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). Arp2/3-mediated F-actin formation controls regulated exocytosis in vivo. Dysferlin is not detected at injury sites until 10 s postinjury, a delay we attribute to an intermediary step involving calpain cleavage. Leikina E, Defour A, Melikov K, Van der Meulen JH, Nagaraju K, Bhuvanendran S, Jaiswal JK (2015). Role of phosphatidylinositol 4, 5-bisphosphate in regulating EHD2 plasma membrane localization. These examples illustrate the far-reaching consequence of lipid movement on structural stability of the plasma membrane and its ability to successfully repair. Gauthier NC, Fardin MA, Roca-Cusachs P, & Sheetz MP (2011). Scar/WAVE has Rac GTPase-independent functions during cell wound repair. All RightsReserved. 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). The goal of signaling during plasma membrane repair is to generate a polarized response such that the repair machinery can be spatially and temporally localized and activated at the repair site. The plasma membrane is semi-permeable, allowing the cell to communicate with and utilize resources from its surrounding environment. Proc Natl Acad Sci U S A. Remorino A, De Beco S, Cayrac F, Di Federico F, Cornilleau G, Gautreau A, Coppey M (2017). The spatial arrangement of lipids at the plasma membrane is not only important for GTPase recruitment, but also for their activity. Because membrane tension limits the ability of cellular membranes to self-seal, cellular mechanisms that reduce membrane tension can promote membrane sealing. 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. The discussion above illustrates several roles for lipids in changing biophysical properties of the injured plasma membrane during repair. The variety of possible phospholipid interconversions, such as these, allows the cell to rapidly change the lipid composition of the plasma membrane. Being the most abundant component of the plasma membrane, lipids are also essential player in the process of plasma membrane repair; however, much of the research committed to identifying the mechanisms of plasma membrane repair has focused on the proteins associated with plasma membrane repair (Cooper & McNeil, 2015). While intracellular MG53 is a redox-sensitive protein capable of facilitating vesicle aggregation, it is proposed to have multiple functions during membrane repair. Federal government websites often end in .gov or .mil. Coping with the inevitable: how cells repair a torn surface membrane Pollet H, Conrard L, Cloos A-S, & Tyteca D (2018). PS) in the inner leaflet, causes the plasma membrane to attain an overall outward curvature. Rapid Changes to Endomembrane System of Infected Root Nodule Cells to Adapt to Unusual Lifestyle. 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). 2022 May 15;23(10):5525. doi: 10.3390/ijms23105525. PC), with a conical shaped, charged phospholipid (e.g. (2009). Gurtner GC, Werner S, Barrandon Y, & Longaker MT (2008). Calcium can activate proteins directly, and ultimately is the initiator of many downstream repair pathways. Of potential interest in this regard is the unconventional phospholipid lysobisphosphatidic acid (LBPA), which is found on endolysosomes. Middel V, Zhou L, Takamiya M, Beil T, Shahid M, Roostalu U, Nienhaus GU (2016). In this review, we have discussed how lipids working at the individual as well as at the population level facilitate the proper orchestration of the repair response. government site. 2022 Aug 4;11:e80778. The common eastern firefly produces light through a chemical reaction that energizes a molecule so it can release aphoton. Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis. Poloxamer 188 facilitates the repair of alveolus resident cells in ventilator-injured lungs, American journal of respiratory and critical care medicine. We here review what is known about the cellular and molecular mechanisms of membrane repair, with particular emphasis on the relevance of repair as it relates to disease pathologies. Sezgin E, Levental I, Mayor S, & Eggeling C (2017). Inclusion in an NLM database does not imply endorsement of, or agreement with, FRET biosensor allows spatiotemporal observation of shear stress-induced polar RhoGDI activation. 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). They may be used to destroy invading viruses and bacteria. 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). This Goldilocks principle applies to several aspects of lipid involvement in the repair process. 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. Treatment with Recombinant Human MG53 Protein Increases Membrane Integrity in a Mouse Model of Limb Girdle Muscular Dystrophy 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. The plasma membrane has a unique lipid composition that helps distinguish its structural and functional properties from the other internal membrane-bound compartments. 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. A decrease in membrane tension precedes successful cell-membrane repair. Skalman LN, Holst MR, Larsson E, & Lundmark R (2018). In some cases, these forces are benign, such as membrane protrusion driven by cortical actin polymerization (Pontes, Monzo, & Gauthier, 2017). Spiders turn liquid into a strong, stretchy fiber by squeezing it through a small space that helps protein molecules to connect with eachother. Furthermore, ASM activity at the injury site would locally produce ceramide from sphingomyelin. Repair of injured plasma membrane by rapid Ca Modeling membrane shaping by proteins: Focus on EHD2 and NBAR domains. With larger injuries, the opposing force of membrane tension exceeds the resealing forces of lipid disorder at the edges of the disruption, negating the driving forces of spontaneous membrane resealing. This site needs JavaScript to work properly. Yet the membrane is also a formidable barrier, allowing some dissolved substances, or solutes, to pass while blocking others. Structurally, the conical ceramide molecule results in negative membrane curvature associated with rapid nucleation of ESCRT complex proteins (Lee, Kai, Carlson, Groves, & Hurley, 2015). 