title: Mechanism of Ca²⁺-triggered ESCRT assembly and regulation of cell membrane repair.
abstract: In muscle and other mechanically active tissue, cell membranes are constantly injured, and their repair depends on the injury-induced increase in cytosolic calcium. Here, we show that injury-triggered Ca(2+) increase results in assembly of ESCRT III and accessory proteins at the site of repair. This process is initiated by the calcium-binding protein-apoptosis-linked gene (ALG)-2. ALG-2 facilitates accumulation of ALG-2-interacting protein X (ALIX), ESCRT III and Vps4 complex at the injured cell membrane, which in turn results in cleavage and shedding of the damaged part of the cell membrane. Lack of ALG-2, ALIX or Vps4B each prevents shedding, and repair of the injured cell membrane. These results demonstrate Ca(2+)-dependent accumulation of ESCRT III-Vps4 complex following large focal injury to the cell membrane and identify the role of ALG-2 as the initiator of sequential ESCRT III-Vps4 complex assembly that facilitates scission and repair of the injured cell membrane.
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research, 111 Michigan Avenue, NW, Washington DC 20010-2970, USA.
authors.forename: Luana L
authors.initials: LL
authors.lastname: Scheffer
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research, 111 Michigan Avenue, NW, Washington DC 20010-2970, USA.
authors.forename: Sen Chandra
authors.initials: SC
authors.lastname: Sreetama
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research, 111 Michigan Avenue, NW, Washington DC 20010-2970, USA.
authors.forename: Nimisha
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research, 111 Michigan Avenue, NW, Washington DC 20010-2970, USA.
authors.forename: Sushma
authors.initials: S
authors.lastname: Medikayala
authors.affiliation: 1] Children's National Medical Center, Center for Genetic Medicine Research, 111 Michigan Avenue, NW, Washington DC 20010-2970, USA [2] Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington DC, USA.
authors.forename: Kristy J
authors.initials: KJ
authors.lastname: Brown
authors.affiliation: Children's National Medical Center, Center for Genetic Medicine Research, 111 Michigan Avenue, NW, Washington DC 20010-2970, USA.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Defour
authors.affiliation: 1] Children's National Medical Center, Center for Genetic Medicine Research, 111 Michigan Avenue, NW, Washington DC 20010-2970, USA [2] Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington DC, USA.
authors.forename: Jyoti K
authors.initials: JK
authors.lastname: Jaiswal
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D032446:Myoblasts / Q000201:enzymology / Q000378:metabolism; D055503:Protein Multimerization; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C097753:PDCD6 protein, human; C117020:PDCD6IP protein, human; D000251:Adenosine Triphosphatases; D025262:Vacuolar Proton-Translocating ATPases; D000074183:ATPases Associated with Diverse Cellular Activities; C490305:VPS4A protein, human; C490304:VPS4B protein, human; D002118:Calcium