In order to provide a cell with energy, these molecules have to pass across the cell membrane, which functions as a barrier but not an impassable one. The wounded cell can survive if a rapid repair response is mounted that restores boundary integrity. ESCRT assembly for membrane shedding is activated by the calcium-dependent ALG-2 protein, which then recruits its interacting partner ALIX leading to subsequent recruitment of the remaining complex members (Scheffer et al., 2014). While small injuries to the plasma membrane (on the nanometer scale) can be spontaneously resealed due to the line tension imposed by plasma membrane lipids alone (McNeil & Terasaki, 2001), larger membrane injuries (on the micron scale) require a series of coordinated mechanisms to undergo repair. Sezgin E, Levental I, Mayor S, & Eggeling C (2017). The precise role of EHD2 in membrane repair is not known, although it is known as a membrane shaping protein that may be involved in membrane fusion (Campelo, Fabrikant, McMahon, & Kozlov, 2010). This study showed that endocytosis occurs after membrane resealing and is mediated by the CLIC/GEEC pathway effector GRAF1, which is implicated in repair of muscle fiber plasma membrane injury (Lenhart et al., 2015). One such mechanism is addition of more membrane via vesicle fusion (Fig 1B ). Slabodnick M, Prevo B, Gross P, Sheung J, Marshall W. J Vis Exp. The common eastern firefly produces light through a chemical reaction that energizes a molecule so it can release aphoton. Plasma membrane lipids can be grouped into three classes glycerophospholipids, sphingolipids, and sterols. 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). Regulation of actin binding proteins by PIP2 occurs in part through electrostatic interactions (Senju et al., 2017), suggesting that clusters of PIP2 molecules may be necessary to achieve build-up of F-actin itself. These phospholipids are important for the formation of other molecules that are involved in cell signaling and help to bind proteins and carbohydrates to the outer cell membrane. Matsuo H, Chevallier J, Mayran N, Le Blanc I, Ferguson C, Faur J, Sadoul R (2004). The spatial arrangement of lipids at the plasma membrane is not only important for GTPase recruitment, but also for their activity. (2017). Cell damage. By studying how the Trypanosoma cruzi parasite enters the cell, Andrews' laboratory discovered that an increase of intracellular calcium was triggering lysosomal . 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. Mechanical feedback between membrane tension and dynamics. Schematic representation of the structural features of the protein families implicated in membrane repair. Accessibility government site. Visualizing cytoplasmic flow during single-cell wound healing in Stentor coeruleus. However, these repair activities can also be observed at the single-cell level. Spatial arrangement of lipids is also known to regulate Rho family GTPase activity (see Section 4.3). 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). Epub 2008 Mar 3. Caveolae protect endothelial cells from membrane rupture during increased cardiac output. Labazi M, McNeil AK, Kurtz T, Lee TC, Pegg RB, Angeli JPF, McNeil PL (2015). With an abundance of uncharged (zwitterionic) lipids and smaller amounts of neutral and anionic glycosphingolipids in the outer leaflet, and the negatively charged phosphatidylserine, phosphatidic acid and phosphatidylinositol within the inner leaflet, there exists a charge differential between the two plasma membrane leaflets (Steck & Lange, 2018; Zachowski, 1993). Living systems must maintain a proper liquid balance, which is especially difficult in dry conditions. 2023 Apr 4;122(7):1355-1363. doi: 10.1016/j.bpj.2023.03.001. 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. doi: 10.1016/j.cub.2017.12.034. Potez S, Luginbhl M, Monastyrskaya K, Hostettler A, Draeger A, & Babiychuk EB (2011). In: StemBook [Internet]. The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. 2022 Dec 14;10(12):3256. doi: 10.3390/biomedicines10123256. This form of membrane remodeling maintains lipid homeostasis and plasma membrane functionality. Skalman LN, Holst MR, Larsson E, & Lundmark R (2018). 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. Muscle fibers have a complex plasma membrane network with a repeating register of deep plasma membrane invaginations called the t-tubule network. 