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. 2023 Apr 4;122(7):1355-1363. doi: 10.1016/j.bpj.2023.03.001. McDade JR, Archambeau A, & Michele DE (2014). Int J Mol Sci. FOIA 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). 2021 Apr 2;19(1):63. doi: 10.1186/s12915-021-00970-0. Idone V, Tam C, Goss JW, Toomre D, Pypaert M, Andrews NW. 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. Why Can Membranes Can Self Repair - BikeHike Self-repairing cells: How single cells heal membrane ruptures and restore lost structures Many organisms and tissues display the ability to heal and regenerate as needed for normal physiology and as a result of pathogenesis. 2017 Jul 11;114(28):7283-7288. doi: 10.1073/pnas.1705059114. Within a single leaflet, lateral heterogeneity is found in the form of lipid microdomains, such as the cholesterol and sphingolipid-rich domains that serve as signaling platforms to accumulate plasma membrane-associated proteins. Annexin A1 deficiency does not affect myofiber repair but delays regeneration of injured muscles. Following this, accumulation of Annexin 4 and Annexin 6 results in folding and inward contraction of the injured membrane, respectively (Boye et al., 2017). Plasma membrane integrity in health and disease: significance and This raises the intriguing possibility that MG53 may affect plasma membrane structural properties. What happens when cell membrane is damaged? - Studybuff Water is essential to life. Subsequent insult(s) of eccentric stretch result in a more severe wound and global hypercontraction, producing fiber retraction within the muscle bundle (53). (2013). Dr. Norma Andrews overviews the mechanisms of cellular plasma membrane repair. 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. Van Meer G, Voelker DR, & Feigenson GW (2008). Lipid domaindependent regulation of single-cell wound repair, Rho family GTPases bring a familiar ring to cell wound repair. Cholesterol and various proteins are also embedded within the . National Library of Medicine This is called apoptosis. A different model for plasma membrane repair began to emerge when mammalian cells injured mechanically or by SLO pores were found to undergo massive endocytosis, after Ca 2+ -triggered exocytosis of lysosomes ( Figure 1 C). These mediators promote wound resolution by acting upon the immune and endothelial cells and help to control the duration and nature of the immune and phagocytic cell infiltration at the injury site (Serhan, 2014). 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. The wounded cell can survive if a rapid repair response is mounted that restores boundary integrity. Mechanical feedback between membrane tension and dynamics. Membrane repair is a conserved physiologic process in multiple tissues Organ Type of mechanical force Principal cells stressed Cell wounding Self-repairing cells: How single cells heal membrane ruptures and Muscle fibers are subject to huge variations in membrane tension, due to their contractile activity. By studying how the Trypanosoma cruzi parasite enters the cell, Andrews' laboratory discovered that an increase of intracellular calcium was triggering lysosomal . Class Mammalia (breast): Bats, cats, whales, horses, humans. Given their ability to traverse away from the site of synthesis (Verweij et al., 2019), the EVs generated during plasma membrane injury may activate both local and distant tissue regeneration responses needed for repair. Before Caveolae protect endothelial cells from membrane rupture during increased cardiac output. 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. This relies upon the coordinated action of the machinery that polarizes the repair response to the site of injury, resulting in resealing of the damaged membrane and subsequent remodeling to return the injured plasma membrane to its pre-injury state. An official website of the United States government. 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). Use of lipidomics during epidermal wound repair identified that several of the plasma membrane lipids discussed above are enriched during wound repair. Eukaryotic cells have been shown to utilize calcium-activated exocytosis to reduce membrane tension and promote repair via lipid-disorder driven attractions. FOIA Additionally, in contrast to PS, which recruits proteins directly involved in repair, DAG appears to recruit signaling proteins such as protein kinase C (PKC) (Vaughan et al., 2014; Zuzek, Fan, Spaeth, & Bittner, 2013). Similar to PLC, phospholipase D (PLD) activity is also increased after injury and is required for repair (Arun et al., 2013). BMC Biol. 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. Cell before mitosis showing the location of the centrioles, microtubules, nuclear membrane, nucleolus, and DNA (Let's Talk Science using an image by Aldona via iStockphoto). Limiting the spread of lipid hydroperoxides may also explain the beneficial effect of vitamin E treatment on plasma membrane repair (Howard, McNeil, & McNeil, 2011; Labazi et al., 2015). These enzymes initiate signaling through the generation of new lipid species, providing an added spatial, as well as a temporal component to lipid signaling, helping to more precisely coordinate the repair response. "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.