ORF45-Mediated Prolonged c-Fos Accumulation Accelerates Viral Transcription during the Late Stage of Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus
ORF45-Mediated Prolonged c-Fos Accumulation Accelerates Viral Transcription during the Late Stage of Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus
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ORF45介导的c-Fos长时间积累加速卡波西肉瘤相关疱疹病毒裂解复制后期的病毒转录
DOI：
10.1128/jvi.00274-15
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发表时间：
2015-07-01
影响因子：
5.4
通讯作者：
Kuang, Ersheng
中科院分区：
文献类型：
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作者：
Li, Xiaojuan;Du, Shumin;Kuang, Ersheng
卡波西肉瘤相关疱疹病毒（KSHV）编码多种病毒蛋白，激活细胞外信号调节激酶（ERK）-丝裂原活化蛋白激酶（MAPK）级联反应。这些病毒蛋白之一ORF 45在KSHV裂解复制期间介导持续的ERK-p90核糖体S6激酶（RSK）活化，并通过真核翻译起始因子eIF 4 B的磷酸化促进病毒翻译。ERK-RSK激活对KSHV病毒转录的重要性已被证明;然而，哪种转录因子感知持续的MAPK信号传导并导致病毒转录仍然知之甚少。在这里，我们表明，ORF 45的存在下，导致长期积累的c-Fos在KSHV裂解复制的后期阶段，通过ERK-RSK依赖的磷酸化和稳定化和c-Fos的耗尽破坏病毒裂解转录。全基因组筛选结果表明，c-Fos直接结合多个病毒基因启动子，并增强病毒的转录。c-Fos的ERK-RSK磷酸化位点的突变抑制KSHV裂解基因表达和病毒体产生。这些结果表明，c-Fos的长期积累促进了病毒转录从早期到晚期的进展，并在KSHV裂解生命周期中持续ORF 45-ERK-RSK激活时加速病毒裂解复制。重要说明在KSHV裂解复制过程中，ERK-RSK的瞬时激活和持续激活分别诱导病毒立即早期（IE）转录和晚期转录。研究表明，ERK-RSK激活了Ets、AP-1、CREB和C/EBP等多种与IE基因表达相关的转录因子，从而导致依赖ERK-RSK激活的IE瞬时转录。尽管c-Fos作为持续的ERK-RSK激活的传感器，ORF 45-ERK-RSK信号转导介导c-Fos磷酸化和KSHV裂解性复制后期的积累，从而通过c-Fos与多个KSHV启动子的直接结合促进病毒转录。这一发现表明，在KSHV裂解生命周期期间，c-Fos在持续的ERK-RSK信号转导后介导不同的病毒转录进展。
Kaposi's sarcoma-associated herpesvirus (KSHV) encodes multiple viral proteins that activate extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) cascades. One of these viral proteins, ORF45, mediates sustained ERK-p90 ribosomal S6 kinase (RSK) activation during KSHV lytic replication and facilitates viral translation through the phosphorylation of a eukaryotic translation initiation factor, eIF4B. The importance of ERK-RSK activation for KSHV viral transcription has been shown; however, which transcription factor senses the sustained MAPK signaling and leads to viral transcription remains poorly understood. Here we show that the presence of ORF45 leads to the prolonged accumulation of c-Fos during the late stage of KSHV lytic replication through ERK-RSK-dependent phosphorylation and stabilization and that the depletion of c-Fos disrupts viral lytic transcription. Genome-wide screening revealed that c-Fos directly binds to multiple viral gene promoters and enhances viral transcription. Mutation of the ERK-RSK phosphorylation sites of c-Fos restrains KSHV lytic gene expression and virion production. These results indicate that the prolonged accumulation of c-Fos promotes the progression of viral transcription from early to late stages and accelerates viral lytic replication upon sustained ORF45-ERK-RSK activation during the KSHV lytic life cycle.IMPORTANCEDuring KSHV lytic replication, transient activation and sustained activation of ERK-RSK induce viral immediate early (IE) transcription and late transcription, respectively. Studies have revealed that ERK-RSK activates several transcription factors involved in IE gene expression, including Ets, AP-1, CREB, and C/EBP, which lead to the transient ERK-RSK activation-dependent IE transcription. Whereas c-Fos acts as a sensor of sustained ERK-RSK activation, ORF45-ERK-RSK signaling mediates c-Fos phosphorylation and accumulation during late KSHV lytic replication, consequently promoting viral transcription through the direct binding of c-Fos to multiple KSHV promoters. This finding indicates that c-Fos mediates distinct viral transcriptional progression following sustained ERK-RSK signaling during the KSHV lytic life cycle.