title: tRNA-controlled nuclear import of a human tRNA synthetase.
abstract: Aminoacyl-tRNA synthetases, essential components of the cytoplasmic translation apparatus, also have nuclear functions that continue to be elucidated. However, little is known about how the distribution between cytoplasmic and nuclear compartments is controlled. Using a combination of methods, here we showed that human tyrosyl-tRNA synthetase (TyrRS) distributes to the nucleus and that the nuclear import of human TyrRS is regulated by its cognate tRNA(Tyr). We identified a hexapeptide motif in the anticodon recognition domain that is critical for nuclear import of the synthetase. Remarkably, this nuclear localization signal (NLS) sequence motif is also important for interacting with tRNA(Tyr). As a consequence, mutational alteration of the hexapeptide simultaneously attenuated aminoacylation and nuclear localization. Because the NLS is sterically blocked when the cognate tRNA is bound to TyrRS, we hypothesized that the nuclear distribution of TyrRS is regulated by tRNA(Tyr). This expectation was confirmed by RNAi knockdown of tRNA(Tyr) expression, which led to robust nuclear import of TyrRS. Further bioinformatics analysis showed that to have nuclear import of TyrRS directly controlled by tRNA(Tyr) in higher organisms, the NLS of lower eukaryotes was abandoned, whereas the new NLS was evolved from an anticodon-binding hexapeptide motif. Thus, higher organisms developed a strategy to make tRNA a regulator of the nuclear trafficking of its cognate synthetase. The design in principle should coordinate nuclear import of a tRNA synthetase with the demands of protein synthesis in the cytoplasm.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Guangsen
authors.initials: G
authors.lastname: Fu
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.forename: Na
authors.initials: N
authors.lastname: Wei
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000926:Anticodon / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012346:RNA, Transfer, Amino Acyl / Q000378:metabolism*; D014448:Tyrosine-tRNA Ligase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000926:Anticodon; D019913:Nuclear Localization Signals; D012346:RNA, Transfer, Amino Acyl; D014448:Tyrosine-tRNA Ligase