8600 Rockville Pike Spontaneous resealing of plasma membrane, Spontaneous resealing of plasma membrane injuries in the nanometer range is opposed by, Calcium-activated exocytosis reduces membrane tension, Calcium-activated exocytosis reduces membrane tension and promotes spontaneous repair driven by lipid disorder, Very large plasma membrane disruptions (micron diameter) require membrane patching. Bookshelf 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). PKC, in turn, influences a wide variety of downstream pathways known to facilitate repair including vesicle fusion, Rho GTPase patterning, as well as repair potentiation (Togo, 2004; Vaughan et al., 2014; Zuzek et al., 2013). Rapid actin-cytoskeletondependent recruitment of plasma membranederived dysferlin at wounds is critical for muscle membrane repair. PC), with a conical shaped, charged phospholipid (e.g. A decrease in membrane tension precedes successful cell-membrane repair. Epub 2012 Jul 9. Int J Mol Sci. The site is secure. While it is unclear whether caveolae can provide structural assistance to the damaged membrane in the context of a large membrane injury (as opposed to sub-injury threshold stress, (Sinha et al., 2011)), caveolae may still provide a signaling function during the repair process. Furthermore, ASM activity at the injury site would locally produce ceramide from sphingomyelin. Scheffer LL, Sreetama SC, Sharma N, Medikayala S, Brown KJ, Defour A, & Jaiswal JK (2014). 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). Interestingly, as a result of caveolae flattening, EHD2 dissociates from the plasma membrane and translocates to the nucleus where it alters gene transcription (Torrino et al., 2018). 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). GRAF1 deficiency blunts sarcolemmal injury repair and exacerbates cardiac and skeletal muscle pathology in dystrophin-deficient mice. 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). Before F-actin reorganization during repair is coordinated by the activity of lipids through their regulation of signaling proteins (reviewed in (Horn & Jaiswal, 2018)), as well as through direct interaction with actin-binding proteins such as F-actin bundling by the Annexin A2-S100 A11 complex (Jaiswal et al., 2014). 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. 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. 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. Cells as part of multicellular systems rarely act alone, instead having ways to signal to start and complete simple to quite complex interactions. HHS Vulnerability Disclosure, Help Eukaryotic cells have been shown to utilize calcium-activated exocytosis to reduce membrane tension and promote repair via lipid-disorder driven attractions. Plasma membrane damage needs to be rapidly repaired to avoid cell death. It also works extracellularly to improve repair of injured muscle and other cells (Gushchina et al., 2017; Weisleder et al., 2012). When . The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). These domains decrease the local fluidity in the membrane relative to the regions comprised primarily of phospholipids. 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. calcium, which when constantly increased, induces apoptosis. 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). Hall ED, Wang JA, Miller DM, Cebak JE, & Hill RL (2018). How does the cell membrane self heal? 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). Along with DAG, IP3 is also generated by the activity of PLC. Self-repair: Our bodies are packages within packages. In the subsequent sections, we will discuss how this is achieved and utilized by the cell. Unauthorized use of these marks is strictly prohibited. The https:// ensures that you are connecting to the Mitochondrial redox signaling enables repair of injured skeletal muscle cells. Proc Natl Acad Sci U S A. Sreetama SC, Chandra G, Van der Meulen JH, Ahmad MM, Suzuki P, Bhuvanendran S, Jaiswal JK (2018). As she describes, a lesion is followed by a Ca2+-dependent movement of vesicles to the plasma membrane. What might membrane injury to muscle fibers look like? Sarcolemmal repair is a slow process and includes EHD2, Effect of oxidative stress on membrane structure: small-angle X-ray diffraction analysis. Evidence suggests these pores are removed both by endosomal degradative pathways (123, 164, 280) and exosomal shedding (14, 118, 136). PTRF Anchors MG53 to Cell Injury Site for Initiation of Membrane Repair. Cell death occurs mainly by two methods: necrosis and apoptosis. This allows local and functional diversity between the two leaflets as well as various parts of the single contiguous plasma membrane (Figure 2B). Membrane stabilization by modified steroid offers a potential therapy for muscular dystrophy due to dysferlin deficit, Transverse distribution of plasma membrane bilayer cholesterol: Picking sides. While PC exists in both the inner and outer leaflet of the plasma membrane, the charged phospholipids PE, PI, and PS are almost exclusively maintained within the inner leaflet (Nicolson, 2014; van Meer, 1989). The basement membrane of the basal cells attaches via hemidesmosomes to the underlying Bowman's layer, while anchoring fibrils pass through . Shed microvesicles containing streptolysin-O have been shown to also contain annexins A1 and A6 (219). Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. See this image and copyright information in PMC. Careers. 