Annexin A1 deficiency does not affect myofiber repair but delays regeneration of injured muscles. Another critical shared feature is a set of highly-specialized teeth. Each of these lipids contributes their own qualities that affect the structural and signaling characteristics of the plasma membrane (Nicolson, 2014). MG53 nucleates assembly of cell membrane repair machinery. Rapid actin-cytoskeletondependent recruitment of plasma membranederived dysferlin at wounds is critical for muscle membrane repair. The plasma membrane is semi-permeable, allowing the cell to communicate with and utilize resources from its surrounding environment. 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). The spatial arrangement of lipids at the plasma membrane is not only important for GTPase recruitment, but also for their activity. 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). Epub 2017 Jun 26. It is unclear what role, if any, that IP3 may have in repair, but its role in calcium signaling and the fact that injured cells secrete IP3 for hours post-injury (Lamb et al., 1997) suggest a possible signaling role in repair that may extend beyond the process of membrane resealing, which needs further investigation. 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). The plasma membrane separates the extracellular environment from the cell interior, where biochemical reactions necessary for life occur. Accessibility Accumulation of GRAF1 at the repair site occurs 2 minutes after injury, supporting its potential role in membrane remodeling following resealing. Cell damage can be reversible or irreversible. Similar to the changes in tension described above, the fluidity of the plasma membrane is also dynamic after injury. Cell damage. This preferential association between different lipids results in an important feature of the plasma membrane its transverse and lateral heterogeneity. The antioxidant requirement for plasma membrane repair in skeletal muscle. 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). Phospholipids and sphingolipids are connected by the head group choline, found on both PC and sphingomyelin (SM). Gauthier NC, Fardin MA, Roca-Cusachs P, & Sheetz MP (2011). In the case of lipid mobility, this principle is exemplified by the observation that decreasing the excessive lipid mobility in LGMD2B patient cells using a membrane permeant modified glucocorticoid improves repair (Sreetama et al., 2018). 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). Importantly, sequestration of cholesterol alone increased PLD activity, supporting the idea that transient increase in lipid fluidity after membrane injury may be required for PLD-mediated signaling. 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. Mechanochemical feedback control of dynamin independent endocytosis modulates membrane tension in adherent cells, Long-term Potentiation of Wound-induced Exocytosis and Plasma Membrane Repair Is Dependant on cAMP-response Element-mediated Transcription via a Protein Kinase C-and p38 MAPK-dependent Pathway. 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. Muscle fibers are subject to huge variations in membrane tension, due to their contractile activity. Biophys J. Caveolae internalization repairs wounded cells and muscle fibers, Regulation of endocytosis, exocytosis, and shape by membrane tension, Paper presented at the Cold Spring Harbor symposia on quantitative biology. For example, when inserted into a region abundant in phospholipids, cholesterol has a rigidifying effect; however, the opposite can be true with sphingolipids. Healing of a punctured, The regeneration and reorganization of the oral apparatus (green) of, Wound healing studies in model cells such as. Stem cell extracellular vesicles: extended messages of regeneration, Annual review of pharmacology and toxicology. The .gov means its official. 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. (D) The lipid make-up of the plasma membrane constantly changes. Calcium-activated exocytosis reduces membrane tension and promotes spontaneous repair driven by lipid disorder for injuries hundreds of nanometers in diameter. From PA, cells generate DAG, or cytidine diphosphate-DAG (CDP-DAG), which serve as inputs into the phospholipid biosynthetic pathways (Figure 1A, ,B).B). Slabodnick M, Prevo B, Gross P, Sheung J, Marshall W. J Vis Exp. 