title: Sumoylation of Daxx regulates IFN-induced growth suppression of B lymphocytes and the hormone receptor-mediated transactivation.
abstract: Daxx has been shown to play an essential role in type I IFN-mediated suppression of B cell development and apoptosis. Recently, we demonstrated that Tyk2 is directly involved in IFN signaling for the induction and translocation of Daxx, which may result in growth arrest and/or apoptosis of B lymphocyte progenitors. To clarify the molecular mechanisms of how Daxx acts on growth suppression of B lymphocytes, we examined functions of a sumoylation-defective Daxx KA mutant (Daxx K630/631A), which substituted Lys 630 and Lys 631 to Ala. Importantly, Daxx KA localized in the cytoplasm, whereas wild-type Daxx localized in the nucleus. Murine pro-B cell line Ba/F3 expressing Daxx KA revealed a resistance to the IFN-induced growth suppression. It is noteworthy that treatment with an exportin inhibitor, leptomycin B, resulted in nuclear localization of Daxx KA and recovery of the IFN-induced growth suppression in Ba/F3 cells. Moreover, Daxx KA decreased the binding potential to promyelocytic leukemia protein (PML), and overexpression of PML recruited Daxx KA into PML oncogenic domains. Notably, a Daxx-small ubiquitin-related modifier fusion protein exhibited increased nuclear localization and ability to suppress cell growth in Ba/F3 cells. These results demonstrate that the IFN-induced growth suppression of B lymphocytes requires nuclear localization of Daxx through its sumoylation and proper interactions with PML.
authors.affiliation: Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku, Kita 12 Nishi 6, Sapporo 060-0812, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Muromoto
authors.forename: Masato
authors.initials: M
authors.lastname: Ishida
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugiyama
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sekine
authors.forename: Kenji
authors.initials: K
authors.lastname: Oritani
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007372:Interferons / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008239:Lysine / Q000235:genetics; D051379:Mice; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000071156:Promyelocytic Leukemia Protein; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C491473:Daxx protein, mouse; D006131:Growth Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D011965:Receptors, Glucocorticoid; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D007372:Interferons; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9; D008239:Lysine; D000409:Alanine