Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis
Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis
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DOI：
10.1038/ncb1747
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发表时间：
2008-07-01
影响因子：
21.3
通讯作者：
Sawa, Akira
中科院分区：
文献类型：
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作者：
Sen, Nilkantha;Hara, Makoto R.;Sawa, Akira
除了在糖酵解中的作用外，甘油醛-3-磷酸脱氢酶（GAPDH）还启动细胞死亡级联反应（1-9）。不同的凋亡刺激激活诱导型一氧化氮合酶（iNOS）或神经元型NOS（nNOS），产生的一氧化氮（NO）S-亚硝基化GAPDH，消除其催化活性并赋予其结合Siah 1（具有核定位信号（NLS）的E3-泛素连接酶）的能力。GAPDH-Siah 1蛋白复合物，反过来，易位到细胞核和介导细胞死亡;这些过程被阻止的程序，干扰GAPDH-Siah 1结合。GAPDH诱导的杀死细胞的核事件一直不清楚。在这里，我们表明，核GAPDH是乙酰化在赖氨酸160的乙酰转移酶p300/CREB结合蛋白（CBP）通过直接的蛋白质相互作用，这反过来又刺激乙酰化和催化活性的p300/CBP。因此，p300/CBP的下游靶点，如p53（参考文献10-15）被激活并导致细胞死亡。一个显性负性突变体GAPDH与取代赖氨酸160精氨酸（GAPDH-K160 R）防止激活p300/CBP，阻断诱导凋亡基因，减少细胞死亡。我们的研究结果揭示了NO诱导的核GAPDH通过p300/CBP介导细胞死亡的途径。
Besides its role in glycolysis, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) initiates a cell death cascade(1-9). Diverse apoptotic stimuli activate inducible nitric oxide synthase ( iNOS) or neuronal NOS ( nNOS), with the generated nitric oxide ( NO) S-nitrosylating GAPDH, abolishing its catalytic activity and conferring on it the ability to bind to Siah1, an E3-ubiquitin-ligase with a nuclear localization signal (NLS). The GAPDH-Siah1 protein complex, in turn, translocates to the nucleus and mediates cell death; these processes are blocked by procedures that interfere with GAPDH-Siah1 binding. Nuclear events induced by GAPDH to kill cells have been obscure. Here we show that nuclear GAPDH is acetylated at Lys 160 by the acetyltransferase p300/CREB binding protein (CBP) through direct protein interaction, which in turn stimulates the acetylation and catalytic activity of p300/CBP. Consequently, downstream targets of p300/CBP, such as p53 (refs 10-15), are activated and cause cell death. A dominant-negative mutant GAPDH with the substitution of Lys 160 to Arg (GAPDH-K160R) prevents activation of p300/CBP, blocks induction of apoptotic genes and decreases cell death. Our findings reveal a pathway in which NO-induced nuclear GAPDH mediates cell death through p300/CBP.