Qu Xueping, Zou Zhongju, Sun Qihua, Luby-Phelps Kate, Cheng Pengfei, Hogan Robert N, Gilpin Christopher, Levine Beth
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell. 2007 Mar 9;128(5):931-46. doi: 10.1016/j.cell.2006.12.044.
Autophagy is commonly observed in metazoan organisms during programmed cell death (PCD), but its function in dying cells has been unclear. We studied the role of autophagy in embryonic cavitation, the earliest PCD process in mammalian development. Embryoid bodies (EBs) derived from cells lacking the autophagy genes, atg5 or beclin 1, fail to cavitate. This defect is due to persistence of cell corpses, rather than impairment of PCD. Dying cells in autophagy gene null EBs fail to express the "eat-me" signal, phosphatidylserine exposure, and secrete lower levels of the "come-get-me" signal, lysophosphatidylcholine. These defects are associated with low levels of cellular ATP and are reversed by treatment with the metabolic substrate, methylpyruvate. Moreover, mice lacking atg5 display a defect in apoptotic corpse engulfment during embryonic development. We conclude that autophagy contributes to dead-cell clearance during PCD by a mechanism that likely involves the generation of energy-dependent engulfment signals.
自噬现象在多细胞生物的程序性细胞死亡（PCD）过程中普遍存在，但其在濒死细胞中的功能尚不清楚。我们研究了自噬在胚胎空化过程中的作用，胚胎空化是哺乳动物发育过程中最早的程序性细胞死亡过程。源自缺乏自噬基因atg5或beclin 1的细胞的胚状体（EBs）无法形成空泡。这种缺陷是由于细胞尸体的持续存在，而非程序性细胞死亡受损所致。自噬基因缺失的胚状体中的濒死细胞无法表达“吃我”信号（磷脂酰丝氨酸暴露），并分泌较低水平的“来吞噬我”信号（溶血磷脂酰胆碱）。这些缺陷与细胞内ATP水平较低有关，用代谢底物丙酮酸钠处理可使其逆转。此外，缺乏atg5的小鼠在胚胎发育过程中表现出凋亡尸体吞噬缺陷。我们得出结论，自噬通过一种可能涉及产生能量依赖性吞噬信号的机制，有助于程序性细胞死亡过程中死亡细胞的清除。
