PtdSer (arrows) on an extruded nuclei (shown) signals to macrophages to digest it.


Mammalian red blood cells get rid of their nuclei as they mature. Now, Hideyuki Yoshida, Shigekazu Nagata (Osaka University Medical School, Osaka, Japan), and colleagues show that the extruded nuclei cover themselves with the marks of dying cells. As a result, macrophages engulf and degrade the nuclei, as they do apoptotic cells.

The mark of an apoptotic cell that calls in macrophages is phosphatidylserine (PtdSer). Macrophage receptors such as MGF-E8 initiate phagocytosis when they sense this phospholipid in the dying cell's plasma membrane. Yoshida et al. found that PtdSer also appears on the plasma membrane surrounding an extruded nucleus. Masking PtdSer prevented macrophages from engulfing the nuclei.PtdSer is normally retained in the inner leaflet of the plasma membrane by an ATP-dependent mechanism. But once separated from their cell body, the extruded nuclei were unable to generate their own ATP. PtdSer thus rapidly appeared on the outer surface of the membrane. Since ATP levels remain high in apoptotic cells, lone nuclei and dying cells must generate the PtdSer marks via different means.

Autoimmune problems in mice expressing a mutant MFG-E8 have been attributed to persistent apoptotic cells. But since at least tenfold more red blood cells than dying cells are generated per day, the unscavenged nuclei are probably the bigger issue.


Yoshida, H., et al.