Flipping the dogma - Phosphatidylserine in non-apoptotic cell death

Inbar Shlomovitz, Mary Speir, Motti Gerlic*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


The exposure of phosphatidylserine (PS) on the outer plasma membrane has long been considered a unique feature of apoptotic cells. Together with other "eat me" signals, it enables the recognition and phagocytosis of dying cells (efferocytosis), helping to explain the immunologically-silent nature of apoptosis. Recently, however, PS exposure has also been reported in non-apoptotic forms of regulated inflammatory cell death, such as necroptosis, challenging previous dogma. In this review, we outline the evidence for PS exposure in non-apoptotic cells and extracellular vesicles (EVs), and discuss possible mechanisms based on our knowledge of apoptotic-PS exposure. In addition, we examine the outcomes of non-apoptotic PS exposure, including the reversibility of cell death, efferocytosis, and consequent inflammation. By examining PS biology, we challenge the established approach of distinguishing apoptosis from other cell death pathways by AnnexinV staining of PS externalization. Finally, we re-evaluate how PS exposure is thought to define apoptosis as an immunologically silent process distinct from other non-apoptotic and inflammatory cell death pathways. Ultimately, we suggest that a complete understanding of how regulated cell death processes affect the immune system is far from being fully elucidated. Graphical abstract: [Figure not available: see fulltext.]

Original languageEnglish
Article number139
JournalCell Communication and Signaling
Issue number1
StatePublished - 29 Oct 2019


  • AnnexinV
  • Apoptosis
  • Cell death
  • Efferocytosis
  • Extracellular vesicles
  • Inflammation
  • Necroptosis
  • Phagocytosis
  • Phosphatidylserine


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