Department of Chemistry, University of Cambridge, Cambridge, UK.
1] Tumour Immunology, Department of Immunology, Clive Berghofer Cancer Research Centre, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. [2] QIMR Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Nat Chem Biol. 2014 May;10(5):358-64. doi: 10.1038/nchembio.1479. Epub 2014 Mar 16.
Viruses that establish latent infections have evolved unique mechanisms to avoid host immune recognition. Maintenance proteins of these viruses regulate their synthesis to levels sufficient for maintaining persistent infection but below threshold levels for host immune detection. The mechanisms governing this finely tuned regulation of viral latency are unknown. Here we show that mRNAs encoding gammaherpesviral maintenance proteins contain within their open reading frames clusters of unusual structural elements, G-quadruplexes, which are responsible for the cis-acting regulation of viral mRNA translation. By studying the Epstein-Barr virus-encoded nuclear antigen 1 (EBNA1) mRNA, we demonstrate that destabilization of G-quadruplexes using antisense oligonucleotides increases EBNA1 mRNA translation. In contrast, pretreatment with a G-quadruplex-stabilizing small molecule, pyridostatin, decreases EBNA1 synthesis, highlighting the importance of G-quadruplexes within virally encoded transcripts as unique regulatory signals for translational control and immune evasion. Furthermore, these findings suggest alternative therapeutic strategies focused on targeting RNA structure within viral ORFs.
潜伏感染病毒已进化出独特的机制来逃避宿主免疫识别。这些病毒的维持蛋白调节其合成水平，使其足以维持持续感染，但低于宿主免疫检测的阈值水平。调节病毒潜伏的这种精细调控的机制尚不清楚。在这里，我们表明编码γ疱疹病毒维持蛋白的 mRNAs 在其开放阅读框内包含簇状的不寻常结构元素，即 G-四联体，它们负责病毒 mRNA 翻译的顺式作用调节。通过研究 Epstein-Barr 病毒编码的核抗原 1（EBNA1）mRNA，我们证明使用反义寡核苷酸破坏 G-四联体可增加 EBNA1 mRNA 的翻译。相比之下，用 G-四联体稳定小分子吡啶硫酮预处理会降低 EBNA1 的合成，这突出了病毒编码转录本中 G-四联体作为翻译控制和免疫逃避的独特调节信号的重要性。此外，这些发现表明，针对病毒 ORFs 内的 RNA 结构的替代治疗策略具有重要意义。
