Protein phosphatase 2A dephosphorylates phosphoserines in nucleocytoplasmic shuttling and secretion of high mobility group box 1
Protein phosphatase 2A dephosphorylates phosphoserines in nucleocytoplasmic shuttling and secretion of high mobility group box 1
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DOI：
10.1093/jb/mvt056
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发表时间：
2013-09-01
影响因子：
2.7
通讯作者：
Higashimoto, Yuichiro
中科院分区：
文献类型：
--
作者：
Taira, Junichi;Kida, Yutaka;Higashimoto, Yuichiro
高迁移率族蛋白 1 (HMGB1) 是一种非组蛋白染色体蛋白，是一种促炎细胞因子。有两种已知的 HMGB1 释放到细胞外环境的途径：被动途径和主动途径。被动途径可归因于细胞因损伤或坏死而死亡，主动途径是促炎刺激激活的免疫活性细胞的分泌。最近的研究表明，HMGB1 的翻译后修饰（包括磷酸化）参与了 HMGB1 重新定位到细胞质和随后的分泌。关于 HMGB1 磷酸化，Youn 和 Shin [HMGB1 的核质穿梭受到磷酸化的调节，从而将其重定向至分泌。 JImmunol 2006；177：7889-97]报道用冈田酸处理鼠巨噬细胞RAW264.7导致核细胞质易位和HMGB1的分泌。在此，我们证明了 RAW264.7 中 HMGB1 和蛋白磷酸酶 2A (PP2A) 之间的物理相互作用。体外磷酸酶测定的结果进一步表明，PP2A 使 HMGB1 的两个核定位信号 (NLS) 之一内的特定磷酸丝氨酸残基去磷酸化。通过用 Ala 替换 NLS 内的 Ser 残基，可显着抑制 HMGB1 通过 PP2A 抑制进行的细胞质重定位。这些结果意味着 PP2A 与 HMGB1 的核质穿梭相关。
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.