Bovine leukemia virus-derived long-noncoding RNA, AS1-S, binds to bovine hnRNPM and alters interaction properties between hnRNPM and host mRNAs
Bovine leukemia virus-derived long-noncoding RNA, AS1-S, binds to bovine hnRNPM and alters interaction properties between hnRNPM and host mRNAs
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DOI：
10.1101/2023.02.27.530377
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发表时间：
2023-02
期刊：
影响因子：
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通讯作者：
Kiyohiko Andoh;A. Nishimori;Y. Matsuura
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文献类型：
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作者：
Kiyohiko Andoh;A. Nishimori;Y. Matsuura
病毒利用几种策略来发展潜伏感染和逃避宿主免疫反应。长非编码RNA(Long Non-Coding RNA，LncRNA)是一类编码RNA的非蛋白质，通过与RNA结合蛋白相互作用来调节细胞的各种功能，由于其缺乏抗原性，是导致病毒潜伏的关键因素。牛白血病病毒属于逆转录病毒科，其编码的LncRNAAS1-S是潜伏感染细胞表达的主要转录本。在这里，我们通过RNA-蛋白质下拉实验确定了位于细胞核中的一种RNA结合蛋白-牛hnRNPM为AS1-S的结合伙伴。利用重组hnRNPM突变体进行的下拉实验表明，位于牛hnRNPM N端区域的RNA识别基序1和2负责与AS1-S结合。此外，RNA免疫沉淀实验表明，AS1-S的引入增加了MDBK细胞中与牛hnRNPM免疫共沉淀的mRNA的数量。这些结果表明，As1-S可以改变hnRNPM与宿主mRNAs之间的相互作用，可能在细胞核内mRNAs成熟的初始阶段干扰细胞的功能。由于大多数已鉴定的与hnRNPM结合增加的mRNAs与KEGG术语“癌症中的途径”相关，因此AS1-S可能影响BLV感染细胞的增殖和扩张，并促进肿瘤的进展。重要的BLV感染牛B细胞并引起恶性淋巴瘤，给畜牧业造成严重的经济损失。由于其发病率低，潜伏期长，其发展为淋巴瘤的分子机制仍然是个谜。最近在BLV基因组中发现了几个非编码RNA，如miRNA和lncRNA，这些非编码RNA与BLV致病机理的关系引起了人们的关注。然而，这些转录本的大部分分子功能仍未确定。据我们所知，这是第一份描述BLV来源的LncRNA AS1-S的分子功能的报告。这些发现揭示了BLV致病的新机制，不仅可以为BLV研究提供重要的见解，也可以为逆转录病毒的比较研究提供重要的见解。
Viruses utilize several strategies to develop latent infection and evade host immune responses. Long non-coding RNA (lncRNA), a class of non-protein encoding RNA that regulates various cellular functions by interacting with RNA binding proteins, is a key factor for viral latency because of its lack of antigenicity. Bovine leukemia virus (BLV), which belongs to the family Retroviridae, encodes the BLV-derived lncRNA AS1-S, which is a major transcript expressed in latently infected cells. We herein identified bovine hnRNPM, an RNA-binding protein located in the nucleus, as the binding partner for AS1-S using an RNA-protein pull-down assay. The pull-down assay using recombinant hnRNPM mutants showed that RNA recognition motif 1 and 2, located in the N-terminal region of bovine hnRNPM, are responsible for binding AS1-S. Furthermore, an RNA immunoprecipitation assay showed that introduction of AS1-S increased the number of mRNA that co-immunoprecipitated with bovine hnRNPM in MDBK cells. These results suggested that AS1-S could alter the interaction between hnRNPM and host mRNAs, potentially interfering with cellular functions during the initial phase of mRNA maturation in the nucleus. Since most of the identified mRNAs that exhibited increased binding to hnRNPM were correlated with the KEGG term “Pathways in cancer”, AS1-S may affect proliferation and expansion of BLV-infected cells and contribute to tumor progression. Importance BLV infects bovine B cells and causes malignant lymphoma, resulting in severe economic losses in the livestock industry. Due to its low incidence rate and long latent period, the molecular mechanisms underlying the progression to lymphoma remain enigmatic. Several non-coding RNAs, such as miRNA and lncRNA, have recently been discovered in the BLV genome and the relationship between BLV pathogenesis and these non-coding RNAs is attracting attention. However, most of the molecular functions of these transcripts remain un-identified. To the best of our knowledge, this is the first report describing a molecular function for the BLV-derived lncRNA AS1-S. The findings reported herein reveal a novel mechanism underlying BLV pathogenesis that could provide important insights for not only BLV research but also comparative studies of retroviruses.