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      Endoplasmic reticulum maintains ion homeostasis required for plasma membrane repair


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          Calcium entry into the injured cell activates their repair, but how cells cope with this excess calcium is not fully understood. Chandra et al. show that cells sequester this calcium in the ER, which is compromised in muscular dystrophy caused by the loss of an ER-resident calcium-activated chloride channel.


          Of the many crucial functions of the ER, homeostasis of physiological calcium increase is critical for signaling. Plasma membrane (PM) injury causes a pathological calcium influx. Here, we show that the ER helps clear this surge in cytoplasmic calcium through an ER-resident calcium pump, SERCA, and a calcium-activated ion channel, Anoctamin 5 (ANO5). SERCA imports calcium into the ER, and ANO5 supports this by maintaining electroneutrality of the ER lumen through anion import. Preventing either of these transporter activities causes cytosolic calcium overload and disrupts PM repair (PMR). ANO5 deficit in limb girdle muscular dystrophy 2L (LGMD2L) patient cells compromises their cytosolic and ER calcium homeostasis. By generating a mouse model of LGMD2L, we find that PM injury causes cytosolic calcium overload and compromises the ability of ANO5-deficient myofibers to repair. Addressing calcium overload in ANO5-deficient myofibers enables them to repair, supporting the requirement of the ER in calcium homeostasis in injured cells and facilitating PMR.

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          Most cited references53

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          Ca2+ indicators based on computationally redesigned calmodulin-peptide pairs.

          The binding interface of calmodulin and a calmodulin binding peptide were reengineered by computationally designing complementary bumps and holes. This redesign led to the development of sensitive and specific pairs of mutant proteins used to sense Ca(2+) in a second generation of genetically encoded Ca(2+) indicators (cameleons). These cameleons are no longer perturbed by large excesses of native calmodulin, and they display Ca(2+) sensitivities tuned over a 100-fold range (0.6-160 microM). Incorporation of circularly permuted Venus in place of Citrine results in a 3- to 5-fold increase in the dynamic range. These redesigned cameleons show significant improvements over previous versions in the ability to monitor Ca(2+) in the cytoplasm as well as distinct subcellular localizations, such as the plasma membrane of neurons and the mitochondria.
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            A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B.

            The limb-girdle muscular dystrophies are a genetically heterogeneous group of inherited progressive muscle disorders that affect mainly the proximal musculature, with evidence for at least three autosomal dominant and eight autosomal recessive loci. The latter mostly involve mutations in genes encoding components of the dystrophin-associated complex; another form is caused by mutations in the gene for the muscle-specific protease calpain 3. Using a positional cloning approach, we have identified the gene for a form of limb-girdle muscular dystrophy that we previously mapped to chromosome 2p13 (LGMD2B). This gene shows no homology to any known mammalian gene, but its predicted product is related to the C. elegans spermatogenesis factor fer-1. We have identified two homozygous frameshift mutations in this gene, resulting in muscular dystrophy of either proximal or distal onset in nine families. The proposed name 'dysferlin' combines the role of the gene in producing muscular dystrophy with its C. elegans homology.
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              Plasma membrane disruption: repair, prevention, adaptation.

              Many metazoan cells inhabit mechanically stressful environments and, consequently, their plasma membranes are frequently disrupted. Survival requires that the cell rapidly repair or reseal the disruption. Rapid resealing is an active and complex structural modification that employs endomembrane as its primary building block, and cytoskeletal and membrane fusion proteins as its catalysts. Endomembrane is delivered to the damaged plasma membrane through exocytosis, a ubiquitous Ca2+-triggered response to disruption. Tissue and cell level architecture prevent disruptions from occurring, either by shielding cells from damaging levels of force, or, when this is not possible, by promoting safe force transmission through the plasma membrane via protein-based cables and linkages. Prevention of disruption also can be a dynamic cell or tissue level adaptation triggered when a damaging level of mechanical stress is imposed. Disease results from failure of either the preventive or resealing mechanisms.

                Author and article information

                J Cell Biol
                J Cell Biol
                The Journal of Cell Biology
                Rockefeller University Press
                03 May 2021
                10 March 2021
                : 220
                : 5
                : e202006035
                [1 ]Center of Genetic Medicine Research, Children’s National Health System, Washington, DC
                [2 ]Généthon, Institut National de la Santé et de la Recherche Médicale, U951, INTEGRARE Research Unit, University Paris-Saclay, Evry, France
                [3 ]Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC
                Author notes
                Correspondence to Jyoti K. Jaiswal: jkjaiswal@ 123456cnmc.org
                Author information
                © 2021 Chandra et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                : 06 June 2020
                : 11 December 2020
                : 27 January 2021
                Page count
                Pages: 12
                Funded by: Association Française contre les Myopathies, DOI http://dx.doi.org/10.13039/100007393;
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases, DOI http://dx.doi.org/10.13039/100000069;
                Award ID: R01AR055686
                Funded by: National Institute of Child Health and Human Development, DOI http://dx.doi.org/10.13039/100000071;
                Award ID: U54HD090257
                Membrane and Lipid Biology

                Cell biology
                Cell biology


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