The adenoviral E4orf6 protein induces atypical apoptosis in response to DNA damage
The adenoviral E4orf6 protein induces atypical apoptosis in response to DNA damage
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DOI：
10.1074/jbc.m610405200
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发表时间：
2007-03-02
影响因子：
4.8
通讯作者：
Koumenis, Constantinos
中科院分区：
文献类型：
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作者：
Hart, Lori S.;Ornelles, David;Koumenis, Constantinos
腺病毒蛋白质与宿主细胞蛋白质相互作用，以利用或抑制细胞功能用于病毒繁殖的目的。E4 orf 6是E4基因的34 kDa基因产物，与双链断裂修复（DSBR）蛋白DNA依赖性蛋白激酶相互作用，并与结合伴侣E1 B-55 K合作降解米泽11，阻止病毒DNA多联体形成。我们先前证明，E4 orf 6通过抑制DSBR，特别是在E1 B-55 K不存在的情况下，使人肿瘤细胞放射增敏。在这里，我们报告说，E4 orf 6通过抑制蛋白磷酸酶2A（PP 2A）的活性来抑制DNA损伤的信号传导，PP 2A是一种负责γ H2 AX去磷酸化的磷酸酶。PP 2A的抑制发生而不显著破坏DNA再连接速率。在E4 orf 6存在下DNA损伤的延长信号传导启动半胱天冬酶依赖性和非依赖性细胞死亡。这伴随着聚（ADP-核糖）聚合酶（PARP）的超活化和线粒体到细胞核的凋亡诱导因子（AIF）的易位。通过shRNA敲低AIF挽救了E4 orf 6诱导的放射增敏作用。总之，这些数据表明，E4 orf 6通过抑制PP 2A破坏细胞DSBR信号传导，导致延长的H2 AX磷酸化，PARP的超活化和AIF易位到细胞核。在没有其他腺病毒基因产物的情况下，E4 orf 6作为PP 2A的抑制剂和PARP的激活剂的功能在描述腺病毒-宿主细胞相互作用中是重要的。
Adenoviral proteins interact with host-cell proteins to either exploit or inhibit cellular functions for the purpose of viral propagation. E4orf6, the 34-kDa gene product of the E4 gene, interacts with the double-strand break repair (DSBR) protein DNA-dependent protein kinase and cooperates with binding partner E1B-55K to degrade MIZE 11, preventing viral DNA concatemer formation. We previously demonstrated that E4orf6 radiosensitizes human tumor cells through the inhibition of DSBR, notably in the absence of E1B-55K. Here, we report that E4orf6 prolongs the signaling of DNA damage by inhibiting the activity of protein phosphatase 2A (PP2A), the phosphatase responsible for dephosphorylating gamma H2AX. The inhibition of PP2A occurs without significant disruption of the DNA re-ligation rate. Prolonged signaling of DNA damage in the presence of E4orf6 initiates caspase-dependent and independent cell death. This is accompanied by poly(ADP-ribose) polymerase (PARP) hyper-activation and the translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus. Knockdown of AIF by shRNA rescues the radiosensitization induced by E4orf6. Taken together, these data suggest that E4orf6 disrupts cellular DSBR signaling by inhibiting PP2A, leading to prolonged H2AX phosphorylation, hyperactivation of PARP, and AIF translocation to the nucleus. The function of E4orf6 as an inhibitor of PP2A and activator of PARP in the absence of other adenoviral gene products is of importance in delineating the adenovirus-host cell interplay.