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首页> 外文期刊>The FEBS journal >Hepatitis delta virus interacts with splicing factor SF3B155 and alters pre-mRNA splicing of cell cycle control genes
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Hepatitis delta virus interacts with splicing factor SF3B155 and alters pre-mRNA splicing of cell cycle control genes

机译：肝炎Delta病毒与剪接因子SF3B155相互作用，并改变细胞周期控制基因的前mRNA剪接

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Hepatitis delta virus (HDV) is the agent responsible for the most severe form of human viral hepatitis. The HDV genome consists of a single-stranded circular RNA molecule that encodes for one single protein, the delta antigen. Given its simplicity, HDV must make use of several host cellular proteins to accomplish its life cycle processes, including transcription, replication, post-transcriptional, and post-translational modifications. Consequently, identification of the interactions established between HDV components and host proteins assumes a pivotal interest in the search of novel therapeutic targets. Here, we used the yeast three-hybrid system to screen a human liver cDNA library to identify host proteins that interact with the HDV genomic RNA. One of the identified proteins corresponded to the splicing factor SF3B155, a component of the U2snRNP complex that is essential for the early recognition of 3 ' splice sites in the pre-mRNAs of human genes. We show that the interaction between the HDV genomic RNA and SF3B155 occurs in vivo and that the expression of HDV promotes changes in splicing of human genes whose alternative splicing is SF3B155-dependent. We further show that expression of HDV triggers alterations in several constitutive and alternative splicing events in the tumor suppressor RBM5 transcript, with consequent reduction of its protein levels. This is the first description that HDV expression promotes changes in the splicing of human genes, and we suggest that the HDV-induced alternative splicing changes, through SF3B155 sequester, may contribute for the early progression to hepatocellular carcinoma characteristic of HDV-infected patients.
机译：肝炎Delta病毒（HDV）是负责最严重的人类病毒性肝炎的代理。 HDV基因组由单链圆形RNA分子组成，所述单链圆形RNA分子，其编码一个单一蛋白质，δ抗原。鉴于其简单性，HDV必须利用几种宿主细胞蛋白来完成其生命周期过程，包括转录，复制，转录后和翻译后修改。因此，鉴定HDV组分和宿主蛋白之间建立的相互作用假设在寻找新的治疗靶标的枢轴兴趣。在这里，我们使用酵母三杂化系统筛选人肝cDNA文库，鉴定与HDV基因组RNA相互作用的宿主蛋白。所识别的蛋白质之一对应于剪接因子SF3B155，U2SNRNP复合物的组分，这对于人类基因前MRNA中的3'接头位点至关重要。我们表明，HDV基因组RNA和SF3B155之间的相互作用发生在体内，并且HDV的表达促进了人类基因剪接的变化，其替代剪接为SF3B155依赖性。我们进一步表明，HDV触发的表达在肿瘤抑制器RBM5转录物中的几个组成型和替代剪接事件中的改变，其蛋白质水平的降低。这是第一个描述HDV表达促进人类基因剪接变化，并且我们建议通过SF3B155序列促进HDV诱导的替代剪接变化，这可能有助于HDV感染患者的早期进展到肝细胞癌特征。

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