Gammaherpesviral gene expression and virion composition are broadly controlled by accelerated mRNA degradation.
Gammaherpesviral gene expression and virion composition are broadly controlled by accelerated mRNA degradation.
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DOI：
10.1371/journal.ppat.1003882
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发表时间：
2014-01
期刊：
影响因子：
6.7
通讯作者：
Glaunsinger B
中科院分区：
文献类型：
--
作者：
Abernathy E;Clyde K;Yeasmin R;Krug LT;Burlingame A;Coscoy L;Glaunsinger B
裂解性γ疱疹病毒感染通过病毒核酸内切酶SOX的活性促进细胞质mRNA的广泛降解来限制宿主基因表达。尽管通常认为SOX对细胞转录物具有选择性，但SOX影响病毒mRNA稳定性的程度仍然未知。我们使用小鼠γ疱疹病毒MHV 68模型解决了这个问题，出乎意料地发现，病毒基因表达的所有阶段都是通过mRNA降解来控制的。使用全面的RNA表达谱和半衰期研究，我们揭示了大多数病毒mRNA的水平，但不是非编码RNA的缓和MHV 68 SOX（muSOX）的活动。muSOX对病毒mRNA的靶向作用在功能上是重要的，因为它影响细胞内病毒蛋白丰度和子代病毒体组成。在不存在muSOX施加的基因表达控制的情况下，病毒颗粒显示增加的细胞表面结合和进入以及增强的立即早期基因表达。这些表型最终导致多种细胞类型以及体内的病毒复制缺陷，突出了在γ疱疹病毒感染期间维持病毒RNA适当平衡的重要性。这是病毒在宿主关闭期间未能广泛区分细胞和病毒转录物的第一个例子，而是使用病毒信息的靶向来微调整体基因表达。许多病毒在感染过程中限制宿主基因表达，可能是为了给病毒转录物提供竞争性表达优势。因此，诱导这种“宿主关闭”表型的病毒通常具有选择性地保留病毒基因的机制，这并不奇怪。γ疱疹病毒通过诱导广泛的mRNA降解促进宿主关闭，这是由病毒SOX核酸酶启动的过程。然而，SOX在感染过程中对病毒mRNA的影响尚不清楚。在这里，我们发现，在感染鼠γ疱疹病毒MHV 68，大多数的病毒转录的所有动力学类广泛下调，通过活动的MHV 68 SOX蛋白（muSOX）。我们进一步证明，在没有muSOX诱导的病毒mRNA丰度控制的情况下，病毒蛋白水平增加，从而影响子代病毒颗粒的组成。改变的病毒体组成直接影响早期事件，如进入和诱导裂解基因表达在随后的几轮复制。此外，通过整体mRNA降解降低病毒和宿主基因表达对于体外和体内以细胞类型特异性方式进行病毒复制至关重要。这是第一个真核病毒的宿主关闭机制类似地调节病毒基因表达的例子，并强调了γ疱疹病毒基因表达必须微调以确保复制成功的程度。
Lytic gammaherpesvirus infection restricts host gene expression by promoting widespread degradation of cytoplasmic mRNA through the activity of the viral endonuclease SOX. Though generally assumed to be selective for cellular transcripts, the extent to which SOX impacts viral mRNA stability has remained unknown. We addressed this issue using the model murine gammaherpesvirus MHV68 and, unexpectedly, found that all stages of viral gene expression are controlled through mRNA degradation. Using both comprehensive RNA expression profiling and half-life studies we reveal that the levels of the majority of viral mRNAs but not noncoding RNAs are tempered by MHV68 SOX (muSOX) activity. The targeting of viral mRNA by muSOX is functionally significant, as it impacts intracellular viral protein abundance and progeny virion composition. In the absence of muSOX-imposed gene expression control the viral particles display increased cell surface binding and entry as well as enhanced immediate early gene expression. These phenotypes culminate in a viral replication defect in multiple cell types as well as in vivo, highlighting the importance of maintaining the appropriate balance of viral RNA during gammaherpesviral infection. This is the first example of a virus that fails to broadly discriminate between cellular and viral transcripts during host shutoff and instead uses the targeting of viral messages to fine-tune overall gene expression. Many viruses restrict host gene expression during infection, presumably to provide a competitive expression advantage to viral transcripts. Not surprisingly, viruses that induce this ‘host shutoff’ phenotype therefore generally possess mechanisms to selectively spare viral genes. Gammaherpesviruses promote host shutoff by inducing widespread mRNA degradation, a process initiated by the viral SOX nuclease. However, the effect of SOX on viral mRNA during infection was unknown. Here, we reveal that during infection with the murine gammaherpesvirus MHV68, the majority of viral transcripts of all kinetic classes are broadly down regulated through the activity of the MHV68 SOX protein (muSOX). We further demonstrate that in the absence of muSOX-induced control of viral mRNA abundance, viral protein levels increase, thereby affecting the composition of progeny viral particles. Altered virion composition directly impacts early events such as entry and induction of lytic gene expression in subsequent rounds of replication. Furthermore, decreasing both virus and host gene expression via global mRNA degradation is critical for viral replication in a cell type specific manner both in vitro and in vivo. This is the first example of a eukaryotic virus whose host shutoff mechanism similarly tempers viral gene expression, and highlights the degree to which gammaherpesviral gene expression must be fine tuned to ensure replicative success.
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