ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages.
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.
Jehle
Andreas W
AW
Department of Medicine, Columbia University, New York, NY 10032, USA. aj2115@columbia.edu
Gardai
Shyra J
SJ
Li
Suzhao
S
Linsel-Nitschke
Patrick
P
Morimoto
Konosuke
K
Janssen
William J
WJ
Vandivier
R William
RW
Wang
Nan
N
Greenberg
Steven
S
Dale
Benjamin M
BM
Qin
Chunbo
C
Henson
Peter M
PM
Tall
Alan R
AR
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D015922:Complement C1q / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D018390:Gene Targeting; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000502:physiology*; D034622:RNA Interference; D011973:Receptors, LDL / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
C577836:ABCA1 protein, human; C411895:ABCA7 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; C112887:CED-7 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D015922:Complement C1q; D048049:Extracellular Signal-Regulated MAP Kinases