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. In general, PIP2 is a positive regulator of F-actin polymerization and the presence of PIP2 increases the stability of the actin cytoskeletonplasma membrane interface. In the subsequent sections, we will discuss how this is achieved and utilized by the cell. Plasma membrane repair in health and disease. Microfluidic guillotine reveals multiple timescales and mechanical modes of wound response in Stentor coeruleus. The poor repair of these patient cells can be mirrored in healthy cells by increasing their membrane lipid mobility through the removal of cholesterol or by addition of a glucocorticoid (prednisone) (Heier et al., 2013; Sreetama et al., 2018). An official website of the United States government. sharing sensitive information, make sure youre on a federal Single-molecule tracking of small GTPase Rac1 uncovers spatial regulation of membrane translocation and mechanism for polarized signaling, Proceedings of the National Academy of Sciences. Negative membrane curvature catalyzes nucleation of endosomal sorting complex required for transport (ESCRT)-III assembly. These phospholipids are derived from glycerol-3-phosphate, itself a product of cellular metabolism that is enzymatically modified into phosphatidic acid (PA). The https:// ensures that you are connecting to the With their calcium and lipid affinities spanning a wide spectrum, annexins accumulate slightly differently from each other at the site of injury and perform different functions to facilitate repair of the wounded plasma membrane (see Section 4.1). Plasma membrane damage caused by listeriolysin O is not repaired through endocytosis of the membrane pore. Among these lipids, PC is the most abundant in the plasma membrane and is formed by adding choline to the DAG backbone. Verweij FJ, Revenu C, Arras G, Dingli F, Loew D, Pegtel DM, Zimmermann P (2019). Collectively, these changes enable lipids to initiate/regulate local signaling allowing precise spatial and temporal control over downstream plasma membrane repair pathways. PA is itself generated primarily from glycerol-3-phosphate, which is a product of glycolysis. Bouter A, Gounou C, Brat R, Tan S, Gallois B, Granier T, Brisson AR. Cambridge (MA): Harvard Stem Cell Institute; 2008. During the repair of sarcolemmal lesions, macrophages recognize exposed phosphatidylserine at the site of . Similar to PS, DAG directly binds proteins to provide its signaling function; however, because it is generated de novo after injury, an additional temporal component to signaling is achieved. PMC These examples illustrate the far-reaching consequence of lipid movement on structural stability of the plasma membrane and its ability to successfully repair. We have briefly discussed how such an integral role of lipids in plasma membrane repair also extends into tissue-level repair and restoration of organ function. Plasma membrane wounding and repair in pulmonary diseases, American Journal of Physiology-Lung Cellular and Molecular Physiology, Membrane repair: mechanisms and pathophysiology. PIP2 accumulation was observed as early as 4 seconds in mouse myofibers; however, it continued to accumulate even 1 minute post-injury suggesting a role in the later stages of repair (Demonbreun et al., 2016). These roles of lipids in plasma membrane repair include both a structural role and a signaling role. Remorino A, De Beco S, Cayrac F, Di Federico F, Cornilleau G, Gautreau A, Coppey M (2017). diacylglycerol - DAG) backbone are called glycerophospholipids (referred to as phospholipids hereafter) and make up the majority of the plasma membrane. sharing sensitive information, make sure youre on a federal 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. Inclusion in an NLM database does not imply endorsement of, or agreement with, 2017 Jul 11;114(28):7283-7288. doi: 10.1073/pnas.1705059114. Plasma membrane lipids and proteins interact with the extracellular matrix (ECM) and the cortical actin network, both of which provide sources of tension that support the structure of the membrane. FOIA Calcium can activate proteins directly, and ultimately is the initiator of many downstream repair pathways. Damage control: cellular mechanisms of plasma membrane repair. This process is itself facilitated by mechanisms that regulate membrane tension, in particular the re-establishment of the actin cortex. How does the cell membrane self heal? Sood P, Lin A, Yan C, McGillivary R, Diaz U, Makushok T, Nadkarni AV, Tang SKY, Marshall WF. 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). 2008 Mar 10;180(5):905-14. doi: 10.1083/jcb.200708010. These domains decrease the local fluidity in the membrane relative to the regions comprised primarily of phospholipids. Cells as part of multicellular systems rarely act alone, instead having ways to signal to start and complete simple to quite complex interactions. Int J Mol Sci. National Library of Medicine PMC Cell walls provide structural support for the cell. Muscle fibers have a, Schematic representation of the structural, Schematic representation of the structural features of the protein families implicated in membrane, A cartoon depicting the potential role of dysferlin-mediated vesicle fusion in membrane repair., MeSH GRAF1 deficiency blunts sarcolemmal injury repair and exacerbates cardiac and skeletal muscle