Furthermore, individual lipids may be modified by proteins, which generate new lipid species that can change membrane structural properties (red, Cer) or be used for signaling (purple, DAG). The plasma membrane is a dynamic barrier that separates the cell interior from the extracellular space (Figure 2C). 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. These functions also require modulating the membrane area, such as through the processes of exocytosis and endocytosis or by changing the existing membrane architecture (Kozlov & Chernomordik, 2015; Nassoy & Lamaze, 2012). Visualizing cytoplasmic flow during single-cell wound healing in Stentor coeruleus. How does the cell membrane self heal? Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis. Phosphatidylinositol is found in many cell types and tissues, but is particularly abundant in the brain. Houang EM, Haman KJ, Filareto A, Perlingeiro RC, Bates FS, Lowe DA, & Metzger JM (2015). Calise S, Blescia S, Cencetti F, Bernacchioni C, Donati C, & Bruni P (2012). Alkaloid molecules protect plants from bacterial infections. The most abundant component of the cells plasma membrane is the lipids. 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). Microfluidic guillotine for single-cell wound repair studies. Leikina E, Defour A, Melikov K, Van der Meulen JH, Nagaraju K, Bhuvanendran S, Jaiswal JK (2015). Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis, Lipid peroxidation induces cholesterol domain formation in model membranes. There are many differences between cancer cells and normal cells in noncancerous (benign) or cancerous (malignant) tumors. Copolymers such as poloxamer 188 avoid this potential issue by only stabilizing the plasma membrane once lipid packing density is sufficiently reduced, such as after an injury. This process is more efficient when GTPases and their regulatory proteins (which are themselves regulated by lipids) are clustered (Ligeti, Dagher, Hernandez, Koleske, & Settleman, 2004). Cells defend themselves from viruses, bacteria with armor of protein By clicking the Accept button you agree to the terms of our privacy policy. . The lipids in the membrane are fluid, and therefore in motion, and are constantly adapting to the changing environment. Activated calpains cleave dysferlin within a motif specifically encoded by alternately spliced exon 40a (230). However, to successfully repair the cell also needs to restore the barrier function of the resealed membrane. Schematic representation of the structural features of the protein families implicated in membrane repair. The plasma membrane has a unique lipid composition that helps distinguish its structural and functional properties from the other internal membrane-bound compartments. (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). Corrotte M, Almeida PE, Tam C, Castro-Gomes T, Fernandes MC, Millis BA, Maugel TK. 2023 Apr 4;122(7):1355-1363. doi: 10.1016/j.bpj.2023.03.001. This involves a series of distinct, but mutually dependent stages including inflammation, regeneration, and remodeling of the tissue (Gurtner, Werner, Barrandon, & Longaker, 2008). Direct lipid modification of proteins, such as GTPases, provides another method to regulate protein localization and activity (Casey, 1995). Bookshelf 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. In addition to PA, PG is another lipid product of PLD activity relevant to membrane repair, and its synthesis has been implicated in the process of membrane repair and repair of epithelial wounds (Arun et al., 2013; Piazza & Marmer, 2007). Verweij FJ, Revenu C, Arras G, Dingli F, Loew D, Pegtel DM, Zimmermann P (2019). 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). (2011). 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). This role of lipids extends further by way of regulating the response of proteins during the repair process as well as long-term gene expression-based adaptations required for the recovery of injured cells and tissues. Sood P, Lin A, Yan C, McGillivary R, Diaz U, Makushok T, Nadkarni AV, Tang SKY, Marshall WF. 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). From PA, cells generate DAG, or cytidine diphosphate-DAG (CDP-DAG), which serve as inputs into the phospholipid biosynthetic pathways (Figure 1A, ,B).B). 