ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences

Cell. 2017 Apr 6;169(2):286-300.e16. doi: 10.1016/j.cell.2017.03.020.


The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. Here, we show that, during necroptosis, MLKL-dependent calcium (Ca2+) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM "bubbles" with exposed PS that are released from the surface of the otherwise intact cell. The ESCRT-III machinery is required for formation of these bubbles and acts to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT-III controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT-III, cells undergoing necroptosis can express chemokines and other regulatory molecules and promote antigenic cross-priming of CD8+ T cells.

Keywords: ESCRT-III; MLKL; annexin-V; necroptosis; phosphatidylserine; plasma membrane repair.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cell Membrane / metabolism*
  • Cell Survival
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • HT29 Cells
  • Humans
  • Jurkat Cells
  • Mice
  • NIH 3T3 Cells
  • Necrosis / metabolism*
  • Phosphatidylserines
  • Protein Kinases / metabolism
  • Signal Transduction


  • Endosomal Sorting Complexes Required for Transport
  • Phosphatidylserines
  • MLKL protein, human
  • MLKL protein, mouse
  • Protein Kinases
  • Calcium