A New Subfamily of P-type ATPases Involved in Recognition of Apoptotic Cells
The two leaflets of the plasma membrane bilayer of blood cells differ markedly in composition, with the choline phospholipids, phosphatidylcholine (PC) and sphingomyelin (Sph), concentrated in the outer leaflet and the aminophospholipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE), concentrated in the inner leaflet (Figure 1). Our research is directed at elucidating how this asymmetric transbilayer distribution is established and maintained, and its physiologic function.
The asymmetric distribution of phospholiids is under the control of two opposing pathways. An aminophospholipid translocase maintains asymmetry by translocating only aminophospholipids from the outer to the inner leaflet; an opposing Ca2+-induced pathway (scramblase) permits all the phospholipids to pass from either leaflet to the other, dissipating asymmetry (Figure 1). We have cloned the gene encoding the translocase and it identifies a previously unrecognized subfamily of P-type ATPases with multiple members. Representatives of this new subfamily are found in yeast, nematodes, mammals and plants, and recently, mutations in one of the genes in the subfamily have been identified as responsible for two forms of human inherited cholestasis, or inpaired bile flow. Current research is directed toward elucidating the functions of the other numerous members of the subfamily.
In lymphocytes and neutrophils undergoing apoptosis, or programmed cell death, the translocase in downregulated and the scramblase upregulated, exposing PS on the cell surface. This surface PS is recognized by macrophages, allowing them to phagocytose apoptotic cells before they can lyse and cause inflammation and tissue damage. Current research is directed toward identifying the receptor on macrophages which recognizes PS, other recognition signals displayed on the surface of apoptotic cells, and the receptors which recognize them.
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