title: Protein phosphatase 2A dephosphorylates phosphoserines in nucleocytoplasmic shuttling and secretion of high mobility group box 1.
abstract: High mobility group box 1 (HMGB1), a non-histone chromosomal protein, is a proinflammatory cytokine. There are two known pathways for the release of HMGB1 into the extracellular milieu-passive and active. The passive pathway is attributable to cell death from damage or necrosis, and the active pathway is secretion from immunocompetent cells activated by proinflammatory stimuli. Recent studies have shown that post-translational modifications of HMGB1, including phosphorylation, are involved in the relocation of HMGB1 to the cytoplasm and subsequent secretion. With regard to the HMGB1 phosphorylation, Youn and Shin [Nucleocytoplasmic shuttling of HMGB1 is regulated by phosphorylation that redirects it toward secretion. J Immunol 2006;177:7889-97] reported that treatment of the murine macrophage RAW264.7 with okadaic acid resulted in nucleocytoplasmic translocation and secretion of HMGB1. Herein, we demonstrate the physical interaction between HMGB1 and protein phosphatase 2A (PP2A) in the RAW264.7. The results of in vitro phosphatase assay further indicate that PP2A dephosphorylates specific phosphoserine residues within one of the two nuclear localization signals (NLSs) of HMGB1. The cytoplasmic relocation of HMGB1 through PP2A inhibition was markedly suppressed by replacement of the Ser residues within the NLS with Ala. These consequences imply that PP2A correlates in the nucleocytoplasmic shuttling of HMGB1.
authors.affiliation: Department of Chemistry, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Taira
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kida
authors.forename: Koichi
authors.initials: K
authors.lastname: Kuwano
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Higashimoto
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000235:genetics* / Q000378:metabolism; D006868:Hydrolysis; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010768:Phosphoserine / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000235:genetics* / Q000378:metabolism; D021382:Protein Sorting Signals; D015398:Signal Transduction
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D021382:Protein Sorting Signals; D010768:Phosphoserine; D054648:Protein Phosphatase 2
keywords: HMGB1; NLS; PP2A; RAW264.7; endothall