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PLoS Biol. 2017 Jun 26;15(6):e2002711. doi: 10.1371/journal.pbio.2002711. eCollection 2017 Jun.

Phosphatidylserine externalization, "necroptotic bodies" release, and phagocytosis during necroptosis.

Author information

1
Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
2
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
3
Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
4
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America.

Abstract

Necroptosis is a regulated, nonapoptotic form of cell death initiated by receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins. It is considered to be a form of regulated necrosis, and, by lacking the "find me" and "eat me" signals that are a feature of apoptosis, necroptosis is considered to be inflammatory. One such "eat me" signal observed during apoptosis is the exposure of phosphatidylserine (PS) on the outer plasma membrane. Here, we demonstrate that necroptotic cells also expose PS after phosphorylated mixed lineage kinase-like (pMLKL) translocation to the membrane. Necroptotic cells that expose PS release extracellular vesicles containing proteins and pMLKL to their surroundings. Furthermore, inhibition of pMLKL after PS exposure can reverse the process of necroptosis and restore cell viability. Finally, externalization of PS by necroptotic cells drives recognition and phagocytosis, and this may limit the inflammatory response to this nonapoptotic form of cell death. The exposure of PS to the outer membrane and to extracellular vesicles is therefore a feature of necroptotic cell death and may serve to provide an immunologically-silent window by generating specific "find me" and "eat me" signals.

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PMID:
28650960
PMCID:
PMC5501695
DOI:
10.1371/journal.pbio.2002711
[Indexed for MEDLINE]
Free PMC Article

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