When Repair Is Suicide

Sci. Signal.  25 Aug 2009:
Vol. 2, Issue 85, pp. ec283
DOI: 10.1126/scisignal.285ec283

Cells that experience nonfatal plasma membrane damage initiate a membrane repair response that is triggered by increased concentration of intracellular calcium and involves first the fusion of lysosomes with the plasma membrane, and then a calcium-inhibited aminophospholipid translocase reestablishes membrane asymmetry once calcium concentrations are restored to normal. Cells that undergo apoptosis exhibit membrane blebbing and loss of membrane asymmetry, which has been attributed to phospholipid scramblase activity activated during apoptosis. However, Mirnikjoo et al. provide evidence that the change in the plasma membranes of apoptotic cells relies on the normal membrane repair response, which fails at the step that establishes membrane asymmetry, leading to the accumulation of phosphatidylserine at the external side of the plasma membrane. Mirnikjoo et al. labeled lysosomes and then triggered apoptosis and found that all cells that were positive for external leaflet phosphatidylserine, a hallmark of an apoptotic cell and a trigger for phagocytosis in vivo, were also positive for the dye that stained the lysosomal membranes and for the lysosomal membrane protein LAMP-1. Disruption of the actin cytoskeleton, but not the microtubule cytoskeleton, prevented lysosome fusion at the plasma membrane and the redistribution of phosphatidylserine. Disruption of lysosomal trafficking with chloroquine also prevented the redistribution of phosphatidylserine and lysosomal fusion with the plasma membrane; however, this did not prevent activation of caspase-3 or DNA fragmentation. Exposure of cells to a calcium ionophore also triggered the lysosome–plasma membrane fusion process and phosphatidylserine externalization, and this was reversed if the cells were washed with a calcium buffer to reduce the calcium concentration. Because phagocytic clearance of cells through recognition of phosphatidylserine is immunologically “silent,” inhibiting lysosome–plasma membrane fusion may improve the effectiveness of chemotherapeutic treatments that rely on triggering apoptosis of the cancer cells, because death of these cells may have an increased chance of triggering an antitumor immune response.

B. Mirnikjoo, K. Balasubramanian, A. J. Schroit, Suicidal membrane repair regulates phosphatidylserine externalization during apoptosis. J. Biol. Chem. 284, 22512–22516 (2009). [Abstract] [Full Text]