Resveratrol inhibits KSHV reactivation by lowering the levels of cellular EGR-1.
Resveratrol inhibits KSHV reactivation by lowering the levels of cellular EGR-1.
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DOI：
10.1371/journal.pone.0033364
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Akula SM
中科院分区：
文献类型：
--
作者：
Dyson OF;Walker LR;Whitehouse A;Cook PP;Akula SM
在疱疹病毒研究领域，这种病毒从潜伏期重新激活的确切分子机制仍然难以捉摸。卡波西肉瘤相关疱疹病毒（KSHV）主要以潜伏状态存在，而在任何特定时间只有1-3%的细胞支持裂解感染。KSHV从潜伏期再激活是一个非常复杂的过程，由病毒和细胞因子的整合介导。以前，我们的实验室已经描述了早期生长反应-1（Egr-1）作为KSHV再激活过程的重要组成部分，通过其介导KSHV ORF 50转录的能力，ORF 50是编码复制和转录激活因子（RTA）的基因，是一种已知控制从潜伏感染到裂解感染的病毒组分。在此，电泳迁移率变动分析（EMSA）和染色质免疫沉淀（ChIP）实验揭示Egr-1在至少两个不同的富含GC的结合结构域中结合KSHV ORF 50启动子（ORF 50 P）。在从头KSHV感染过程中，细胞的EST-I和KSHV编码的ORF 50的表达谱遵循相似的模式。在KSHV感染的细胞中过表达Egr-1（Raf>MEK> ERK 1/2下游的信号传导组分）激活KSHV裂解性复制。通过进行更多的生理相关实验，我们分析了含有白藜芦醇的膳食补充剂对KSHV感染细胞的影响。我们的研究结果，第一次，证明白藜芦醇在降低ERK 1/2的活性和表达的Egr-1在KSHV感染的细胞，导致抑制病毒再激活的潜伏期。总之，这些发现无疑将有助于未来的研究，不仅打击KSHV相关的疾病条件，而且对其他疱疹病毒诱导的发病机制。
In the field of herpesvirus research, the exact molecular mechanism by which such viruses reactivate from latency remains elusive. Kaposi's sarcoma-associated herpesvirus (KSHV) primarily exists in a latent state, while only 1–3% of cells support lytic infection at any specific time. KSHV reactivation from latency is an exceedingly intricate process mediated by the integration of viral and cellular factors. Previously, our lab has described early growth response-1 (Egr-1) as an essential component for the KSHV reactivation process via its ability to mediate transcription of KSHV ORF50, the gene encoding for replication and transcription activator (RTA), a viral component known to control the switch from latent to lytic infection. In here, electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) experiments revealed that Egr-1 binds KSHV ORF50 promoter (ORF50P) in at least two different GC-rich binding domains. Expression profiles of cellular egr-1 and KSHV-encoded ORF50 follow a similar pattern during de novo KSHV infection. Over-expressing Egr-1, a signaling component downstream of Raf>MEK>ERK1/2, in KSHV-infected cells activates KSHV lytic replication. Through performing more physiologically relevant experiments, we analyzed the effect of a dietary supplement containing resveratrol on KSHV-infected cells. Our results, for the first time, demonstrate resveratrol to act in lowering ERK1/2 activity and expression of Egr-1 in KSHV-infected cells, resulting in the suppression of virus reactivation from latency. Taken together, these findings will undoubtedly contribute to future studies on not only combating KSHV related disease conditions, but also on other herpesviruses-induced pathogenesis.
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