title: Opposing action of casein kinase 1 and calcineurin in nucleo-cytoplasmic shuttling of mammalian translation initiation factor eIF6.
abstract: Eukaryotic initiation factor 6 (eIF6), a highly conserved protein from yeast to mammals, is essential for 60 S ribosome biogenesis and assembly. Both yeast and mammalian eIF6 are phosphorylated at Ser-174 and Ser-175 by the nuclear isoform of casein kinase 1 (CK1). The molecular basis of eIF6 phosphorylation, however, remains elusive. In the present work, we show that subcellular distribution of eIF6 in the nuclei and the cytoplasm of mammalian cells is mediated by dephosphorylation and phosphorylation, respectively. This nucleo-cytoplasmic shuttling is dependent on the phosphorylation status at Ser-174 and Ser-175 of eIF6. We demonstrate that Ca(2+)-activated calcineurin phosphatase binds to and promotes nuclear localization of eIF6. Increase in intracellular concentration of Ca(2+) leads to rapid translocation of eIF6 from the cytoplasm to the nucleus, an event that is blocked by specific calcineurin inhibitors cyclosporin A or FK520. Nuclear export of eIF6 is regulated by phosphorylation at Ser-174 and Ser-175 by the nuclear isoform of CK1. Mutation of eIF6 at the phosphorylatable Ser-174 and Ser-175 to alanine or treatment of cells with the CK1 inhibitor, D4476 inhibits nuclear export of eIF6 and results in nuclear accumulation of eIF6. Together, these results establish eIF6 as a substrate for calcineurin and suggest a novel paradigm for calcineurin function in 60 S ribosome biogenesis via regulating the nuclear accumulation of eIF6.
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Arunima
authors.initials: A
authors.lastname: Biswas
authors.forename: Shaeri
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Supratik
authors.initials: S
authors.lastname: Das
authors.forename: Dennis
authors.initials: D
authors.lastname: Shields
authors.forename: Chi Wing
authors.initials: CW
authors.lastname: Chow
authors.forename: Umadas
authors.initials: U
authors.lastname: Maitra
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D019943:Amino Acid Substitution; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D019556:COS Cells; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism*; D047389:Casein Kinase I / Q000037:antagonists & inhibitors / Q000235:genetics; D002522:Chlorocebus aethiops; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007166:Immunosuppressive Agents; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D054683:Ribosome Subunits, Large, Eukaryotic / Q000235:genetics / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C493177:4-(4-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D065095:Calcineurin Inhibitors; C109284:EIF6 protein, human; D004791:Enzyme Inhibitors; D039642:Eukaryotic Initiation Factors; D007093:Imidazoles; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D016572:Cyclosporine; C058028:immunomycin; D047389:Casein Kinase I; D019703:Calcineurin; D002118:Calcium; D016559:Tacrolimus