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(Received for publication, June 5, 1997, and in revised form, August 4, 1997)
From the National Jewish Medical and Research Center,
Denver, Colorado 80206
Phosphatidylserine (PS), ordinarily sequestered in
the plasma membrane inner leaflet, appears in the outer leaflet during apoptosis, where it triggers non-inflammatory phagocytic recognition of
the apoptotic cell. The mechanism of PS appearance during apoptosis is
not well understood but has been associated with loss of
aminophospholipid translocase activity and nonspecific flip-flop of
phospholipids of various classes. The human leukemic cell line HL-60,
the T cell line Jurkat, and peripheral blood neutrophils, undergoing apoptosis induced either with UV irradiation or anti-Fas antibody, were
probed in the cytofluorograph for (i) surface PS using fluorescein isothiocyanate-labeled annexin V, (ii) PS uptake by the
aminophospholipid translocase using
[6-[(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino] caproyl] (NBD)-labeled PS, (iii) nonspecific uptake of
phospholipids (as a measure of transbilayer flip-flop) using
NBD-labeled phosphatidylcholine, and (iv) the appearance of hypodiploid
DNA. In all three types of cells undergoing apoptosis, the appearance
of PS followed loss of aminophospholipid translocase and was
accompanied by nonspecific phospholipid flip-flop. Importantly,
however, in the absence of extracellular calcium, the appearance of PS
was completely inhibited despite DNA fragmentation and loss of
aminophospholipid translocase activity, the latter demonstrating that
loss of the translocase is insufficient for PS appearance during
apoptosis. Furthermore, while both the appearance of PS and nonspecific
phospholipid uptake demonstrated identical extracellular calcium
requirements with an ED50 of nearly 100 µM, the magnitude of PS appearance depended on the level
of aminophospholipid translocase activity. Taken together, the data
strongly suggest that while nonspecific flip-flop is the driving event
for PS appearance in the plasma membrane outer leaflet,
aminophospholipid translocase activity ultimately modulates its
appearance.
Volume 272, Number 42,
Issue of October 17, 1997
pp. 26159-26165
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Appearance of Phosphatidylserine on Apoptotic Cells Requires
Calcium-mediated Nonspecific Flip-Flop and Is Enhanced by Loss of
the Aminophospholipid Translocase
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