Nucleoporin TPR promotes tRNA nuclear export and protein synthesis in lung cancer cells.
Nucleoporin TPR promotes tRNA nuclear export and protein synthesis in lung cancer cells.
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DOI：
10.1371/journal.pgen.1009899
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发表时间：
2021-11
期刊：
影响因子：
4.5
通讯作者：
Deng W
中科院分区：
文献类型：
--
作者：
Chen M;Long Q;Borrie MS;Sun H;Zhang C;Yang H;Shi D;Gartenberg MR;Deng W
癌细胞的强劲增殖需要蛋白质合成水平的极大提高，而蛋白质合成依赖于氨基酰化tRNAs的稳定供应。TRNAs转运到细胞质是一个高度受调控的过程，但tRNA核输出的机制尚未完全阐明。在这项研究中，使用活细胞成像策略可视化特定tRNA基因在酵母中的新生转录，我们确定核篮蛋白Mlp1和Mlp2是人类TPR蛋白的两个同源蛋白，作为tRNA输出的调节因子。TPR在肺癌组织中的表达显著升高，且与预后不良相关。在肺癌细胞系中，TPR基因的敲除一直抑制tRNA核输出、蛋白质合成和细胞生长。我们进一步表明，Nxf1是一种著名的mRNA核输出因子，它与tRNAs结合，并通过核孔介导tRNAs的运输。总而言之，我们的发现揭示了一种调节tRNAs核输出的保守机制，这是真核生物蛋白质合成中的一个限制步骤。蛋白质合成是细胞生长和增殖的基本生物学过程。氨基酸是蛋白质的基石，每一种氨基酸都通过其自身特定的运输RNA(TRNAs)被运送到核糖体进行蛋白质合成。细胞tRNA池的不平衡或功能失调可能会导致细胞生长和增殖失控，这是癌症的特征。核孔复合体由多种蛋白质组成，称为核孔蛋白，它们在细胞核和细胞质之间调节物质的运输。我们先前的研究发现，酵母中的tRNA基因与NPC结合，协调tRNA的合成和核输出。在这里，我们开发了一种活细胞成像策略来阐明tRNA核输出的机制，并确定核孔蛋白TPR是这一过程的调节因子。我们发现，TPR在肺癌组织中过表达，并与不良预后相关，而TPR下调则抑制tRNA核输出、蛋白质合成和细胞生长。我们进一步表明，核出口因子Nxf1与tRNAs相关，并通过NPC介导tRNAs的运输。我们的发现揭示了一种保守的机制，即在tRNAs到达细胞质执行其在蛋白质合成中的作用之前，NPC通过该机制控制tRNAs的数量和质量。
The robust proliferation of cancer cells requires vastly elevated levels of protein synthesis, which relies on a steady supply of aminoacylated tRNAs. Delivery of tRNAs to the cytoplasm is a highly regulated process, but the machinery for tRNA nuclear export is not fully elucidated. In this study, using a live cell imaging strategy that visualizes nascent transcripts from a specific tRNA gene in yeast, we identified the nuclear basket proteins Mlp1 and Mlp2, two homologs of the human TPR protein, as regulators of tRNA export. TPR expression is significantly increased in lung cancer tissues and correlated with poor prognosis. Consistently, knockdown of TPR inhibits tRNA nuclear export, protein synthesis and cell growth in lung cancer cell lines. We further show that NXF1, a well-known mRNA nuclear export factor, associates with tRNAs and mediates their transport through nuclear pores. Collectively, our findings uncover a conserved mechanism that regulates nuclear export of tRNAs, which is a limiting step in protein synthesis in eukaryotes. Protein synthesis is a fundamental biological process for cells to grow and proliferate. Amino acids are the building blocks for proteins, and each is carried to ribosomes for protein synthesis by its own specific transport RNAs (tRNAs). An imbalanced or malfunctioning pool of cellular tRNAs may cause uncontrolled cell growth and proliferation, which are hallmarks of cancer. Nuclear pore complexes (NPCs) consist of multiple proteins termed nucleoporins that mediate transport of materials between the nucleus and the cytoplasm. Our previous study discovered that tRNA genes in yeast associate with NPCs to coordinate tRNA synthesis with nuclear export. Here, we develop a live cell imaging strategy to elucidate the machinery for tRNA nuclear export, and identify the nucleoporin TPR as a regulator of the process. We find that TPR is overexpressed in lung cancer tissues and correlated with poor prognosis, whereas down-regulation of TPR inhibits tRNA nuclear export, protein synthesis and cell growth. We further show that the nuclear export factor NXF1 associates with tRNAs and mediates their transport through NPCs. Our findings uncover a conserved mechanism by which NPCs control the quantity and quality of tRNAs before they reach the cytoplasm to execute their roles in protein synthesis.
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