pathology in dystrophin-deficient mice. Gazzerro E, Sotgia F, Bruno C, Lisanti MP, & Minetti C (2010). The publisher's final edited version of this article is available at, Lipids, plasma membrane, membrane injury, tissue repair. Senju Y, Kalimeri M, Koskela EV, Somerharju P, Zhao H, Vattulainen I, & Lappalainen P (2017). Mechanical feedback between membrane tension and dynamics. Cell membrane disruption initially stimulates repair responses in the wounded cell itself, as described in this chapter, but other cells can subsequently respond to membrane disruption to "help" repair the membrane of the injured cell. A lysosome is a membrane-bound cell organelle that contains digestive enzymes. The primary plasma membrane sphingolipid in mammalian cells is sphingomyelin, which utilizes a ceramide backbone (Merrill Jr, 2008). Constitutive fusion of biosynthetic vesicles is a major mechanism for delivery of new lipids and proteins, which helps to build and maintain the plasma membrane. These same processes also work to dynamically control membrane fluidity by regulating the distribution of phospholipids, sphingolipids, and cholesterol in the membrane. 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. 2018 Apr 23;28(8):R392-R397. 2022 Aug 4;11:e80778. These lipids also exist at the boundary of lipid-ordered domains, such as lipid rafts, indicating that GTPases are targeted to these regions where protein accumulation at the membrane is common (Moissoglu et al., 2014), increasing their relative signaling capacity. Bethesda, MD 20894, Web Policies FRET biosensor allows spatiotemporal observation of shear stress-induced polar RhoGDI activation. doi: 10.1016/j.cub.2017.12.034. PTRF Anchors MG53 to Cell Injury Site for Initiation of Membrane Repair. In this way, lipids play an important role in polarizing the cellular response to an injury. Caveolinopathies: from the biology of caveolin-3 to human diseases, Annexins: linking Ca 2+ signalling to membrane dynamics, Regulation of vinculin binding to talin and actin by phosphatidyl-inositol-45-bisphosphate. 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). Ligeti E, Dagher M-C, Hernandez SE, Koleske AJ, & Settleman J (2004). Vaughan EM, You J-S, Yu H-YE, Lasek A, Vitale N, Hornberger TA, & Bement WM (2014). government site. Viral infection controlled by a calcium-dependent lipid-binding module in ALIX. Patients with muscular dystrophy are more susceptible to injury from eccentric stretch (216), with studies in mouse models suggesting susceptibility to injury can escalate with multiple insults (53). 2021 Apr 2;19(1):63. doi: 10.1186/s12915-021-00970-0. To do so, they must control the movement of liquids across their boundaries. 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. Every cell has a fatty membrane that self-assembles when placed in water, then reassembles when a breach occurs. Arp2/3-mediated F-actin formation controls regulated exocytosis in vivo. 2022 Dec 14;10(12):3256. doi: 10.3390/biomedicines10123256. Jimenez AJ, Maiuri P, Lafaurie-Janvore J, Divoux S, Piel M, & Perez F (2014). Eukaryotic cells have been shown to utilize calcium-activated exocytosis to reduce membrane tension and promote repair via lipid-disorder driven attractions. Clipboard, Search History, and several other advanced features are temporarily unavailable. Cells (whether entire unicellular organisms or parts of multicellular living systems) grow, metabolize nutrients (that is, chemically transform them), produce proteins and enzymes, replicate, and move. Accessibility In mammalian cells, lipids formed upon the phosphate and glycerol (e.g. calcium, which when constantly increased, induces apoptosis. 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. Nojima H, Freeman CM, Gulbins E, & Lentsch AB (2015). However, to successfully repair the cell also needs to restore the barrier function of the resealed membrane. VBP15, a novel antiinflammatory and membranestabilizer, improves muscular dystrophy without side effects, Cellular mechanisms and signals that coordinate plasma membrane repair. Do Heo W, Inoue T, Park WS, Kim ML, Park BO, Wandless TJ, & Meyer T (2006). 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. Cell Calcium. The mystery of membrane organization: composition, regulation and roles of lipid rafts. Int J Mol Sci. 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. Cell death occurs mainly by two methods: necrosis and apoptosis. Plasma membrane lipids can be grouped into three classes glycerophospholipids, sphingolipids, and sterols. Plasma membrane damage needs to be rapidly repaired to avoid cell death. 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. This allows local and functional diversity between the two leaflets as well as various parts of the single contiguous plasma membrane (Figure 2B). The membrane phosphoinositides, and PIP2 in particular, play an important role in regulating the interaction of F-actin with the plasma membrane (Kapus & Janmey, 2013; Saarikangas, Zhao, & Lappalainen, 2010). 