Mechanism of Ca²⁺-triggered ESCRT assembly and regulation of cell membrane repair

Nat Commun. 2014 Dec 23:5:5646. doi: 10.1038/ncomms6646.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Calcium / metabolism*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Membrane / enzymology
  • Cell Membrane / genetics
  • Cell Membrane / metabolism*
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Humans
  • Mice
  • Myoblasts / enzymology
  • Myoblasts / metabolism
  • Protein Multimerization
  • Vacuolar Proton-Translocating ATPases / genetics
  • Vacuolar Proton-Translocating ATPases / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Endosomal Sorting Complexes Required for Transport
  • PDCD6 protein, human
  • PDCD6IP protein, human
  • Adenosine Triphosphatases
  • Vacuolar Proton-Translocating ATPases
  • ATPases Associated with Diverse Cellular Activities
  • VPS4A protein, human
  • VPS4B protein, human
  • Calcium