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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
08:55

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

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

Yi-Nan Gong1, Cliff Guy1, Hannes Olauson2

  • 1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Cell
|April 8, 2017
PubMed

Insights

Receptor-interacting protein kinase-3 (RIPK3) activates mixed lineage kinase-like (MLKL), causing cell membrane disruption during necroptosis. The ESCRT-III machinery manages plasma membrane integrity and promotes CD8+ T cell responses.

Area of Science:

  • Cellular biology
  • Immunology
  • Biochemistry

Background:

  • Receptor-interacting protein kinase-3 (RIPK3) activates mixed lineage kinase-like (MLKL), leading to necroptosis, a form of regulated necrosis.
  • Necroptosis is characterized by plasma membrane (PM) disruption.

Purpose of the Study:

  • To investigate the sequence of events during MLKL activation and necroptosis.
  • To elucidate the role of the ESCRT-III machinery in necroptosis and its consequences.

Main Methods:

  • Observational studies of cells undergoing necroptosis.
  • Analysis of calcium influx and phosphatidylserine exposure.
  • Investigating the role of the ESCRT-III machinery.

Main Results:

  • MLKL activation triggers calcium influx and phosphatidylserine exposure before PM integrity loss.
  • MLKL activation generates shed plasma membrane "bubbles" with exposed phosphatidylserine.
  • The ESCRT-III machinery is essential for bubble formation and regulates plasma membrane integrity duration.
  • ESCRT-III action in necroptosis promotes chemokine expression and CD8+ T cell cross-priming.

Conclusions:

  • The ESCRT-III machinery plays a critical role in managing plasma membrane integrity during necroptosis.
  • ESCRT-III-mediated processes during necroptosis contribute to immune responses, including T cell activation.
Keywords:
ESCRT-IIIMLKLannexin-Vnecroptosisphosphatidylserineplasma membrane repair

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