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

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

Author information

1
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2
Division of Renal Medicine, Clinical Sciences, Intervention and Technology, Karolinska Institutet, 171 76 Stockholm, Sweden.
3
Institute of Pathology, University Hospital of Cologne, 50674 Cologne, Germany.
4
Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, 01307 Dresden, Germany. Electronic address: andreas.linkermann@ukdd.de.
5
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: douglas.green@stjude.org.

Abstract

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

PMID:
28388412
PMCID:
PMC5443414
DOI:
10.1016/j.cell.2017.03.020
[Indexed for MEDLINE]
Free PMC Article

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