Huang Q, Wu Y-T, Tan H-L, Ong C-N, Shen H-M
Department of Community, Occupational & Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
Cell Death Differ. 2009 Feb;16(2):264-77. doi: 10.1038/cdd.2008.151. Epub 2008 Oct 31.
Under oxidative stress, poly(ADP-ribose) polymerase-1 (PARP-1) is activated and contributes to necrotic cell death through ATP depletion. On the other hand, oxidative stress is known to stimulate autophagy, and autophagy may act as either a cell death or cell survival mechanism. This study aims to explore the regulatory role of PARP-1 in oxidative stress-mediated autophagy and necrotic cell death. Here, we first show that hydrogen peroxide (H(2)O(2)) induces necrotic cell death in Bax-/- Bak-/- mouse embryonic fibroblasts through a mechanism involving PARP-1 activation and ATP depletion. Next, we provide evidence that autophagy is activated in cells exposed to H(2)O(2). More importantly, we identify a novel autophagy signaling mechanism linking PARP-1 to the serine/threonine protein kinase LKB1-AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway, leading to stimulation of autophagy. Finally, we demonstrate that autophagy plays a cytoprotective role in H(2)O(2)-induced necrotic cell death, as suppression of autophagy by knockdown of autophagy-related gene ATG5 or ATG7 greatly sensitizes H(2)O(2)-induced cell death. Taken together, these findings demonstrate a novel function of PARP-1: promotion of autophagy through the LKB1-AMPK-mTOR pathway to enhance cell survival in cells under oxidative stress.
在氧化应激条件下，聚（ADP - 核糖）聚合酶 -1（PARP -1）被激活，并通过消耗ATP导致坏死性细胞死亡。另一方面，已知氧化应激会刺激自噬，并且自噬可能作为一种细胞死亡或细胞存活机制。本研究旨在探讨PARP -1在氧化应激介导的自噬和坏死性细胞死亡中的调节作用。在此，我们首先表明过氧化氢（H₂O₂）通过涉及PARP -1激活和ATP消耗的机制，在Bax⁻/⁻Bak⁻/⁻小鼠胚胎成纤维细胞中诱导坏死性细胞死亡。接下来，我们提供证据表明自噬在暴露于H₂O₂的细胞中被激活。更重要的是，我们确定了一种新的自噬信号传导机制，该机制将PARP -1与丝氨酸/苏氨酸蛋白激酶LKB1 - 腺苷酸活化蛋白激酶（AMPK） - 雷帕霉素哺乳动物靶标（mTOR）途径联系起来，从而导致自噬的刺激。最后，我们证明自噬在H₂O₂诱导的坏死性细胞死亡中起细胞保护作用，因为通过敲低自噬相关基因ATG5或ATG7抑制自噬会极大地增加H₂O₂诱导的细胞死亡敏感性。综上所述，这些发现证明了PARP -1的一种新功能：通过LKB1 - AMPK - mTOR途径促进自噬，以增强氧化应激下细胞的存活能力。
