Virus-mediated nucleolar polyadenylation: a novel mechanism of RNA processing compartmentalisation to escape global mRNA degradation

RNA在其核输出和翻译成蛋白质之前必须经历一系列的加工过程。在哺乳动物细胞中，RNA的半衰期从几分钟到几小时不等。这种mRNA的转换可以通过它的3‘加工来调节，这既可以导致RNA的稳定，也可以促进其降解。这一过程特别重要，因为对RNA周转的调节提供了一种有效的方法来改变RNA的量，从而改变蛋白质的产生量。此外，许多人类疾病是由于RNA加工异常引起的，因此，了解病毒克服这些RNA降解途径的基本机制可能为未来的治疗干预提供线索。毫不奇怪，病毒已经进化出控制RNA3‘加工事件和RNA周转的方法。例如，卡波西肉瘤相关疱疹病毒(一种致癌疱疹病毒)的裂解感染导致宿主细胞基因表达的戏剧性和快速关闭；其中大多数细胞mRNAs由于病毒编码的Sox蛋白的表达而降解。SOX通过使细胞RNA具有超长的聚(A)尾巴而影响细胞RNA的3‘处理，这反过来又导致它们的不稳定和最终的降解。然而，一个耐人寻味的问题是，这些病毒RNA是如何逃避这一过程的。病毒mRNAs的转录和处理类似于细胞mRNAs，本质上也应该与细胞mRNAs同时降解。我们有令人兴奋的初步数据表明，一种病毒编码的蛋白质ORF57将细胞3‘处理因子重新分布到核仁中，这是核中一个不同的亚结构，为正确处理病毒RNA提供了替代环境，从而绕过了KSHV Sox介导的细胞mRNA降解机制。因此，这突显了一种病毒用来逃避全球RNA降解过程的新机制。我们现在的目标是进一步研究这些观察结果，并确定由ORF57蛋白重新分布到核仁中的细胞RNA处理复合体的成分。此外，我们将研究多蛋白质复合体是如何移动到核仁的，并评估细胞蛋白质在病毒RNA加工中的作用以及它们的功能是否对病毒复制至关重要。如果是这样的话，这可能为疱疹病毒感染的治疗干预提供新的策略。

RNA has to undergo a series of processing events prior to its nuclear export and translation into protein. In mammalian cells, the half-life of RNA can vary between a few minutes to many hours. This mRNA turnover can be regulated by its 3' processing which can either lead to the stabilisation of the RNA or enhance its degradation. This process is particularly important as the regulation of RNA turnover provides an effective way to alter the amount of RNA and thus the amount of protein produced. Moreover, many human diseases are due to aberrant RNA processing and as such understanding the fundemental mechanisms by which viruses can overcome these RNA degradation pathways may provide clues for therapeutic interventions in the future.It is not surprising that viruses have evolved ways to control RNA 3' processing events and thus RNA turnover. For example Kaposi's sarcoma-associated herpesvirus (an oncogenic herpesvirus) lytic infection leads to a dramatic and rapid shutoff of host cell gene expression; where the majority of cellular mRNAs are degraded due to the expression of the virally-encoded SOX protein. SOX affects the 3' processing of cellular RNAs by causing the RNAs to have extra long poly(A) tails, which in turn leads to their instability and resulting degradation. However, an intriguing question is how do these viral RNAs evade this process. The viral mRNAs are transcribed and processed similar to cellular mRNAs and in essence should also be degraded at the same time as the cellular mRNAs. We have exciting preliminary data to suggest that a virally-encoded protein, ORF57, redistributes cellular 3' processing factors into the nucleolus, a distinct sub-structure in the nucleus, which provides an alternative environment for the correct processing of viral RNAs, therefore bypassing the KSHV SOX-mediated degradation mechanism for cellular mRNAs. As such, this highlights a novel mechanism employed by a virus to evade a global RNA degradation process. We now aim to further investigate these observations and identify the components of the cellular RNA processing complex that are redistributed into the nucleolus by the ORF57 protein. Moreover, we will investigate how the multi-protein complex is moved to the nucleolus and also assess the role of the cellular proteins in viral RNA processing and whether their function is essential for virus replication. If so, this may provide new strategies for the therapeutic intervention of herpesvirus infections.