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Lysosomes are involved with various cell processes. In either case, the outward budding of the membrane produced by these ceramide-rich microdomains is thought to assist in microvesicle shedding. 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. 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). 2022 Aug 4;11:e80778. The most abundant component of the cells plasma membrane is the lipids. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. 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). 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). The wounded cell can survive if a rapid repair response is mounted that restores boundary integrity. A single cell is often a complete organism in itself, such as a bacterium or yeast. 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. 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. 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). It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. This process, facilitated by the dysferlin-mediated release of acid sphingomyelinase (Defour et al., 2014) creates microdomains of ceramide from sphingomyelin. The physical properties of the plasma membrane are governed in large part by the effect of lipid interactions at the population level. 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). EHD2 localization at caveolae results from its affinity for phosphatidylinositol 4,5-bisphosphate (PIP2), which is enriched around the caveolae boundary (Parton & Del Pozo, 2013; Simone, Caplan, & Naslavsky, 2013). Spaeth C, Fan J, Spaeth E, Robison T, Wilcott R, & Bittner G (2012). 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. The tension forces acting on the plasma membrane are generally applied by three sources: the difference in hydrostatic pressure between the cell interior and extracellular space, the cortical cytoskeletal network, and the extracellular matrix to which the cell is attached (Gauthier, Masters, & Sheetz, 2012; Kozlov & Chernomordik, 2015) (Figure 2B). While a common thread in lipid signaling is the modification of a target protein, either directly or indirectly, the numerous mechanisms lipids use to achieve this outcome allows for a great diversity of signaling. Another broad group of lipid carriers that are recognized for their role in activating stem cells are extracellular vesicles (EVs), which are released locally at the site of injury or from a distant site and through their lipid and other cargoes regulate regeneration of injured tissues by way of stem cell activation (Riazifar, Pone, Ltvall, & Zhao, 2017). 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. 'Resealing' is the emergency response required for cell . Calcium-activated exocytosis reduces membrane tension and promotes spontaneous repair driven by lipid disorder for injuries hundreds of nanometers in diameter. Local oxidation at the site of membrane injury activates MG53 oligomerization (Cai et al., 2009), which may locally increase membrane rigidity. diacylglycerol - DAG) backbone are called glycerophospholipids (referred to as phospholipids hereafter) and make up the majority of the plasma membrane. and transmitted securely. Zhu H, Lin P. h., De G, Choi K. h., Takeshima H, Weisleder N, & Ma J (2012). Lysosome fusion is required for the process of repair (Reddy, Caler, & Andrews, 2001). This structural arrangement is important for the organization of cholesterol in biological membranes as it results in the hydroxyl group associating with the neighboring lipid head groups and water, while the majority of the cholesterol molecule resides within the hydrophobic core of the membrane. Gushchina LV, Bhattacharya S, McElhanon KE, Choi JH, Manring H, Beck EX, Weisleder N. (2017). Please enable it to take advantage of the complete set of features! 2008 Dec 31. (2013). Further, PE and PC head groups can be cleaved and replaced with serine to produce PS (Oropeza, 2017). 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). This site needs JavaScript to work properly. 2015 Sep;45:2-9. doi: 10.1016/j.semcdb.2015.09.023. Lipids may serve as ligands for specific proteins, or act as a scaffold to bring cytosolic proteins to the plasma membrane. Of potential interest in this regard is the unconventional phospholipid lysobisphosphatidic acid (LBPA), which is found on endolysosomes. F-actin accumulation is also responsible for providing support to the newly resealed membrane, restoring tension, and preventing subsequent injury. Cebecauer M, Amaro M, Jurkiewicz P, Sarmento M. J. o., achl R, Cwiklik L, & Hof M (2018). Accessibility Thus, local lipid peroxidation may provide transient membrane stabilization, while mechanisms such as redox-dependent MG53 binding may limit the spread of lipid peroxides. 