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Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure

Science  06 Jun 2014:
Vol. 344, Issue 6188, pp. 1164-1168
DOI: 10.1126/science.1252809

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How cells haul down their “eat me” flags

Dead and dying cells expose a membrane lipid called phosphatidylserine (PS) on their cell surface as a sort of “eat me” signal. Segawa et al. identified the membrane enzyme responsible for flipping any PS that inadvertently makes it way from the inner to the outer leaflet of the plasma membrane lipid bilayer. Without the enzyme, macrophages gobbled up healthy cells.

Science, this issue p. 1164

Abstract

Phospholipids are asymmetrically distributed in the plasma membrane. This asymmetrical distribution is disrupted during apoptosis, exposing phosphatidylserine (PtdSer) on the cell surface. Using a haploid genetic screen in human cells, we found that ATP11C (adenosine triphosphatase type 11C) and CDC50A (cell division cycle protein 50A) are required for aminophospholipid translocation from the outer to the inner plasma membrane leaflet; that is, they display flippase activity. ATP11C contained caspase recognition sites, and mutations at these sites generated caspase-resistant ATP11C without affecting its flippase activity. Cells expressing caspase-resistant ATP11C did not expose PtdSer during apoptosis and were not engulfed by macrophages, which suggests that inactivation of the flippase activity is required for apoptotic PtdSer exposure. CDC50A-deficient cells displayed PtdSer on their surface and were engulfed by macrophages, indicating that PtdSer is sufficient as an “eat me” signal.

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