Coordinated destruction of cellular messages in translation complexes by the gammaherpesvirus host shutoff factor and the mammalian exonuclease Xrn1.
Coordinated destruction of cellular messages in translation complexes by the gammaherpesvirus host shutoff factor and the mammalian exonuclease Xrn1.
复制标题
DOI：
10.1371/journal.ppat.1002339
复制
发表时间：
2011-10
期刊：
影响因子：
6.7
通讯作者：
Glaunsinger BA
中科院分区：
文献类型：
--
作者：
Covarrubias S;Gaglia MM;Kumar GR;Wong W;Jackson AO;Glaunsinger BA
几种病毒编码促进宿主mRNA降解的因子以沉默基因表达。然而，目前尚不清楚细胞mRNA转换途径是否参与了这一过程。在卡波西氏肉瘤相关疱疹病毒中，这种表型是由宿主关闭因子SOX制定的。在这里，我们发现SOX诱导的mRNA转换是一个两步过程，其中mRNA首先被SOX本身内部切割，然后被细胞外切酶Xrn1降解。因此，SOX绕过了Xrn1激活通常需要的死基化和脱帽的调节步骤。SOX可能被招募来翻译mrna，因为它与翻译起始复合物共同沉积并消耗多聚体。裂解的mRNA中间体聚集在40S部分，表明识别发生在翻译的早期阶段。这是病毒蛋白控制细胞mRNA转换途径破坏宿主mRNA的第一个例子，表明Xrn1准备耗尽哺乳动物细胞中正在翻译的信息。病毒使用许多策略来控制宿主机器并为其复制创造最佳环境。致癌性γ疱疹病毒（如卡波西肉瘤相关疱疹病毒（KSHV））采用的一种策略是通过广泛破坏mrna来阻断细胞基因表达。一种名为SOX的病毒蛋白足以驱动这种表型，但其机制尚不清楚。在这里，我们表明宿主mRNA的破坏是SOX和细胞RNA降解酶Xrn1协同作用的结果。通过在内部切割mrna， SOX激活Xrn1的活性，同时绕过通常阻止该酶过早降解mrna的调节机制。我们还发现SOX与翻译复合物共同沉积，并在翻译的早期阶段特异性地靶向mrna进行切割。我们假设这允许病毒选择性地靶向mrna，从而解放宿主基因表达机制。总的来说，这些发现描述了伽马疱疹病毒SOX蛋白与细胞降解机制之间的一种新的相互作用，并阐明了单个病毒成分如何劫持细胞机制来有效地破坏信息。
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. Viruses use a number of strategies to commandeer host machinery and create an optimal environment for their replication. One strategy employed by oncogenic gammaherpesviruses such as Kaposi's sarcoma-associated herpesvirus (KSHV) is to block cellular gene expression through extensive destruction of mRNAs. A single viral protein called SOX is sufficient to drive this phenotype, but the mechanism by which it does so has remained unclear. Here we show that host mRNA destruction is the result of the coordinated action of SOX and a cellular RNA degrading enzyme, Xrn1. By cleaving mRNAs internally, SOX recruits the activity of Xrn1 while bypassing the regulatory mechanisms that normally prevent this enzyme from prematurely degrading mRNAs. We also find that SOX co-sediments with translation complexes, and specifically targets mRNAs for cleavage at an early stage of translation. We hypothesize this allows the virus to selectively target mRNAs, thereby liberating host gene expression machinery. Collectively, these findings describe a novel interplay between the gammaherpesvirus SOX protein and cellular degradation machinery, and shed light on how a single viral component can hijack cellular machinery to efficiently destroy messages.
登录
查看更多内容
影响因子：
3.7
作者：
Clyde, Karen;Glaunsinger, Britt A.
通讯作者：
Glaunsinger, Britt A.
影响因子：
5.4
作者：
Covarrubias, Sergio;Richner, Justin M.;Glaunsinger, Britt A.
通讯作者：
Glaunsinger, Britt A.
影响因子：
5.4
作者：
Feng, PH;Everly, DN;Read, GS
通讯作者：
Read, GS
影响因子：
5.4
作者：
Elgadi, MM;Hayes, CE;Smiley, JR
通讯作者：
Smiley, JR
影响因子：
14.9
作者：
BAYLIS, SA;PURIFOY, DJM;LITTLER, E
通讯作者：
LITTLER, E