乙型肝炎病毒前基因組RNA穩定性的調節和組蛋白脫乙酰基酶5

StephenW

Modulation of hepatitis B virus pregenomic RNA stability and splicing by histone deacetylase 5 enhances viral biosynthesis

    Taha Y. Taha,
    Varada Anirudhan,
    Umaporn Limothai,
    Daniel D. Loeb,
    Pavel A. Petukhov ,
    Alan McLachlan
    Published: August 21, 2020
    https://doi.org/10.1371/journal.ppat.1008802

   
Abstract

Hepatitis B virus (HBV) is a worldwide health problem without curative treatments. Investigation of the regulation of HBV biosynthesis by class I and II histone deacetylases (HDACs) demonstrated that catalytically active HDAC5 upregulates HBV biosynthesis. HDAC5 expression increased both the stability and splicing of the HBV 3.5 kb RNA without altering the translational efficiency of the viral pregenomic or spliced 2.2 kb RNAs. Together, these observations point to a broader role of HDAC5 in regulating RNA splicing and transcript stability while specifically identifying a potentially novel approach toward antiviral HBV therapeutic development.
Author summary

This study demonstrates that HDAC5 deacetylation of host cellular factor(s) results in increased HBV biosynthesis by enhancing viral transcript stability and splicing via direct or indirect binding of host factors to viral intron sequences. This represents the first demonstration of this type of post-transcriptional regulation in the liver and is similar to observations seen for cellular transcripts in neural and cardiac cell types. These observations suggest a more general phenomena which could represent an additional posttranscriptional code governing the regulation of RNA:protein interactions and hence RNA metabolism. Therefore, covalent modifications of RNA binding proteins may modulate post-transcriptional gene expression in an analogous manner to the known histone code that controls gene transcription. Although this analysis primarily relates to the mechanism(s) by which HDAC5 governs HBV RNA metabolism, it does have significant therapeutic implications. The inhibition of HDAC5 in combination with current nucleos(t)ide analog drugs targeting the viral reverse transcriptase/DNA polymerase might aid in the treatment and possible resolution of chronic infections by targeting both host and viral factors.

StephenW

乙型肝炎病毒前基因組RNA穩定性的調節和組蛋白脫乙酰基酶5的剪接增強了病毒的生物合成

    Taha Y. Taha，
    Varada Anirudhan，
    烏瑪蓬·李莫泰，
    丹尼爾·勒布（Daniel D. Loeb）
    帕維爾·佩圖霍夫（Pavel A.
    艾倫·麥克拉克倫
    發佈時間：2020年8月21日
    https://doi.org/10.1371/journal.ppat.1008802

   
抽象

乙肝病毒（HBV）是一種全球性的健康問題，無需治療。通過I類和II類組蛋白脫乙酰基酶（HDAC）對HBV生物合成的調控研究表明，催化活性HDAC5上調了HBV生物合成。 HDAC5表達增加了HBV 3.5 kb RNA的穩定性和剪接，而沒有改變病毒前基因組或剪接的2.2 kb RNA的翻譯效率。在一起，這些觀察結果表明HDAC5在調節RNA剪接和轉錄本穩定性方面具有更廣泛的作用，同時專門確定了抗病毒HBV治療發展的潛在新方法。
作者摘要

這項研究表明，宿主細胞因子的HDAC5脫乙酰作用可通過增強病毒轉錄本的穩定性和通過宿主因子與病毒內含子序列的直接或間接結合來剪接，從而導致HBV生物合成增加。這代表了肝臟中這種轉錄後調控的首次證明，並且與神經和心臟細胞類型中細胞轉錄物的觀察結果相似。這些觀察結果表明了一種更普遍的現象，該現象可能代表控制RNA：蛋白質相互作用以及RNA代謝調控的附加轉錄後密碼。因此，RNA結合蛋白的共價修飾可能以類似於控制基因轉錄的已知組蛋白密碼的方式調節轉錄後基因的表達。儘管此分析主要涉及HDAC5控制HBV RNA代謝的機制，但確實具有重要的治療意義。 HDAC5與目前針對病毒逆轉錄酶/ DNA聚合酶的核苷酸類似物藥物的抑製作用可能同時針對宿主和病毒因素，有助於慢性感染的治療和可能的解決。

StephenW

https://journals.plos.org/plospa ... ournal.ppat.1008802