma membrane lipids can be grouped into three classes glycerophospholipids, sphingolipids, and sterols. Muscle fibers have a complex plasma membrane network with a repeating register of deep plasma membrane invaginations called the t-tubule network. 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 vast majority of biochemical assembly and break down processeseven by the most complex organismsoccur within cells. 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. Similarly, peak PIP2 accumulation at the injury site occurred 45 seconds post-injury in Xenopus oocytes (Vaughan et al., 2014).
how does a cell membrane repair itself