title: The processed isoform of the translation termination factor eRF3 localizes to the nucleus to interact with the ARF tumor suppressor.
abstract: The eukaryotic releasing factor eRF3 is a multifunctional protein that plays pivotal roles in translation termination as well as the initiation of mRNA decay. eRF3 also functions in the regulation of apoptosis; eRF3 is cleaved at Ala73 by an as yet unidentified protease into processed isoform of eRF3 (p-eRF3), which interacts with the inhibitors of apoptosis proteins (IAPs). The binding of p-eRF3 with IAPs leads to the release of active caspases from IAPs, which promotes apoptosis. Although full-length eRF3 is localized exclusively in the cytoplasm, p-eRF3 localizes in the nucleus as well as the cytoplasm. We here focused on the role of p-eRF3 in the nucleus. We identified leptomycin-sensitive nuclear export signal (NES) at amino acid residues 61-71 immediately upstream of the cleavage site Ala73. Thus, the proteolytic cleavage of eRF3 into p-eRF3 leads to release an amino-terminal fragment containing NES to allow the relocalization of eRF3 into the nucleus. Consistent with this, p-eRF3 more strongly interacted with the nuclear ARF tumor suppressor than full-length eRF3. These results suggest that while p-eRF3 interacts with IAPs to promote apoptosis in the cytoplasm, p-eRF3 also has some roles in regulating cell death in the nucleus.
authors.affiliation: Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Kumagai
authors.affiliation: Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Hosoda
authors.affiliation: Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan. Electronic address: hoshino@phar.nagoya-cu.ac.jp.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Hoshino
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D008969:Molecular Sequence Data; D049790:Nuclear Export Signals; D016366:Open Reading Frames; D010443:Peptide Chain Termination, Translational; D010454:Peptide Termination Factors / Q000032:analysis* / Q000378:metabolism*; D060066:Protein Interaction Maps; D020033:Protein Isoforms / Q000032:analysis / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000032:analysis / Q000378:metabolism*; D000097606:Exportin 1 Protein
chemical_list: D028884:Karyopherins; D049790:Nuclear Export Signals; D010454:Peptide Termination Factors; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D025803:Tumor Suppressor Protein p14ARF; D000097606:Exportin 1 Protein; C087971:peptide-chain-release factor 3
keywords: ARF; Apoptosis; IAP; NES; Translation termination; eRF3