Antiapoptotic activity of the herpesvirus saimiri-encoded Bcl-2 homolog: Stabilization of mitochondria and inhibition of caspase-3-like activity
Antiapoptotic activity of the herpesvirus saimiri-encoded Bcl-2 homolog: Stabilization of mitochondria and inhibition of caspase-3-like activity
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DOI：
10.1128/jvi.72.7.5897-5904.1998
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发表时间：
1998-07-01
影响因子：
5.4
通讯作者：
Meinl, E
中科院分区：
文献类型：
--
作者：
Derfuss, T;Fickenscher, H;Meinl, E
病毒已经进化出不同的策略来干扰宿主细胞凋亡，松鼠猴疱疹病毒（HVS）和其他嗜淋巴细胞疱疹病毒编码与细胞抗凋亡Bcl-2同源的蛋白。在这项研究中，HVS-Bcl-2在人白血病细胞系Jurkat和鼠T细胞杂交瘤DO中稳定表达，以评估其抗凋亡谱并进一步了解其作用模式。HVS-Bcl-2可以预防细胞内稳态失调而发生的细胞凋亡，例如DNA损伤或甲萘醌（会产生氧自由基）。在Jurkat细胞中，HVS-Bcl-2还抑制由死亡受体CD 95介导的凋亡。在DO细胞中，HVS-Bcl-2不干扰CD 95介导的凋亡，但阻断地塞米松诱导的细胞死亡。线粒体损伤是不同刺激诱导细胞凋亡的中心协调事件。为了评估线粒体的完整性，我们使用了罗丹明123，这是在线粒体膜电位的干扰释放，并确定释放细胞色素c到胞质溶胶。这两种线粒体损伤的迹象都被HVS-Bcl-2阻止。该病毒蛋白还抑制半胱天冬酶-3样DEVDase活性的产生，并阻断聚（ADP-核糖）聚合酶（半胱天冬酶-3样蛋白酶的天然底物）的切割。总之，HVS-Bcl-2保护免受多种凋亡刺激，稳定线粒体，并在半胱天冬酶-3样活性的产生的上游起作用。
Viruses have evolved different strategies to interfere with host cell apoptosis, Herpesvirus saimiri (HVS) and other lymphotropic herpesviruses code for proteins that are homologous to the cellular antiapoptotic Bcl-2. In this study HVS-Bcl-2 was stably expressed in the human leukemia cell line Jurkat and in the murine T-cell hybridoma DO to assess its antiapoptotic spectrum and to gain further insight into its mode of action. HVS-Bcl-2 prevented apoptosis that occurs as a result of a disturbance of intracellular homeostasis by, for example, DNA damage or menadione, which gives rise to oxygen radicals. In Jurkat cells, HVS-Bcl-2 also inhibited apoptosis mediated by the death receptor CD95. In DO cells, HVS-Bcl-2 did not interfere with CD95-mediated apoptosis but blocked dexamethasone-induced cell death. Mitochondrial damage is a central coordinating event in apoptosis induced by different stimuli. To assess the integrity of mitochondria, we used rhodamine 123, which is released upon disturbance of the mitochondrial membrane potential, and determined the release of cytochrome c into the cytosol. Both signs of mitochondrial damage were prevented by HVS-Bcl-2. This viral protein also inhibited the generation of caspase-3-like DEVDase activity and blocked the cleavage of poly(ADP-ribose) polymerase, a natural substrate of caspase-3-like proteases, In conclusion, HVS-Bcl-2 protects against a great variety of apoptotic stimuli, stabilizes mitochondria, and acts upstream of the generation of caspase-3-like activity.