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). The site is secure. Individual lipids can serve as signaling molecules on their own or through binding proteins, and chemical changes to a single lipid can initiate change in local membrane composition. Bacterial pore-forming toxins oligomerize and insert in the plasma membrane of target cells forming a diffusible pore. Vaughan EM, You J-S, Yu H-YE, Lasek A, Vitale N, Hornberger TA, & Bement WM (2014). Mechanical feedback between membrane tension and dynamics. This phenomenon may be explained by the kinetic energy imparted on the membrane lipids by mechanical disruption, which can result in lipid mixing without relying on membrane tension (Petersen, Chung, Nayebosadri, & Hansen, 2016). 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. 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). 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. Int J Mol Sci. Thus, the signaling role of lipids affects membrane structure and how the wound is eventually resealed and remodeled, returning the plasma membrane to homeostasis. Compared with cytosolic antioxidants, which can be detrimental to repair (Spaeth et al., 2012), vitamin E is membrane-localized and could therefore allow for the local buildup of oxidized lipids at the site of injury while preventing the global spread of lipid oxidation. Petersen EN, Chung H-W, Nayebosadri A, & Hansen SB (2016). 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). 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). Cong X, Hubmayr RD, Li C, & Zhao X (2017). Development of cell therapy and regenerative medicine using stem cells is expanding the medical industry and businesses as well as increasing the understanding of the nature of the cell itself. Heier CR, Damsker JM, Yu Q, Dillingham BC, Huynh T, Van der Meulen JH, Scheffer L. (2013). Federal government websites often end in .gov or .mil. However, these repair activities can also be observed at the single-cell level. To achieve these tasks, cells employ signaling networks, which respond to the changing microenvironment after injury and activate the diverse plasma membrane repair mechanisms with precise control in time and space. The radiation could damage the cell's DNA, but the DNA repairs itself. Similarly, peak PIP2 accumulation at the injury site occurred 45 seconds post-injury in Xenopus oocytes (Vaughan et al., 2014). Before An actin-dependent annexin complex mediates plasma membrane repair in muscle. A surprise arrived when heart muscle cells were analyzed. Many of the sphingolipids also contain a glycosidically bound carbohydrate moiety causing formation of the glycosphingolipids. Many organisms and tissues display the ability to heal and regenerate as needed for normal physiology and as a result of pathogenesis. This is especially important in sensing membrane damage. Cebecauer M, Amaro M, Jurkiewicz P, Sarmento M. J. o., achl R, Cwiklik L, & Hof M (2018). Lethal Injury (Cell Death) In many situations, the damage to a cell may be so severe that the cell cannot survive. FOIA Sezgin E, Levental I, Mayor S, & Eggeling C (2017). Disclaimer. Coping with the inevitable: how cells repair a torn surface membrane This process is itself facilitated by mechanisms that regulate membrane tension, in particular the re-establishment of the actin cortex. Jimenez AJ, Maiuri P, Lafaurie-Janvore J, Divoux S, Piel M, & Perez F (2014). 2008 Dec 31. Sealing holes in cellular membranes | The EMBO Journal The antioxidant requirement for plasma membrane repair in skeletal muscle. Neurite transection produces cytosolic oxidation, which enhances plasmalemmal repair. Annexins are a class of calcium-sensitive proteins that rapidly accumulate at the site of a membrane injury (Potez et al., 2011). Nojima H, Freeman CM, Gulbins E, & Lentsch AB (2015). Johnson JL, Erickson JW, & Cerione RA (2012). Togo T, Krasieva TB, & Steinhardt RA (2000). In mammalian cells, lipids formed upon the phosphate and glycerol (e.g. 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. 2022 Dec 1;11(1):38. doi: 10.1186/s13619-022-00141-8. National Library of Medicine 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). Thus, local lipid peroxidation may provide transient membrane stabilization, while mechanisms such as redox-dependent MG53 binding may limit the spread of lipid peroxides. A decrease in membrane tension precedes successful cell-membrane repair. 8600 Rockville Pike 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. Biosci Rep. 2023 Feb 27;43(2):BSR20220765. Slabodnick M, Prevo B, Gross P, Sheung J, Marshall W. J Vis Exp. 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. The physical properties of the plasma membrane are governed in large part by the effect of lipid interactions at the population level. Epub 2012 Jul 9. This method of extracellular communication may allow for the proper execution of inflammatory and regenerative responses needed for appropriate tissue remodeling required to restore organ function.