YTHDF1和YTHDC1 m6A读取器蛋白调控HTLV-1 tax和hbz活性。

IF 4 2区 医学 Q2 VIROLOGY
Journal of Virology Pub Date : 2025-03-18 Epub Date: 2025-02-04 DOI:10.1128/jvi.02063-24
Emily M King, Amanda Midkiff, Karsyn McClain, Sanggu Kim, Amanda R Panfil
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引用次数: 0

摘要

人类t细胞白血病病毒1型(HTLV-1)是一种逆转录病毒,可导致成人t细胞白血病/淋巴瘤(ATLL)和HTLV-1相关的脊髓病/热带痉挛性截瘫(HAM/TSP),这是一种进行性神经退行性疾病。病毒基因表达的调控在病毒的持久性和发病机制中起着关键作用。然而,这种微调调控的分子机制仍然知之甚少。关于HTLV-1 RNA的化学修饰以及这些修饰如何影响病毒生物学和疾病发展,我们知之甚少。RNA的转录后化学修饰在真核生物中很常见,其中n6 -甲基腺苷(m6A)最为普遍。在这项研究中,我们研究了m6A RNA修饰对HTLV-1基因表达的作用。使用MeRIP-Seq,我们将m6A修饰位点定位到病毒基因组的3'端。我们发现HTLV-1 RNA以及病毒致癌基因转录本tax和hbz都含有m6A修饰。htlv -1转化细胞中m6a的缺失降低了义源性病毒基因(Tax、Gag和Env),增加了反义源性Hbz的表达。在HTLV-1 t细胞系中,Tax和hbz转录本被读卡器蛋白YTHDF1和YTHDC1结合。通过表达载体和shrna介导的敲低,我们发现YTHDF1对病毒基因表达有相反的作用,减少义源性病毒基因,增加反义源性病毒基因。进一步研究发现,YTHDF1对税收丰度的影响依赖于税收m6A沉积。核m6A解读蛋白YTHDC1影响了正义和反义衍生病毒转录本的丰度,并特异性地增强了税收转录本的核输出。总之,我们的研究结果表明,全球m6A水平和m6A解读蛋白YTHDF1和YTHDC1调节HTLV-1基因的表达。人类t细胞白血病病毒1型(HTLV-1)的持久性和发病机制是通过严格调控病毒基因表达来控制的。RNA的命运可以通过影响基因表达而不改变DNA序列的表观遗传修饰来控制。我们的研究详细介绍了n6 -甲基腺苷(m6A) RNA化学修饰对HTLV-1基因表达的影响。我们发现,全球m6A水平的降低影响了病毒基因表达,降低了Tax和其他义源性病毒基因,而增加了反义源性Hbz。我们的研究结果表明,细胞中的致癌病毒转录物tax和hbz是m6a修饰的。我们发现这些病毒RNA修饰由YTHDF1和YTHDC1解读,它们决定了病毒RNA的命运。了解HTLV-1 RNA的化学修饰为HTLV-1相关疾病的新治疗策略提供了潜在的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
YTHDF1 and YTHDC1 m6A reader proteins regulate HTLV-1 tax and hbz activity.

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus responsible for adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive neurodegenerative disease. Regulation of viral gene expression plays a key role in viral persistence and pathogenesis. However, the molecular mechanisms underlying this fine-tuned regulation remain poorly understood. Little is known regarding RNA chemical modifications of HTLV-1 RNA and how these affect viral biology and disease development. Post-transcriptional chemical modification of RNA is common in eukaryotes, with N6-methyladenosine (m6A) being the most prevalent. In this study, we investigated the role of m6A RNA modifications on HTLV-1 gene expression. Using MeRIP-Seq, we mapped the sites of m6A modification to the 3' end of the viral genome. We found HTLV-1 RNA, as well as viral oncogene transcripts tax and hbz, contained m6A modifications. m6A-depletion in HTLV-1-transformed cells decreased sense-derived viral genes (Tax, Gag, and Env) and increased antisense-derived Hbz expression. Tax and hbz transcripts were bound by reader proteins YTHDF1 and YTHDC1 in a panel of HTLV-1 T-cell lines. Using expression vectors and shRNA-mediated knockdown, we found that YTHDF1 had opposing effects on viral gene expression, decreasing sense-derived viral genes and increasing antisense-derived Hbz. Upon further study, the YTHDF1 effects on tax abundance were dependent on tax m6A deposition. The nuclear m6A reader protein YTHDC1 affected the abundance of both sense- and antisense-derived viral transcripts and specifically enhanced the nuclear export of tax transcript. Collectively, our results demonstrate global m6A levels and m6A reader proteins YTHDF1 and YTHDC1 regulate HTLV-1 gene expression.IMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) persistence and pathogenesis are controlled through tight regulation of viral gene expression. The fate of RNA can be controlled by epigenetic modifications that impact gene expression without altering the DNA sequence. Our study details the impact of N6-methyladenosine (m6A) RNA chemical modifications on HTLV-1 gene expression. We found that reductions in global m6A levels affected viral gene expression, decreasing Tax and other sense-derived viral genes, whereas increasing the antisense-derived Hbz. Our results suggest the oncogenic viral transcripts, tax and hbz, are m6A-modified in cells. We found that these viral RNA modifications are interpreted by reader proteins YTHDF1 and YTHDC1, which dictate the fate of the viral RNA. Understanding HTLV-1 RNA chemical modifications offers potential insights into novel therapeutic strategies for HTLV-1-associated diseases.

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来源期刊
Journal of Virology
Journal of Virology 医学-病毒学
CiteScore
10.10
自引率
7.40%
发文量
906
审稿时长
1 months
期刊介绍: Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.
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