XRN1 stalling in the 5' UTR of Hepatitis C virus and Bovine Viral Diarrhea virus is associated with dysregulated host mRNA stability.
XRN1 stalling in the 5' UTR of Hepatitis C virus and Bovine Viral Diarrhea virus is associated with dysregulated host mRNA stability.
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DOI：
10.1371/journal.ppat.1004708
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发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Wilusz J
中科院分区：
文献类型：
--
作者：
Moon SL;Blackinton JG;Anderson JR;Dozier MK;Dodd BJ;Keene JD;Wilusz CJ;Bradrick SS;Wilusz J
我们证明，丙型肝炎病毒（HCV）和牛病毒性腹泻病毒（BVDV）在其5'UTR中均含有停滞和抑制细胞5'-3 '核糖核酸外切酶XRN 1酶活性的区域，导致细胞mRNA稳定性发生显著变化。我们使用生化测定、病毒感染以及在不存在其他病毒基因产物的情况下转染HCV和BVDV 5'非翻译区来直接证明这种新型宿主-病毒相互作用的存在和机制。在HCV感染的背景下，我们观察到mRNA的稳定性总体增加，导致编码各种相关癌基因和血管生成因子的正常短寿命mRNA的丰度显著增加。这些发现表明，来自黄病毒科多个属的非编码区干扰XRN 1并影响转录后过程，导致细胞基因表达的整体失调，这可能促进细胞生长和发病。了解丙型肝炎病毒（HCV）等持续性病毒在感染过程中如何与细胞机制相互作用，可以为致病机制提供重要见解。我们证明，当试图降解HCV转录物时，一种称为XRN 1的主要细胞外切核酸酶停滞并在病毒mRNA的5'非编码区受到抑制。有趣的是，XRN 1在5' UTR中停滞的区域包括翻译起始所需的病毒IRES，揭示了这个充分研究的区域的新的、意想不到的功能。差异mRNA稳定性是细胞中基因表达的主要调节因子。奇怪的是，细胞XRN 1核酸外切酶的抑制与HCV感染细胞中mRNA衰减的一般抑制有关。因此，在HCV感染期间，许多细胞mRNA以失调的方式稳定和积累。正常情况下，短寿命的mRNAs会受到不成比例的影响，包括编码免疫调节因子和致癌基因的mRNAs。因此，本研究提示HCV的5' UTR在包括肝细胞癌在内的分子发病机制中具有新的作用。此外，牛病毒性腹泻病毒的5' UTR还抑制XRN 1酶并稳定细胞mRNA。因此，5'UTR介导的XRN 1抑制策略似乎在黄病毒科的载体非依赖性成员中是保守的。
We demonstrate that both Hepatitis C virus (HCV) and Bovine Viral Diarrhea virus (BVDV) contain regions in their 5’ UTRs that stall and repress the enzymatic activity of the cellular 5’-3’ exoribonuclease XRN1, resulting in dramatic changes in the stability of cellular mRNAs. We used biochemical assays, virus infections, and transfection of the HCV and BVDV 5’ untranslated regions in the absence of other viral gene products to directly demonstrate the existence and mechanism of this novel host-virus interaction. In the context of HCV infection, we observed globally increased stability of mRNAs resulting in significant increases in abundance of normally short-lived mRNAs encoding a variety of relevant oncogenes and angiogenesis factors. These findings suggest that non-coding regions from multiple genera of the Flaviviridae interfere with XRN1 and impact post-transcriptional processes, causing global dysregulation of cellular gene expression which may promote cell growth and pathogenesis. Understanding how a persistent virus like Hepatitis C Virus (HCV) interfaces with the cellular machinery during infection can provide significant insights into mechanisms of pathogenesis. We demonstrate that while trying to degrade HCV transcripts, a major cellular exonuclease called XRN1 stalls and gets repressed in the 5’ noncoding region of the viral mRNA. Interestingly, the region where XRN1 stalls in the 5’ UTR includes the viral IRES that is required for translation initiation, uncovering a novel, unexpected function for this well-studied region. Differential mRNA stability is a major regulator of gene expression in cells. Curiously, repression of the cellular XRN1 exonuclease is associated with a general repression of mRNA decay in general in HCV-infected cells. Thus numerous cellular mRNAs are stabilized and accumulate in a dysregulated fashion during HCV infection. Normally short-lived mRNAs are disproportionately affected—including mRNAs that encode immune regulators and oncogenes. Thus, this study suggests a novel role for the 5’ UTR of HCV in molecular pathogenesis—including hepatocellular carcinoma. Furthermore, the 5’ UTR of Bovine Viral Diarrhea virus also represses the XRN1 enzyme and stabilizes cellular mRNA. Therefore a strategy of 5’ UTR-mediated XRN1 repression appears to be conserved among the vector-independent members of the Flaviviridae.
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