title: Dual mechanisms regulate the nucleocytoplasmic localization of human DDX6.
abstract: DDX6 is a conserved DEAD-box protein (DBP) that plays central roles in cytoplasmic RNA regulation, including processing body (P-body) assembly, mRNA decapping, and translational repression. Beyond its cytoplasmic functions, DDX6 may also have nuclear functions because its orthologues are known to localize to nuclei in several biological contexts. However, it is unclear whether DDX6 is generally present in human cell nuclei, and the molecular mechanism underlying DDX6 subcellular distribution remains elusive. In this study, we showed that DDX6 is commonly present in the nuclei of human-derived cells. Our structural and molecular analyses deviate from the current model that the shuttling of DDX6 is directly mediated by the canonical nuclear localization signal (NLS) and nuclear export signal (NES), which are recognized and transported by Importin-α/β and CRM1, respectively. Instead, we show that DDX6 can be transported by 4E-T in a piggyback manner. Furthermore, we provide evidence for a novel nuclear targeting mechanism in which DDX6 enters the newly formed nuclei by "hitch-hiking" on mitotic chromosomes with its C-terminal domain during M phase progression. Together, our results indicate that the nucleocytoplasmic localization of DDX6 is regulated by these dual mechanisms.
authors.affiliation: Department of Life Science, College of Life Science, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Jo-Hsi
authors.initials: JH
authors.lastname: Huang
authors.affiliation: School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei 24205, Taiwan.
authors.forename: Wei-Chi
authors.initials: WC
authors.lastname: Ku
authors.affiliation: Department of Life Science, College of Life Science, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Yen-Chun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei 24205, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Department of Life Science, College of Life Science, National Taiwan University, Taipei 10617, Taiwan.|Center for Systems Biology, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Chia-Ying
authors.initials: CY
authors.lastname: Chu
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism*; D002877:Chromosomes, Human / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000378:metabolism
chemical_list: C411571:EIF4ENIF1 protein, human; C557041:MALAT1 long non-coding RNA, human; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D029543:Nucleocytoplasmic Transport Proteins; D011518:Proto-Oncogene Proteins; D062085:RNA, Long Noncoding; C094683:DDX6 protein, human; D053487:DEAD-box RNA Helicases