Nucleoporin TPR promotes tRNA nuclear export and protein synthesis in lung cancer cells

Author summaryProtein 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 nucleus and 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. 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.

Automated summary

The nuclear pore protein TPR and export factor NXF1 play essential roles in regulating tRNA nuclear export and protein synthesis, with TPR being overexpressed in lung cancer tissues and associated with poor prognosis.