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. As dysferlin may only be detected at injury sites with antibodies recognizing COOH-terminal epitopes, and not several antibodies to NH. However, these repair activities can also be observed at the single-cell level. Quantification of membrane tension after injury to fibroblasts demonstrated that a minimum tension force was reached by approximately 30 seconds post-injury, but tension was fully restored by 80 seconds post-injury (Togo et al., 2000). If you break a bone, your body immediately begins producing new cells to heal the damage. 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. Regulation of the actin cytoskeleton-plasma membrane interplay by phosphoinositides. Mitochondrial fragmentation and ROS signaling in wound response and repair. Marmots maintain strong bones during hibernation by building up without breakingdown. GTPases are molecular switches that require the cycling of nucleotides to remain active. Instead, distinct inter- and intra-leaflet heterogeneity exists. This is due to their lack of integration into the membrane under normal lipid packing conditions. 2013 Dec 19;(82):e50848. (2009). 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). 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. 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. All RightsReserved. Modular, cascade-like transcriptional program of regeneration in, R01 GM113602/GM/NIGMS NIH HHS/United States. During the G1 stage, the cell prepares for division by increasing its mass. Epub 2023 Mar 3. doi: 10.3791/50848. Zhu H, Lin P. h., De G, Choi K. h., Takeshima H, Weisleder N, & Ma J (2012). Defour A, Van der Meulen JH, Bhat R, Bigot A, Bashir R, Nagaraju K, & Jaiswal JK (2014). As described above, damage to the plasma membrane transiently increases the mobility of individual lipids. Plasma membrane repair relies on the coordinated activity of repair machinery, which carries out vesicle fusion to the membrane, membrane shedding, and polymerization of F-actin at the site of repair (Horn & Jaiswal, 2018). These shortened sarcomeres induce a concomitant lengthening of adjacent sarcomeres and increased lateral strain to the plasma membrane. Scattered throughout the bloodstream are lens-shaped structures that serve to plug thewound. Structurally, the conical ceramide molecule results in negative membrane curvature associated with rapid nucleation of ESCRT complex proteins (Lee, Kai, Carlson, Groves, & Hurley, 2015). Recombinant MG53 protein modulates therapeutic cell membrane repair in treatment of muscular dystrophy. 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. 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. 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). Sphingomyelin also confers different properties to the plasma membrane than the phospholipids, not least due to its preferential association with sterols (Ramstedt & Slotte, 2006). What might membrane injury to muscle fibers look like? The fatty membranes of cells are capable of self-repair using a mechanism that involves calcium-dependent exocytosis. This mechanism is particularly intriguing in light of the redox-sensitive nature of MG53. Failure or delay in these processes, as in chronic inflammatory conditions and conditions of regenerative deficit would lead to aberrant tissue remodeling resulting in fibrotic or adipogenic replacement of the lost tissue. This is especially important for membrane signaling functions as the liquid-ordered domains often serve to aggregate membrane-associated proteins (Cebecauer et al., 2018). Shear stress on the plasma membrane also results in the dissociation of the negative regulator RhoGDI and its binding partner Rho (Shao et al., 2018). Pollet H, Conrard L, Cloos A-S, & Tyteca D (2018). Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding? Lipids may serve as ligands for specific proteins, or act as a scaffold to bring cytosolic proteins to the plasma membrane. 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). Membrane lipids: where they are and how they behave. This raises the intriguing possibility that MG53 may affect plasma membrane structural properties. 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 most abundant component of the cells plasma membrane is the lipids. PC), with a conical shaped, charged phospholipid (e.g. Petersen EN, Chung H-W, Nayebosadri A, & Hansen SB (2016). Boye TL, Maeda K, Pezeshkian W, Snder SL, Haeger SC, Gerke V, Nylandsted J. 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). ASM activity at the plasma membrane has been shown to facilitate microvesicle shedding (Bianco et al., 2009).

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