Cell
Volume 169, Issue 2, 6 April 2017, Pages 286-300.e16
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Article
ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences

https://doi.org/10.1016/j.cell.2017.03.020Get rights and content
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Highlights

  • Phosphatidylserine is exposed prior to loss of cell integrity during necroptosis

  • ESCRT-III facilitates the shedding of MLKL-damaged plasma membrane from intact cells

  • ESCRT-III supports cell survival and functions downstream of active MLKL

  • ESCRT-III allows necroptotic cells to signal surrounding cells

Summary

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

annexin-V
phosphatidylserine
necroptosis
MLKL
ESCRT-III
plasma membrane repair

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