Gleiss Bettina, Gogvadze Vladimir, Orrenius Sten, Fadeel Bengt
Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Stockholm, Sweden.
FEBS Lett. 2002 May 22;519(1-3):153-8. doi: 10.1016/s0014-5793(02)02743-6.
Recognition signals are displayed on the cell surface during apoptosis that enable macrophages to engulf and dispose of the dying cell. A common signal is the externalization of phosphatidylserine (PS). Studies in erythrocytes and platelets have suggested that PS exposure requires the concomitant activation of a phospholipid scramblase (PLS) and inhibition of an adenosine triphosphate (ATP)-dependent aminophospholipid translocase. However, the molecular mechanism underlying PS exposure during apoptosis remains poorly understood. In this study, we provide evidence that expression of PLS is neither necessary nor sufficient for PS exposure during Fas-triggered apoptosis. On the other hand, egress of PS is shown to correlate with a decline in intracellular ATP and inhibition of aminophospholipid translocase activity upon Fas stimulation. Moreover, suppression of intracellular ATP levels by the glucose anti-metabolite, 2-deoxyglucose, alone or in combination with glucose-free medium, potentiates Fas-induced PS exposure in the PLS-expressing Jurkat cell line and enables PLS-defective Raji cells to externalize PS in response to Fas ligation. These studies suggest that intracellular ATP levels can modulate the externalization of PS during apoptosis, and implicate the ATP-dependent aminophospholipid translocase in this process.
凋亡过程中，细胞表面会显示识别信号，使巨噬细胞能够吞噬和处理濒死细胞。一种常见的信号是磷脂酰丝氨酸（PS）外化。对红细胞和血小板的研究表明，PS暴露需要磷脂翻转酶（PLS）的同时激活以及对三磷酸腺苷（ATP）依赖性氨基磷脂转位酶的抑制。然而，凋亡过程中PS暴露的分子机制仍知之甚少。在本研究中，我们提供证据表明，在Fas触发的凋亡过程中，PLS的表达对于PS暴露既非必要条件也非充分条件。另一方面，PS的流出与细胞内ATP的下降以及Fas刺激后氨基磷脂转位酶活性的抑制相关。此外，葡萄糖抗代谢物2-脱氧葡萄糖单独或与无葡萄糖培养基联合使用来抑制细胞内ATP水平，可增强表达PLS的Jurkat细胞系中Fas诱导的PS暴露，并使PLS缺陷的Raji细胞在Fas连接时能够外化PS。这些研究表明，细胞内ATP水平可在凋亡过程中调节PS的外化，并表明ATP依赖性氨基磷脂转位酶参与了这一过程。
