AIF-mediated caspase-independent necroptosis requires ATM and DNA-PK-induced histone H2AX Ser139 phosphorylation.
AIF-mediated caspase-independent necroptosis requires ATM and DNA-PK-induced histone H2AX Ser139 phosphorylation.
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AIF介导的caspase非依赖性坏死作用需要ATM和DNA-PK诱导的组蛋白H2AX Ser139磷酸化。
DOI：
10.1038/cddis.2012.120
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发表时间：
2012-09-13
影响因子：
9
通讯作者：
Susin, S. A.
中科院分区：
文献类型：
--
作者：
Baritaud, M.;Cabon, L.;Delavallee, L.;Galan-Malo, P.;Gilles, M-E;Brunelle-Navas, M-N;Susin, S. A.
烷化剂DNA损伤剂N-甲基-N′-硝基-N-亚硝基胍（MNNG）诱导一种与线粒体黄素蛋白凋亡诱导因子（AIF）有关的非半胱天冬酶依赖性坏死性凋亡。在PARP-1（聚ADP-核糖聚合酶-1）、钙蛋白酶、BID（BH 3相互作用结构域死亡激动剂）和BAX（Bcl-2相关X蛋白）激活后，AIF（tAIF）的致凋亡形式易位至细胞核，在细胞核中与丝氨酸139磷酸化组蛋白H2 AX（γ H2 AX）结合，产生DNA降解复合物，引起染色质溶解和坏死性凋亡导致的细胞死亡。γ H2 AX的产生对于这种形式的细胞死亡是至关重要的，因为H2 AX Ser 139突变为Ala或H2 AX的遗传消融消除了染色质溶解和坏死性凋亡。相反，将H2 AX-wt或磷酸化模拟H2 AX突变体（H2 AX-S139 E）重新引入H2 AX −/−细胞会使MNNG触发的坏死性凋亡重新敏感。采用药理学方法和基因敲除细胞，我们还证明了磷脂酰肌醇-3-OH激酶相关激酶（PIKKs）ATM（共济失调毛细血管扩张突变）和DNA依赖性蛋白激酶（DNA-PK）介导γ H2 AX的产生，从而介导MNNG诱导的坏死性凋亡。相比之下，H2 AX磷酸化不受ATR或其他H2 AX相关激酶（例如JNK）的调节。有趣的是，ATM和DNA-PK以协同方式在Ser 139处磷酸化H2 AX，具有不同的活化动力学。在MNNG处理后早期，ATM产生γ H2 AX。此外，DNA-PK有助于H2 AX Ser 139磷酸化。在揭示PIKKs在MNNG诱导的细胞死亡中的关键作用时，我们的数据揭示了调节AIF介导的非半胱天冬酶依赖性坏死性凋亡机制的里程碑。
The alkylating DNA-damage agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) induces a form of caspase-independent necroptosis implicating the mitochondrial flavoprotein apoptosis-inducing factor (AIF). Following the activation of PARP-1 (poly(ADP-ribose) polymerase-1), calpains, BID (BH3 interacting domain death agonist), and BAX (Bcl-2-associated X protein), the apoptogenic form of AIF (tAIF) is translocated to the nucleus where, associated with Ser139-phosphorylated histone H2AX (γH2AX), it creates a DNA-degrading complex that provokes chromatinolysis and cell death by necroptosis. The generation of γH2AX is crucial for this form of cell death, as mutation of H2AX Ser139 to Ala or genetic ablation of H2AX abolish both chromatinolysis and necroptosis. On the contrary, reintroduction of H2AX-wt or the phosphomimetic H2AX mutant (H2AX-S139E) into H2AX−/− cells resensitizes to MNNG-triggered necroptosis. Employing a pharmacological approach and gene knockout cells, we also demonstrate in this paper that the phosphatidylinositol-3-OH kinase-related kinases (PIKKs) ATM (ataxia telangiectasia mutated) and DNA-dependent protein kinase (DNA-PK) mediate γH2AX generation and, consequently, MNNG-induced necroptosis. By contrast, H2AX phosphorylation is not regulated by ATR or other H2AX-related kinases, such as JNK. Interestingly, ATM and DNA-PK phosphorylate H2AX at Ser139 in a synergistic manner with different kinetics of activation. Early after MNNG treatment, ATM generates γH2AX. Further, DNA-PK contributes to H2AX Ser139 phosphorylation. In revealing the pivotal role of PIKKs in MNNG-induced cell death, our data uncover a milestone in the mechanisms regulating AIF-mediated caspase-independent necroptosis.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
64.8
作者：
Downs, JA;Lowndes, NF;Jackson, SP
通讯作者：
Jackson, SP
影响因子：
14.8
作者：
Degterev, Alexei;Hitomi, Junichi;Yuan, Junying
通讯作者：
Yuan, Junying
影响因子：
4.8
作者：
Rogakou, EP;Nieves-Neira, W;Bonner, WM
通讯作者：
Bonner, WM
影响因子：
64.5
作者：
Celeste, A;Difilippantonio, S;Nussenzweig, A
通讯作者：
Nussenzweig, A