Mechanism of Ca(2+)-triggered ESCRT assembly and regulation of cell membrane repair

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 ESCRTIII 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 ESCRTIII-Vps4 complex following large focal injury to the cell membrane and identify the role of ALG-2 as the initiator of sequential ESCRTIII-Vps4 complex assembly that facilitates scission and repair of the injured cell membrane.