mRNA出核转运及其偶联网络

真核细胞中,编码蛋白质基因的表达是一个复杂的、分步骤进行的过程,这个过程从转录和新生pre-mRNA的核内加工开始,经过正确加工的成熟mRNA从加工位点释放,出核转运后在细胞质内翻译成蛋白质。mRNA出核转运是基因表达中的关键步骤,由进化上高度保守的特定蛋白质介导完成。mRNA出核与转录和mRNA加工步骤密切偶联,这样的偶联可以提高基因表达的有效性和准确性。     

mRNA的出核转运

mRNA的出核转运是真核生物基因表达的重要步骤之一,它与pre-mRNA的各个加工过程都存在密切的偶联。这种偶联对于基因表达的高效准确完成至关重要。本文介绍了mRNA出核转运与pre-mRNA加工及质量监控之间的关联,并总结了近年来关于mRNA出核转运的研究进展。     

Mechanisms of nuclear mRNA export: A structural perspective

Export of mRNA from the nucleus to the cytoplasm is a critical process for all eukaryotic gene expression. As mRNA is synthesized, it is packaged with a myriad of RNA‐binding proteins to form ribonucleoprotein particles (mRNPs). For each step in the processes of maturation and export, mRNPs must have the correct complement of proteins. Much of the mRNA export pathway revolves around the heterodimeric export receptor yeast Mex67?Mtr2/human NXF1?NXT1, which is recruited to signal the completion of nuclear mRNP assembly, mediates mRNP targeting/translocation through the nuclear pore complex (NPC), and is displaced at the cytoplasmic side of the NPC to release the mRNP into the cytoplasm. Directionality of the transport is governed by at least two DEAD‐box ATPases, yeast Sub2/human UAP56 in the nucleus and yeast Dbp5/human DDX19 at the cytoplasmic side of the NPC, which respectively mediate the association and dissociation of Mex67?Mtr2/NXF1?NXT1 onto the mRNP. Here we review recent progress from structural studies of key constituents in different steps of nuclear mRNA export. These findings have laid the foundation for further studies to obtain a comprehensive mechanistic view of the mRNA export pathway.     

Structure and functions of the translation initiation factor eIF4E and its role in cancer development and treatment

In eukaryotic cells, protein synthesis is a complex and multi-step process that has several mechanisms to start the translation including cap-dependent and cap-independent initiation. The translation control of eukaryotic gene expression occurs principally at the initiation step. In this context, it is critical that the eukaryotic translation initiation factor eIF4E bind to the 7-methylguanosine (m7G) cap present at the 5′-UTRs of most eukaryotic mRNAs. Combined with other initiation factors, eIF4E mediates the mRNA recruitment on ribosomes to start the translation. Moreover, the eIF4E nuclear bodies are involved in the export of specific mRNAs from the nucleus to the cytoplasm. In this review, we focus on the eIF4E structure and its physiological functions, and describe the role of eIF4E in cancer development and progression and the current therapeutic strategies to target eIF4E.     

Nucleophosmin deposition during mRNA 3' end processing influences poly(A) tail length

During polyadenylation, the multi-functional protein nucleophosmin (NPM1) is deposited onto all cellular mRNAs analysed to date. Premature termination of poly(A) tail synthesis in the presence of cordycepin abrogates deposition of the protein onto the mRNA, indicating natural termination of poly(A) addition is required for NPM1 binding. NPM1 appears to be a bona fide member of the complex involved in 3' end processing as it is associated with the AAUAAA-binding CPSF factor and can be co-immunoprecipitated with other polyadenylation factors. Furthermore, reduction in the levels of NPM1 results in hyperadenylation of mRNAs, consistent with alterations in poly(A) tail chain termination. Finally, knockdown of NPM1 results in retention of poly(A)(+) RNAs in the cell nucleus, indicating that NPM1 influences mRNA export. Collectively, these data suggest that NPM1 has an important role in poly(A) tail length determination and may help network 3' end processing with other aspects of nuclear mRNA maturation.     

Stressed out! Effects of environmental stress on mRNA metabolism

Exposure of yeast cells to environmental stresses can disrupt essential intracellular processes, especially those carried out by large macromolecular complexes. The production of mature, translatable mRNAs is most sensitive to stress owing to the inhibition of messenger RNA splicing and alterations in the export of mRNA from the nucleus. Changes in the cytoplasmic pools of mRNAs also occur following exposure to stress conditions. Messenger RNAs accumulate in discrete cytoplasmic foci such as processing bodies and stress granules. These dynamic changes in RNA metabolism, following exposure to stress, ensure the preferential production and export of heat-shock mRNAs and the sequestering of general cellular mRNAs in the nucleus or in cytoplasmic foci, thus allowing for a redirection of the translational machinery to encode stress proteins, which aid in cellular recovery following stress. Stress proteins, such as Hsp70p and Hsp104p, have been shown to play a direct role in the repair of macromolecular complexes involved in RNA metabolism in yeast cells, thus ensuring that the cell returns to homeostasis.     

Splicing promotes the nuclear export of β-globin mRNA by overcoming nuclear retention elements

Most current models of mRNA nuclear export in vertebrate cells assume that an mRNA must have specialized signals in order to be exported from the nucleus. Under such a scenario, mRNAs that lack these specialized signals would be shunted into a default pathway where they are retained in the nucleus and eventually degraded. These ideas were based on the selective use of model mRNA reporters. For example, it has been shown that splicing promotes the nuclear export of certain model mRNAs, such as human β-globin, and that in the absence of splicing, the cDNA-derived mRNA is retained in the nucleus and degraded. Here we provide evidence that β-globin mRNA contains an element that actively retains it in the nucleus and degrades it. Interestingly, this nuclear retention activity can be overcome by increasing the length of the mRNA or by splicing. Our results suggest that contrary to many current models, the default pathway for most intronless RNAs is to be exported from the nucleus, unless the RNA contains elements that actively promote its nuclear retention.     

核内不均一核糖核蛋白在前体mRNA加工中的功能

核内不均一核糖核蛋白(hnRNP)是一类存在于真核生物体内具有类似结构特征的高丰度RNA结合蛋白,一般均匀分布在核内。多种hnRNP具有多样的功能,参与从转录调节,前体mRNA剪接,mRNA输出到mRNA降解等多种生物过程,从而进行基因表达调控。现着重介绍hnRNP在前体mRNA加工过程(加帽,剪接,加尾,输出,选择性降解)中的功能及研究进展。     

异二聚体介导的mRNA核输出机制

真核生物mRNA在细胞核内被转录,而到达细胞质内翻译成为蛋白质,因此跨越核孔的核输出过程是必须的。现在已确定异二聚体TAP/NXT(在酵母中为Mex67p/Mtr2p)在此过程中是最基本的元件,此外其他相关因子如Aly、UAP56等也参与了这个复杂的过程,包括结合、输出、解离和载体输入。本文简要介绍了mRNA输出的基本机制。