Coordinated Destruction of Cellular Messages in Translation Complexes by the Gammaherpesvirus Host Shutoff Factor and the Mammalian Exonuclease Xrn1

Several viruses encode factors that promote host mRNA degradation to silence gene expression. It is unclear, however, whether cellular mRNA turnover pathways are engaged to assist in this process. In Kaposi's sarcoma-associated herpesvirus this phenotype is enacted by the host shutoff factor SOX. Here we show that SOX-induced mRNA turnover is a two-step process, in which mRNAs are first cleaved internally by SOX itself then degraded by the cellular exonuclease Xrn1. SOX therefore bypasses the regulatory steps of deadenylation and decapping normally required for Xrn1 activation. SOX is likely recruited to translating mRNAs, as it cosediments with translation initiation complexes and depletes polysomes. Cleaved mRNA intermediates accumulate in the 40S fraction, indicating that recognition occurs at an early stage of translation. This is the first example of a viral protein commandeering cellular mRNA turnover pathways to destroy host mRNAs, and suggests that Xrn1 is poised to deplete messages undergoing translation in mammalian cells.

多种病毒可编码促进宿主mRNA降解以沉默基因表达的因子。然而目前尚不明确细胞mRNA代谢通路是否会参与协助这一过程。在卡波西肉瘤相关疱疹病毒（Kaposi's sarcoma-associated herpesvirus）中，该表型由宿主基因表达关闭因子SOX介导。本研究发现，SOX诱导的mRNA降解分为两步：首先由SOX自身对mRNA进行内部切割，随后由细胞外切核酸酶Xrn1完成降解。因此，SOX绕过了Xrn1激活通常所需的脱腺苷酸化与脱帽调控步骤。SOX大概率被招募至正在翻译的mRNA分子，因其可与翻译起始复合物共沉降并耗竭多聚核糖体。切割产生的mRNA中间产物在40S组分中积累，表明识别过程发生于翻译早期阶段。这是首个病毒蛋白劫持细胞mRNA代谢通路以破坏宿主mRNA的研究案例，同时提示哺乳动物细胞中Xrn1可随时靶向耗竭正在进行翻译的mRNA。