程红研究组最新文章揭示乙肝病毒调控机制

　　

       近日，国际学术期刊Nucleic Acids Research在线发表了中科院上海生化与细胞所程红研究组的最新研究成果“A Sub-Element in PRE enhances nuclear export of intronless mRNAs by recruiting the TREX complex via ZC3H18”，揭示了PRE中一个顺式作用元件通过ZC3H18招募出核复合物TREX促进mRNA出核转运的分子机制。
 
        乙肝病毒（Hepatitis B Virus）是导致乙型肝炎的病毒，其感染在全球范围内每年导致约100万人死亡。乙肝病毒共表达七个蛋白，编码这些蛋白的mRNA都需要在不经历剪接的情况下运输出核。 HBV mRNA上的一个顺式元件PRE（post-transcriptional regulatory element）可以有效促进病毒无内含子mRNA的出核，但是PRE促进mRNA出核的具体机制还不清楚。
 
        在这项研究中，迟斌凯博士和同事在程红研究员的指导下，通过系统短缩实验在PRE序列中发现了两个独立的促进无内含子mRNA出核的顺式元件（SEP1和SEP2）。利用其中较短的SEP1 进行的RNA-蛋白复合物纯化显示SEP1与若干宿主细胞蛋白结合，其中包括mRNA出核复合物TREX。

       研究人员通过进一步的生化和细胞实验表明，SEP1 RNA直接结合锌指蛋白ZC3H18，并通过ZC3H18招募TREX从而促进mRNA的出核。他们分析比较了SEP1介导的mRNA出核方式与细胞mRNA的出核方式的异同，发现两者存在多种相似性，提示这两种出核通路可能共用某些出核因子。

      与此推论相符的是，他们在SEP1 RNA结合蛋白中发现了4种新的真核mRNA出核因子。该研究不仅揭示了SEP1促进无内含子mRNA出核的作用机制，还为进一步了解细胞mRNA出核的分子机制提供了重要帮助。
 
        该研究工作是与中国科学院大连化学物理研究所李国辉研究员及其课题组合作完成的。研究得到国家科技部和国家自然科学基金委的经费资助。

原文摘要：

A Sub-Element in PRE enhances nuclear export of intronless mRNAs by recruiting the TREX complex via ZC3H18

Viral RNA elements that facilitate mRNA export are useful tools for identifying cellular RNA export factors. Here we show that hepatitis B virus post-transcriptional element (PRE) is one such element, and using PRE several new cellular mRNA export factors were identified. We found that PRE drastically enhances the cytoplasmic accumulation of cDNA transcripts independent of any viral protein. Systematic deletion analysis revealed the existence of a 116 nt functional Sub-Element of PRE (SEP1). The RNP that forms on the SEP1 RNA was affinity purified, in which TREX components as well as several other proteins were identified. TREX components and the SEP1-associating protein ZC3H18 are required for SEP1-mediated mRNA export. Significantly, ZC3H18 directly binds to the SEP1 RNA, interacts with TREX and is required for stable association of TREX with the SEP1-containing mRNA. Requirements for SEP1-mediated mRNA export are similar to those for splicing-dependent mRNA export. Consistent with these similarities, several SEP1-interacting proteins, including ZC3H18, ARS2, Acinus and Brr2, are required for efficient nuclear export of polyA RNAs. Together, our data indicate that SEP1 enhances mRNA export by recruiting TREX via ZC3H18. The new mRNA export factors that we identified might be involved in cap- and splicing-dependent TREX recruitment to cellular mRNAs.