Schematic representation of the structural features of the protein families implicated in membrane repair. Just like cells have membranes to hold everything in, these mini-organs are also bound in a double layer of phospholipids to insulate their little compartments within the larger cells. Calcium-activated exocytosis reduces membrane tension and promotes spontaneous repair driven by lipid disorder for injuries hundreds of nanometers in diameter. 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. Skalman LN, Holst MR, Larsson E, & Lundmark R (2018). 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. 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). Verweij FJ, Revenu C, Arras G, Dingli F, Loew D, Pegtel DM, Zimmermann P (2019). The site is secure. This homeostatic process of vesicle fusion that maintains the plasma membrane at rest also enables plasma membrane repair through regulated fusion of vesicles triggered by calcium influx following plasma membrane injury (Horn & Jaiswal, 2018; McNeil & Steinhardt, 2003). However, ceramide formation also changes membrane dynamics by forming rigid microdomains and potentially by displacing cholesterol from lipid rafts (London, 2004). The site is secure. Learn whats new on AskNature by signing up for our e-newsletter. Blood cells called platelets release clotting factors to stop the bleeding; white blood cells rid the area of foreign materials and release molecules to coordinate healing; cells called fibroblasts start rebuilding using proteins called collagen; new blood vessels form; and skin cells called keratinocytes create the newsurface. The role of lipids during plasma membrane repair goes far beyond a passive role in vesicle-mediated delivery of membrane lipids. Why does our body heal itself? Annexins are a class of calcium-sensitive proteins that rapidly accumulate at the site of a membrane injury (Potez et al., 2011). Lipids contribute to cellular physiology at both an individual and population level. Muscle fibers are subject to huge variations in membrane tension, due to their contractile activity. 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. 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. Trends Cell Biol. 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). EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription. 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). 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. This occurs primarily through the direct interaction of PIP2 with actin-binding proteins, and change in PIP2 distribution has been shown to precede actin build-up at the plasma membrane (Nebl, Oh, & Luna, 2000; Senju & Lappalainen, 2019; Tran, Masedunskas, Weigert, & Ten Hagen, 2015). This is in part achieved through the activity of lipid modifying enzymes, such as kinases, phosphatases, and phospholipases. While no defined roles for PA after membrane injury are known, PA has been observed to rapidly appear at the wound edge (Vaughan et al., 2014), which fits with the fast (650 s) timescale of PA generation by PLD (Petersen et al., 2016). This cytoskeletal assembly is regulated by Rho GTPase activity, which triggers F-actin accumulation at the site of injury. Arp2/3-mediated F-actin formation controls regulated exocytosis in vivo. Sphingosine 1-phosphate stimulates proliferation and migration of satellite cells: role of S1P receptors, Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. SM utilizes the ceramide (Cer) backbone and can be used to generate the signaling lipid sphingosine-1-phosphate (S1P). Abstract. One dead cell is not a big problem. PMC 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. Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis, Lipid peroxidation induces cholesterol domain formation in model membranes. Zhu H, Lin P. h., De G, Choi K. h., Takeshima H, Weisleder N, & Ma J (2012). Phospholipid signalling through phospholipase D and phosphatidic acid. GTPases are molecular switches that require the cycling of nucleotides to remain active. Very large plasma membrane disruptions (micron diameter) require membrane patching. The basement membrane of the basal cells attaches via hemidesmosomes to the underlying Bowman's layer, while anchoring fibrils pass through . Collectively, these changes enable lipids to initiate/regulate local signaling allowing precise spatial and temporal control over downstream plasma membrane repair pathways. In either case, the outward budding of the membrane produced by these ceramide-rich microdomains is thought to assist in microvesicle shedding. This suggests the possibility that caveolae could act as mechanosensors that facilitate adaptation to membrane injury through gene transcription, although this remains to be explored. For example, a scallop prevents structural failure from fracture because its shell is comprised of two materials of varying stiffness. 2023 Feb 28;24(5):4647. doi: 10.3390/ijms24054647. Membrane-stabilizing copolymers confer marked protection to dystrophic skeletal muscle in vivo, Molecular Therapy-Methods & Clinical Development. Plasma membrane lipids help with successful repair by being part of the affected entity that also works to sense membrane injury, providing spatial and temporal cues to trigger signaling for downstream repair pathways, and ultimately being the benefactor of the successful wound repair response. Bennett APS, de la Torre-Escudero E, Dermott SSE, Threadgold LT, Hanna REB, Robinson MW. Examples of self-repairing cells. These examples illustrate the far-reaching consequence of lipid movement on structural stability of the plasma membrane and its ability to successfully repair. Membrane proteins also help locally shape and provide rigidity to the plasma membrane by interacting with specific lipids or lipid domains (Cebecauer et al., 2018). An actin-dependent annexin complex mediates plasma membrane repair in muscle. 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. Houang EM, Sham YY, Bates FS, & Metzger JM (2018). (B) The plasma membrane is not a homogenous mixture of proteins and lipids (as in A). The wounded cell can survive if a rapid repair respons Membrane Repair: Mechanisms and Pathophysiology Early observations of cells undergoing plasma membrane repair identified that membrane bound vesicles are involved in the process of membrane resealing (Bi, Alderton, & Steinhardt, 1995). Sezgin E, Levental I, Mayor S, & Eggeling C (2017). There are mechanisms that allow some products to enter or leave the cell either actively or passively. MG53 nucleates assembly of cell membrane repair machinery. 2015 Sep;45:2-9. doi: 10.1016/j.semcdb.2015.09.023. Would you like email updates of new search results? Interphase has three stages: G1, S and G2. Mechanistic principles underlying regulation of the actin cytoskeleton by phosphoinositides, Regulation of actin dynamics by PI (4, 5) P2 in cell migration and endocytosis, Pro-resolving lipid mediators are leads for resolution physiology. All of the above mechanisms for regulating the physical properties of the membrane play important roles in determining how a cell responds to plasma membrane injury and undergoes successful repair. The basement membrane plays an important role in cellular functions, including those involved in healing, by controlling the binding of growth factors and their local concentrations between cell layers. 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. 1Childrens National Health System, Center for Genetic Medicine Research, 111 Michigan Avenue NW, Washington, DC 20010-2970 USA, 2Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC USA. 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. 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). These observations on PIP2 kinetics line up remarkably well with the accumulation of F-actin at the injury site, which begins around 30 seconds after injury and extends for several minutes (Godin, Vergen, Prakash, Pagano, & Hubmayr, 2011; Horn et al., 2017). During the repair of sarcolemmal lesions, macrophages recognize exposed phosphatidylserine at the site of .
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