ADP-ribosyl-acceptor hydrolase 3 regulates poly (ADP-ribose) degradation and cell death during oxidative stress
ADP-ribosyl-acceptor hydrolase 3 regulates poly (ADP-ribose) degradation and cell death during oxidative stress
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DOI：
10.1073/pnas.1312783110
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发表时间：
2013-11-19
影响因子：
11.1
通讯作者：
Moss, Joel
中科院分区：
文献类型：
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作者：
Mashimo, Masato;Kato, Jiro;Moss, Joel
聚腺苷二磷酸核糖（PAR）聚合酶1在遗传毒性应激反应中催化的PAR形成介导了细胞坏死和凋亡。PAR糖水解酶（PARG）被认为是体内唯一负责水解PAR的酶。然而，我们显示了另一种PAR降解途径，由ADP核糖基受体水解酶（ARH）3的作用引起。PARG和ARH3协同作用，调节过氧化氢（H2O2）暴露后细胞核和细胞质PAR降解。PAR负责诱导parthanatos，这是一种非半胱天冬酶依赖性细胞死亡的机制，由线粒体释放细胞凋亡诱导因子（AIF）并将其转运到细胞核引发DNA切割。PARG通过从多聚ADP核糖基化蛋白产生无蛋白PAR，使PAR移位成为可能。ARH3的保护作用是由于其降低细胞核和细胞质中的PAR水平，从而防止AIF从线粒体释放及其在细胞核中的积累。因此，PARG释放PAR连接到核蛋白，然后ARH3裂解PAR，是必不可少的调节PAR依赖性AIF释放线粒体和parthanatos。
Poly (ADP ribose) (PAR) formation catalyzed by PAR polymerase 1 in response to genotoxic stress mediates cell death due to necrosis and apoptosis. PAR glycohydrolase (PARG) has been thought to be the only enzyme responsible for hydrolysis of PAR in vivo. However, we show an alternative PAR-degradation pathway, resulting from action of ADP ribosyl-acceptor hydrolase (ARH) 3. PARG and ARH3, acting in tandem, regulate nuclear and cytoplasmic PAR degradation following hydrogen peroxide (H2O2) exposure. PAR is responsible for induction of parthanatos, a mechanism for caspase-independent cell death, triggered by apoptosis-inducing factor (AIF) release from mitochondria and its translocation to the nucleus, where it initiates DNA cleavage. PARG, by generating protein-free PAR from poly-ADP ribosylated protein, makes PAR translocation possible. A protective effect of ARH3 results from its lowering of PAR levels in the nucleus and the cytoplasm, thereby preventing release of AIF from mitochondria and its accumulation in the nucleus. Thus, PARG release of PAR attached to nuclear proteins, followed by ARH3 cleavage of PAR, is essential in regulating PAR-dependent AIF release from mitochondria and parthanatos.