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Published 14 August 2006. doi:10.1083/jcb.200601030
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 4, 547-556
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Article

 ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages

Andreas W. Jehle1, Shyra J. Gardai3,4, Suzhao Li1, Patrick Linsel-Nitschke1, Konosuke Morimoto3, William J. Janssen3, R. William Vandivier3, Nan Wang1, Steven Greenberg1,2, Benjamin M. Dale2, Chunbo Qin5, Peter M. Henson4, and Alan R. Tall1

1 Department of Medicine and 2 Department of Pharmacology, Columbia University, New York, NY 10032
3 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262
4 Program in Cell Biology, the Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206
5 Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021

Correspondence to Andreas W. Jehle: aj2115{at}columbia.edu

The mammalian ATP-binding cassette transporters A1 and A7 (ABCA1 and -A7) show sequence similarity to CED-7, a Caenorhabditis elegans gene that mediates the clearance of apoptotic cells. Using RNA interference or gene targeting, we show that knock down of macrophage ABCA7 but not -A1 results in defective engulfment of apoptotic cells. In response to apoptotic cells, ABCA7 moves to the macrophage cell surface and colocalizes with the low-density lipoprotein receptor–related protein 1 (LRP1) in phagocytic cups. The cell surface localization of ABCA7 and LRP1 is defective in ABCA7-deficient cells. C1q is an opsonin of apoptotic cells that acts via phagocyte LRP1 to induce extracellular signal–regulated kinase (ERK) signaling. We show that ERK signaling is required for phagocytosis of apoptotic cells and that ERK phosphorylation in response to apoptotic cells or C1q is defective in ABCA7-deficient cells. These studies reveal a major role of ABCA7 and not -A1 in the clearance of apoptotic cells and therefore suggest that ABCA7 is an authentic orthologue of CED-7.

Abbreviations used in this paper: ABCA1, ATP-binding cassette transporter A1; apoA-I, apolipoprotein A-I; ERK, extracellular signal–regulated kinase; FcR, Fc receptor; LPS, lipopolysaccharide; PI, phagocytic index.


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