TY - JOUR
T1 - Phosphatidylserine externalization, “necroptotic bodies” release, and phagocytosis during necroptosis
AU - Zargarian, Sefi
AU - Shlomovitz, Inbar
AU - Erlich, Ziv
AU - Hourizadeh, Aria
AU - Ofir-Birin, Yifat
AU - Croker, Ben A.
AU - Regev-Rudzki, Neta
AU - Edry-Botzer, Liat
AU - Gerlic, Motti
N1 - Publisher Copyright:
© 2017 Zargarian et al.
PY - 2017/6/26
Y1 - 2017/6/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85021629176&partnerID=8YFLogxK
U2 - 10.1371/journal.pbio.2002711
DO - 10.1371/journal.pbio.2002711
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C2 - 28650960
AN - SCOPUS:85021629176
SN - 1544-9173
VL - 15
JO - PLoS Biology
JF - PLoS Biology
IS - 6
M1 - e2002711
ER -