The Nuclear Option

Abstract

The redistribution of the phospholipid phosphatidylserine (PS) from the inner to the outer leaflet of the plasma membrane is one of the mechanisms that targets an apoptotic cell for engulfment by a phagocyte. As well as presenting bridging molecules, such as annexin V, that bind to PS on the apoptotic cell, phagocytes are endowed with a PS receptor (PSR). Whereas antibody binding to PSR blocks engulfment of apoptotic cells in vitro, conflicting phenotypes have been observed in a number of species in which the genes for a PSR and its homologs have been disrupted. Controversy also remains over the localization of PSR, with some studies demonstrating expression of PSRs at the cell surface and others showing a nuclear localization of PSRs. Krieser et al . investigated a role for the Drosophila homolog of PSR (dPSR) in development and in mediating the engulfment of apoptotic cells by macrophages. The authors used acridine orange (AO) to stain the embryos of flies in which the dPSR gene was disrupted. AO stains apoptotic cells, and the authors found no difference in the number of AO-stained clusters between wild-type and dPSR-deficient embryos. Microscopic analysis using TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling) staining revealed that there was also no difference in the number of apoptotic cells per macrophage in wild-type and dPSR-deficient flies, leading the authors to conclude that dPSR is not required for engulfment of apoptotic cells. Confocal microscopy showed that a fusion protein of cyan fluorescent protein and dPSR was localized to the nucleus of transfected S2 cells, a Drosophila cell line. In transgenic flies, overexpression of dPSR resulted in developmental defects similar to those seen in flies with mutations in the hid gene. Hid promotes apoptosis necessary for the correct development of various tissues in the fly. Using different fly strains in which the relative abundance of dPSR and Hid were altered, the authors determined that dPSR inhibited Hid-induced apoptosis and promoted cell survival in lattice cells of the developing eye. Puckered (Puc) inhibits c-Jun N-terminal kinase (JNK) activity, and a Drosophila strain in which one copy of puc is lost exhibits increased JNK activity. JNK activity is needed to mediate the pro-apoptotic effects of Hid. The authors found that the loss of one copy of puc almost completely prevented the phenotype caused by the overexpression of dPSR . Together, these data suggest that dPSR is localized to the nucleus and plays no direct role in mediating the engulfment of apoptotic cells but instead protects against apoptosis during development, possibly by inhibiting JNK activity. The authors speculate that because of its role in cell survival, the decrease in apoptotic cell engulfment observed when PSR is deleted in some animal models may be due to increased apoptosis of phagocytic cells. R. J. Krieser, F. E. Moore, D. Dresnek, B. J. Pellock, R. Patel, A. Huang, C. Brachmann, K. White, The Drosophila homolog of the putative phosphatidylserine receptor functions to inhibit apoptosis. Development 134 , 2407-2414 (2007). [Abstract] [Full Text]