Xk-Related Protein 8 and CED-8 Promote Phosphatidylserine Exposure in Apoptotic Cells

Whence the “Eat Me” Signal? Cells are surrounded by a lipid bilayer, the composition of which is asymmetrical and serves as a marker of the physiological status of the cell. The phospholipid, phosphatidylserine (PtdSer), is normally found only on the inner leaflet of the membrane, but in dying cells it appears on the cell surface, thus providing the phagocytes tasked with cleaning up such cellular debris with a way to recognize cells undergoing cell death. Such movement of phospholipids within the membrane requires an elusive enzyme known as a scramblase. Suzuki et al. (p. 403; published online 11 July) identified an enzyme, Xkr8, which appears to act as a scramblase that promotes exposure of PtdSer on the surface of dying mammalian cells. Consistent with such a role, Xkr8 was activated after cleavage by caspase 3, a key protease that promotes apoptotic cell death. Genetic studies with the homolog of Xkr8 expressed in Caenorhabditis elegans indicated that the protein played a similar role in tagging dead cells in the nematode worm during development. An enzyme involved in the flipping of phospholipids in dying cells’ surfaces to mark the cells for removal is identified. A classic feature of apoptotic cells is the cell-surface exposure of phosphatidylserine (PtdSer) as an “eat me” signal for engulfment. We show that the Xk-family protein Xkr8 mediates PtdSer exposure in response to apoptotic stimuli. Mouse Xkr8−/− cells or human cancer cells in which Xkr8 expression was repressed by hypermethylation failed to expose PtdSer during apoptosis and were inefficiently engulfed by phagocytes. Xkr8 was activated directly by caspases and required a caspase-3 cleavage site for its function. CED-8, the only Caenorhabditis elegans Xk-family homolog, also promoted apoptotic PtdSer exposure and cell-corpse engulfment. Thus, Xk-family proteins have evolutionarily conserved roles in promoting the phagocytosis of dying cells by altering the phospholipid distribution in the plasma membrane.