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. However, these repair activities can also be observed at the single-cell level. These examples illustrate the far-reaching consequence of lipid movement on structural stability of the plasma membrane and its ability to successfully repair. EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription. SM utilizes the ceramide (Cer) backbone and can be used to generate the signaling lipid sphingosine-1-phosphate (S1P). Interphase has three stages: G1, S and G2. Interestingly, several methods for PIP2 micro-domain formation may allow for this to occur after plasma membrane injury. . Poloxamer 188 facilitates the repair of alveolus resident cells in ventilator-injured lungs, American journal of respiratory and critical care medicine. Failure of injured cells to repair results in cell death and activates a tissue repair response. Thus, electrostatic interaction with signaling lipids helps to facilitate GTPase localization, which is a critical feature that determines the efficiency and magnitude of the downstream response (Das et al., 2015; Yogurtcu & Johnson, 2018). Bethesda, MD 20894, Web Policies In response to increased stress on the plasma membrane, caveolae have been proposed to act as mechanosensors, buffering membrane tension in response to mechanical stress (Cheng et al., 2015; Sinha et al., 2011). BMC Biol. If you break a bone, your body immediately begins producing new cells to heal the damage. 2022 Aug 23;13(1):4950. doi: 10.1038/s41467-022-31277-5. 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. 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. Similar to the changes in tension described above, the fluidity of the plasma membrane is also dynamic after injury. Demonbreun AR, Quattrocelli M, Barefield DY, Allen MV, Swanson KE, & McNally EM (2016). One such mechanism for this may be mediated by the protein MG53. Dysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair. 2008 Mar 10;180(5):905-14. doi: 10.1083/jcb.200708010. Inflammatory exudates provide insights into the regulation of the first stage of wound repair inflammation. Lenhart KC, ONeill TJ, Cheng Z, Dee R, Demonbreun AR, Li J, Taylor JM (2015). Changing the head group attached to the DAG backbone creates different phospholipid species, which include phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), and PA (Oropeza, 2017) (Figure 1B). Simone LC, Caplan S, & Naslavsky N (2013). One model explaining membrane injury in dystrophin-deficient muscle fibers proposes that an initial injury causes a local influx of calcium and a local region of hypercontraction. This is in part achieved through the activity of lipid modifying enzymes, such as kinases, phosphatases, and phospholipases. 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). Liquids, mostly water, make up 70 to 90% of all living systems, and the loss of even a small percentage can mean the difference between life and death. During the repair of sarcolemmal lesions, macrophages recognize exposed phosphatidylserine at the site of . 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. Many of the sphingolipids also contain a glycosidically bound carbohydrate moiety causing formation of the glycosphingolipids. 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. Once membrane tension is restored, the poloxamer compound is forced out of the outer membrane leaflet (Houang, Sham, Bates, & Metzger, 2018). One signaling function of lipids is the recruitment of peripheral membrane proteins to the plasma membrane. Vaughan EM, You J-S, Yu H-YE, Lasek A, Vitale N, Hornberger TA, & Bement WM (2014). Membrane damage: Damage to the cell membrane disturbs the state of cell electrolytes, e.g. 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. Exocytic fusion reduces membrane tension, and vesicle-vesicle fusion events provide a patch as a replacement for the membrane barrier missing at the disruption site. Boye TL, Maeda K, Pezeshkian W, Snder SL, Haeger SC, Gerke V, Nylandsted J. Lysosome fusion is required for the process of repair (Reddy, Caler, & Andrews, 2001). Int J Mol Sci. In addition to their structural role, and often as an extension of it, lipids also provide a signaling function that facilitates plasma membrane repair. (C) Plasma membrane is dynamic and individual lipids have the capacity to move laterally within a leaflet (shown in pink) and between the leaflets (shown in blue). For example, PIP2 interacts with actin-associated proteins, resulting in a local strengthening of the plasma membrane-cytoskeleton interface. ASM activity at the plasma membrane has been shown to facilitate microvesicle shedding (Bianco et al., 2009). Despite the many different types of tissue, there is a common repair program involved in tissue repair. It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. Repair of injured cells is tied closely to tissue repair and regeneration, as shown by studies demonstrating release of inflammatory mediators, including small molecules, peptides and proteins that signal to cells in the inflammatory and regenerative systems to initiate a tissue level reparative response.
how does a cell membrane repair itself
