EBV tegument protein BNRF1 disrupts DAXX-ATRX to activate viral early gene transcription.
EBV tegument protein BNRF1 disrupts DAXX-ATRX to activate viral early gene transcription.
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DOI：
10.1371/journal.ppat.1002376
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发表时间：
2011-11
期刊：
影响因子：
6.7
通讯作者：
Lieberman PM
中科院分区：
文献类型：
--
作者：
Tsai K;Thikmyanova N;Wojcechowskyj JA;Delecluse HJ;Lieberman PM
疱疹病毒的生产性感染涉及通过病毒编码的被膜蛋白使宿主细胞内在防御失效。EB病毒（EBV）通常建立一个非生产性的，潜伏性感染，目前还不清楚它如何面对宿主细胞的内在防御，限制病毒基因的表达。在这里，我们表明，EB病毒主要被膜蛋白BNRF 1的目标宿主细胞的内在防御蛋白，并促进病毒的早期基因激活。具体来说，我们证明了BNRF 1与宿主核蛋白Daxx在PML核小体（PML-NBs）相互作用，并破坏了Daxx-ATRX染色质重塑复合物的形成。我们将Daxx相互作用域映射到BNRF 1上，并表明该域对于支持EBV原发感染是重要的。通过逆转录PCR和感染试验，我们表明，BNRF 1支持病毒基因表达后，早期感染，这种功能是依赖于Daxx相互作用域。最后，我们表明，敲低Daxx和ATRX诱导潜伏感染的淋巴母细胞系（LCL）的EBV的再活化，这表明Daxx和ATRX在病毒染色质的调节中发挥作用。综上所述，我们的数据表明BNRF 1通过与Daxx和ATRX相互作用在支持EBV早期感染中起重要作用;并表明PML-NB相关抗病毒抗性的被膜破坏是细胞核中疱疹病毒感染的普遍要求。EB病毒（EBV）的持续感染与多种疾病相关，包括淋巴和上皮肿瘤。尽管关于病毒持续存在的机制有大量的信息，但对EBV感染和病毒基因激活的早期步骤知之甚少。宿主细胞积极地对病毒感染产生抵抗力，病毒需要克服这些抵抗力才能入侵细胞。我们已经发现，在包装在EBV病毒颗粒中的蛋白质中，BNRF 1起着抵消细胞防御的重要作用。我们表明，EBV蛋白BNRF 1结合细胞蛋白Daxx和分解的Daxx-ATRX复合物，其中Daxx和ATRX都是细胞蛋白，已知抑制病毒基因表达。我们还证实BNRF 1可以促进早期病毒基因的表达，并且BNRF 1的Daxx结合是该功能所必需的。最后，我们证明了Daxx和ATRX在潜伏期抑制病毒基因表达。我们的结论是，BNRF 1分解细胞的抗病毒防御机制，以促进病毒基因在宿主细胞中的表达。
Productive infection by herpesviruses involve the disabling of host-cell intrinsic defenses by viral encoded tegument proteins. Epstein-Barr Virus (EBV) typically establishes a non-productive, latent infection and it remains unclear how it confronts the host-cell intrinsic defenses that restrict viral gene expression. Here, we show that the EBV major tegument protein BNRF1 targets host-cell intrinsic defense proteins and promotes viral early gene activation. Specifically, we demonstrate that BNRF1 interacts with the host nuclear protein Daxx at PML nuclear bodies (PML-NBs) and disrupts the formation of the Daxx-ATRX chromatin remodeling complex. We mapped the Daxx interaction domain on BNRF1, and show that this domain is important for supporting EBV primary infection. Through reverse transcription PCR and infection assays, we show that BNRF1 supports viral gene expression upon early infection, and that this function is dependent on the Daxx-interaction domain. Lastly, we show that knockdown of Daxx and ATRX induces reactivation of EBV from latently infected lymphoblastoid cell lines (LCLs), suggesting that Daxx and ATRX play a role in the regulation of viral chromatin. Taken together, our data demonstrate an important role of BNRF1 in supporting EBV early infection by interacting with Daxx and ATRX; and suggest that tegument disruption of PML-NB-associated antiviral resistances is a universal requirement for herpesvirus infection in the nucleus. Persistent infection by Epstein-Barr virus (EBV) is associated with a variety of diseases, including lymphoid and epithelial tumors. Despite a wealth of information on the mechanism of viral persistence, relatively little is known about the early steps of EBV infection and viral gene activation. Host cells actively mount resistances against viral infection, which viruses need to overcome to invade the cell. We have found that among the proteins packaged in the EBV viral particle, BNRF1 plays an important role of counteracting cellular defenses. We show that EBV protein BNRF1 binds to the cellular protein Daxx and disassembles the Daxx-ATRX complex, where both Daxx and ATRX are cellular proteins known to inhibit viral gene expression. We also confirm that BNRF1 can promote expression of early viral genes, and that Daxx-binding by BNRF1 is required for this function. Finally, we demonstrate that Daxx and ATRX repress viral gene expression during latency. We conclude that BNRF1 disassembles cellular antiviral defense machinery to promote expression of viral genes in the host cell.
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