Simian Virus 40 Infection Triggers a Balanced Network That Includes Apoptotic, Survival, and Stress Pathways
Simian Virus 40 Infection Triggers a Balanced Network That Includes Apoptotic, Survival, and Stress Pathways
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DOI：
10.1128/jvi.01735-09
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发表时间：
2010-04-01
影响因子：
5.4
通讯作者：
Oppenheim, Ariella
中科院分区：
文献类型：
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作者：
Butin-Israeli, Veronika;Drayman, Nir;Oppenheim, Ariella
猴病毒40（SV 40）的感染过程及其基因组进入非分裂细胞的过程仅部分了解。感染开始于与细胞表面的GM 1受体结合，通过小窝内陷进入细胞，并运输到内质网，在那里病毒解体。为了更深入地了解宿主功能对这一过程的贡献，我们研究了感染病毒引起的细胞信号传导。Western blotting和免疫荧光染色检测信号蛋白。这项研究得到了初步蛋白质组学筛选的帮助。使用特异性抑制剂评估信号蛋白对感染过程的贡献。我们发现CV-1细胞通过激活聚ADP核糖聚合酶1（PARP-1）介导的凋亡信号对SV 40感染作出反应，该信号被Akt-1存活通路和应激反应所阻止。协调这三种途径的单个关键调节因子是磷脂酶C-γ（PLC γ）。由于受感染的细胞既不经历凋亡也不增殖，因此抵消凋亡和存活途径是稳健平衡的。令人惊讶的是，我们发现凋亡途径，包括PARP-1和半胱天冬酶的激活，是感染进行所必需的。因此，SV 40劫持宿主防御以促进其感染。PLC γ和Akt-1的活性也是必需的，并且它们的抑制消除了感染。值得注意的是，这个信号网络在T抗原表达前数小时被激活。重组空衣壳，缺乏DNA的实验表明，主要衣壳蛋白VP 1单独触发这个早期信号网络。新兴的强大信号网络反映了宿主-病毒关系中攻击和防御之间的微妙进化平衡。
The infection process by simian virus 40 (SV40) and entry of its genome into nondividing cells are only partly understood. Infection begins by binding to GM1 receptors at the cell surface, cellular entry via caveolar invaginations, and trafficking to the endoplasmic reticulum, where the virus disassembles. To gain a deeper insight into the contribution of host functions to this process, we studied cellular signaling elicited by the infecting virus. Signaling proteins were detected by Western blotting and immunofluorescence staining. The study was assisted by a preliminary proteomic screen. The contribution of signaling proteins to the infection process was evaluated using specific inhibitors. We found that CV-1 cells respond to SV40 infection by activating poly(ADP-ribose) polymerase 1 (PARP-1)-mediated apoptotic signaling, which is arrested by the Akt-1 survival pathway and stress response. A single key regulator orchestrating the three pathways is phospholipase C-gamma (PLC gamma). The counteracting apoptotic and survival pathways are robustly balanced as the infected cells neither undergo apoptosis nor proliferate. Surprisingly, we have found that the apoptotic pathway, including activation of PARP-1 and caspases, is absolutely required for the infection to proceed. Thus, SV40 hijacks the host defense to promote its infection. Activities of PLC gamma and Akt-1 are also required, and their inhibition abrogates the infection. Notably, this signaling network is activated hours before T antigen is expressed. Experiments with recombinant empty capsids, devoid of DNA, indicated that the major capsid protein VP1 alone triggers this early signaling network. The emerging robust signaling network reflects a delicate evolutionary balance between attack and defense in the host-virus relationship.