Nucleoporin TPR promotes tRNA nuclear export and protein synthesis in lung cancer cells
Autor: | Wuguo Deng, Han Yang, Dingbo Shi, Marc R. Gartenberg, Miao Chen, Changlin Zhang, Melinda S. Borrie, Qian Long, Haohui Sun |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Cancer Research
Cytoplasm Lung Neoplasms Protein Synthesis QH426-470 Biochemistry Lung and Intrathoracic Tumors RNA Transport NXF1 RNA Transfer Protein biosynthesis Medicine and Health Sciences Tumor Cells Cultured Nuclear pore Genetics (clinical) Messenger RNA Eukaryota Chemical Synthesis Genomics Small interfering RNA Prognosis Cell biology Neoplasm Proteins Nucleic acids Oncology Transfer RNA Nucleoporin Cellular Structures and Organelles Research Article Biosynthetic Techniques Biology Research and Analysis Methods Genome Complexity Proto-Oncogene Proteins Genetics Humans Nuclear export signal Non-coding RNA Molecular Biology Ecology Evolution Behavior and Systematics Cell Nucleus Biology and life sciences Cell growth Organisms Fungi Cancers and Neoplasms Proteins Computational Biology Cell Biology Yeast Introns Gene regulation Nuclear Pore Complex Proteins RNA Gene expression |
Zdroj: | PLoS Genetics PLoS Genetics, Vol 17, Iss 11, p e1009899 (2021) |
ISSN: | 1553-7404 1553-7390 |
Popis: | 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. Author summary 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. |
Databáze: | OpenAIRE |
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