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. The spatial arrangement of lipids at the plasma membrane is not only important for GTPase recruitment, but also for their activity. Rapid actin-cytoskeletondependent recruitment of plasma membranederived dysferlin at wounds is critical for muscle membrane repair. Accessibility 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. Inherent plasticity and microfracture toughening mechanisms work together to prevent antlers from breaking. This allows for the movement and patterning of lipids into signaling domains, changing the spatial arrangement of proteins that selectively interact with a particular lipid species. Plasma membrane damage increases the fluidity of individual lipids, allowing them more freedom to migrate laterally, rotate, or even flip appearing in the opposite leaflet of the membrane. Int J Mol Sci. Leikina E, Defour A, Melikov K, Van der Meulen JH, Nagaraju K, Bhuvanendran S, Jaiswal JK (2015). Living systems do this using structures or waterproof materials to prevent or slow liquid movement. What feature of a cell membrane allows it to repair itself quickly? Similar inter-leaflet heterogeneity exists among sphingolipids, with the glycosphingolipids maintained exclusively in the outer leaflet. Sarcolemmal repair is a slow process and includes EHD2, Effect of oxidative stress on membrane structure: small-angle X-ray diffraction analysis. An official website of the United States government. BMC Biol. This is due to their lack of integration into the membrane under normal lipid packing conditions. Federal government websites often end in .gov or .mil. Survival from bacterial pore-forming toxins utilizes both exocytic and endocytic responses. As she describes, a lesion is followed by a Ca2+-dependent movement of vesicles to the plasma membrane. However, whether caveolae facilitate repair by buffering membrane tension remains unclear because, unlike the capacity of CLIC/GEEC endocytosis, caveolae make up a small portion (as small as 0.03%) of the membrane area and are not found ubiquitously in all cells (Gauthier et al., 2012; Sinha et al., 2011). Learn whats new on AskNature by signing up for our e-newsletter. See this image and copyright information in PMC. Definition. 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. Diz-Muoz A, Fletcher DA, & Weiner OD (2013). (D) The lipid make-up of the plasma membrane constantly changes. Accumulation of PS at the site of membrane injury allows it to act as a damage sensor, marking a key site for the recruitment of repair proteins such as annexins (Boye et al., 2017). 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. 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). Before Dr. Norma Andrews overviews the mechanisms of cellular plasma membrane repair. Very large plasma membrane disruptions (micron diameter) require membrane patching. The mystery of membrane organization: composition, regulation and roles of lipid rafts. Mechanistically, the process of membrane shedding is mediated by the endosomal sorting complexes required for transport (ESCRT) proteins (Jimenez et al., 2014; Scheffer et al., 2014). Plasma membrane wounding and repair in pulmonary diseases, American Journal of Physiology-Lung Cellular and Molecular Physiology, Membrane repair: mechanisms and pathophysiology. 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). "Self-repair: Our bodies are packages within packages. calcium, which when constantly increased, induces apoptosis. Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. Recombinant MG53 protein modulates therapeutic cell membrane repair in treatment of muscular dystrophy. Role of calcium-sensor proteins in cell membrane repair. The discussion above illustrates several roles for lipids in changing biophysical properties of the injured plasma membrane during repair. While PLC is able to cleave PC, the classic substrate of PLC is PIP2, which upon cleavage generates the membrane bound DAG and the cytosolic inositol trisphosphate (IP3) both of which are increased after injury (Lamb, Harper, McKinney, Rzigalinski, & Ellis, 1997; Vaughan et al., 2014). Live tracking of inter-organ communication by endogenous exosomes in vivo. The reduction in membrane tension is likely due directly to the addition of phospholipids to reduced lipid packing, as well as due in part to the cytoskeletal remodeling associated with vesicular transport at the plasma membrane. Following injury, lysosomes are known to fuse with the damaged membrane and may deposit LBPA at the site of injury, which would in turn facilitate ALIX-mediated vesicle shedding.