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
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