Site-specific Acetylation of the Proteasome Activator REGγ Directs Its Heptameric Structure and Functions
Site-specific Acetylation of the Proteasome Activator REGγ Directs Its Heptameric Structure and Functions
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DOI：
10.1074/jbc.m112.437129
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发表时间：
2013-06-07
影响因子：
4.8
通讯作者：
Li, Xiaotao
中科院分区：
文献类型：
--
作者：
Liu, Jiang;Wang, Ying;Li, Xiaotao
据报道，蛋白酶体激活剂REG γ以泛素和ATP非依赖性方式促进类固醇受体辅激活因子-3和细胞周期蛋白依赖性激酶抑制剂p21、p16和p19的降解。最近对小鼠和人体组织中REG γ表达的比较分析揭示了特定细胞类型中REG γ的独特模式，表明该分子的未公开功能和生物学重要性。尽管REG γ相关研究取得了新的进展，但REG γ功能如何调节仍有待探索。在这项研究中，我们首次报告，REG γ可以乙酰化主要是在其赖氨酸195（Lys-195）残基CREB结合蛋白（CBP），这可以逆转沉默调节蛋白1（SIRT 1）在哺乳动物细胞。定点突变消除了Lys-195的乙酰化，并显著减弱了REG γ降解其靶底物p21和丙型肝炎病毒核心蛋白的能力。从机理上讲，Lys-195处的乙酰化对于REG γ单体之间的相互作用是重要的，并最终影响REG γ七聚化。含有REG γ-WT或REG γ-K195 R突变体的细胞的生物学分析表明乙酰化对REG γ介导的细胞增殖和细胞周期进程调节的影响。这些研究结果揭示了一个以前未知的机制，在调节REG γ组装和活动，这表明一个潜在的场所的干预泛素独立的REG γ蛋白酶体活性。
The proteasome activator REG gamma has been reported to promote degradation of steroid receptor coactivator-3 and cyclin-dependent kinase inhibitors p21, p16, and p19 in a ubiquitin- and ATP-independent manner. A recent comparative analysis of REG gamma expression in mouse and human tissues reveals a unique pattern of REG gamma in specific cell types, suggesting undisclosed functions and biological importance of this molecule. Despite the emerging progress made in REG gamma-related studies, how REG gamma function is regulated remains to be explored. In this study, we report for the first time that REG gamma can be acetylated mostly on its lysine 195 (Lys-195) residue by CREB binding protein (CBP), which can be reversed by sirtuin 1 (SIRT1) in mammalian cells. Site-directed mutagenesis abrogated acetylation at Lys-195 and significantly attenuated the capability of REG gamma to degrade its target substrates, p21 and hepatitis C virus core protein. Mechanistically, acetylation at Lys-195 is important for the interactions between REG gamma monomers and ultimately influences REG gamma heptamerization. Biological analysis of cells containing REG gamma-WT or REG gamma-K195R mutant indicates an impact of acetylation on REG gamma-mediated regulation of cell proliferation and cell cycle progression. These findings reveal a previously unknown mechanism in the regulation of REG gamma assembly and activity, suggesting a potential venue for the intervention of the ubiquitin-independent REG gamma proteasome activity.