The Baculovirus Antiapoptotic p35 Protein Functions as an Inhibitor of the Host RNA Interference Antiviral Response
The Baculovirus Antiapoptotic p35 Protein Functions as an Inhibitor of the Host RNA Interference Antiviral Response
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DOI：
10.1128/jvi.00802-15
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发表时间：
2015-08-01
影响因子：
5.4
通讯作者：
Asgari, Sassan
中科院分区：
文献类型：
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作者：
Mehrabadi, Mohammad;Hussain, Mazhar;Asgari, Sassan
RNA 干扰 (RNAi) 被认为是包括昆虫在内的多种生物体中一种古老的抗病毒防御机制。病毒感染产生双链 RNA (dsRNA)，触发 RNAi 机制将 dsRNA 加工成病毒源性短干扰 RNA (vsiRNA)，其目标是病毒基因组、mRNA 或复制中间体。反过来，病毒进化出了RNAi病毒抑制因子（VSR）来对抗宿主的抗病毒RNAi。最近发现昆虫对 DNA 病毒产生 RNAi 反应，在这项研究中，我们发现苜蓿银纹夜蛾多核多角体病毒 (AcMNPV) 感染同样会在感染后产生大量 vsiRNA，从而在草地贪夜蛾细胞中诱导 RNAi 反应。有趣的是，我们发现 AcMNPV 表达有效的 VSR 来对抗 RNAi。病毒 p35 基因是众所周知的细胞凋亡抑制剂，被发现负责抑制多种昆虫和哺乳动物细胞中的 RNAi。 p35 无效的 AcMNPV 进一步证实了 p35 的 VSR 活性，该 AcMNPV 不会抑制反应。此外，我们的结果表明，VSR 活性不是由于 Dicer-2 对 dsRNA 切割的抑制，而是作用于 RNAi 途径的下游。此外，我们发现 VSR 活性与该蛋白的抗凋亡活性无关。总体而言，我们的结果为双链 DNA 病毒中存在 VSR 活性提供了证据，并确定了参与抑制 RNAi 和细胞凋亡的相关基因。重要性我们的研究结果表明，昆虫对杆状病毒 (AcMNPV) 发生 RNAi 反应，杆状病毒在微生物控制、生物和生物医学研究以及蛋白质表达中得到广泛利用。此外，我们的研究还鉴定出了 RNAi 活性的病毒抑制因子以及负责该活性的基因。值得注意的是，该基因也是细胞凋亡的有效抑制剂。结果表明病毒编码蛋白在消除细胞凋亡和 RNAi 两种关键抗病毒反应方面发挥双重作用。
RNA interference (RNAi) is considered an ancient antiviral defense in diverse organisms, including insects. Virus infections generate double-strand RNAs (dsRNAs) that trigger the RNAi machinery to process dsRNAs into virus-derived short interfering RNAs (vsiRNAs), which target virus genomes, mRNAs, or replication intermediates. Viruses, in turn, have evolved viral suppressors of RNAi (VSRs) to counter host antiviral RNAi. Following recent discoveries that insects mount an RNAi response against DNA viruses, in this study, we found that Autographa californica multiple nucleopolyhedrovirus (AcMNPV) infection similarly induces an RNAi response in Spodoptera frugiperda cells by generating a large number of vsiRNAs postinfection. Interestingly, we found that AcMNPV expresses a potent VSR to counter RNAi. The viral p35 gene, which is well known as an inhibitor of apoptosis, was found to be responsible for the suppression of RNAi in diverse insect and mammalian cells. The VSR activity of p35 was further confirmed by a p35-null AcMNPV that did not suppress the response. In addition, our results showed that the VSR activity is not due to inhibition of dsRNA cleavage by Dicer-2 but acts downstream in the RNAi pathway. Furthermore, we found that the VSR activity is not linked to the antiapoptotic activity of the protein. Overall, our results provide evidence for the existence of VSR activity in a double-stranded DNA virus and identify the responsible gene, which is involved in the inhibition of RNAi as well as apoptosis.IMPORTANCEOur findings demonstrate the occurrence of an insect RNAi response against a baculovirus (AcMNPV) that is highly utilized in microbial control, biological and biomedical research, and protein expression. Moreover, our investigations led to the identification of a viral suppressor of RNAi activity and the gene responsible for the activity. Notably, this gene is also a potent inhibitor of apoptosis. The outcomes signify the dual role of a virus-encoded protein in nullifying two key antiviral responses, apoptosis and RNAi.