The von Hippel-Lindau Protein pVHL Inhibits Ribosome Biogenesis and Protein Synthesis*
The von Hippel-Lindau Protein pVHL Inhibits Ribosome Biogenesis and Protein Synthesis*
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DOI：
10.1074/jbc.m113.455121
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发表时间：
2013-04
期刊：
影响因子：
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通讯作者：
Wen Zhao;Cheng Zhou;Xuebing Li;Yunfang Zhang;Li Fan;J. Pelletier;Jing Fang
中科院分区：
文献类型：
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作者：
Wen Zhao;Cheng Zhou;Xuebing Li;Yunfang Zhang;Li Fan;J. Pelletier;Jing Fang
背景：pVHL是一种肿瘤抑制因子，作为E3-连接酶复合体的底物识别成分，以缺氧诱导因子1α为靶点进行破坏。结果：pVHL与核糖体蛋白RPS3结合，干扰核糖体组装，抑制蛋白质合成。结论：pVHL抑制核糖体的生物合成和蛋白质合成。意义：这些发现揭示了pVHL的一个新功能，并为核糖体生物发生的调控提供了洞察力。PVHL是von Hippel-Lindau(von Hippel-Lindau)抑癌基因的产物，作为E3-泛素连接酶复合体的底物识别成分，针对缺氧诱导因子α(HIF-α)进行泛素化和降解。除HIF-α外，pVHL还可与其他蛋白质相互作用，具有多种功能。在这里，我们报告pVHL抑制核糖体的生物发生和蛋白质的合成。我们发现pVHL与40S核糖体蛋白S3(RPS3)相关，但并不针对它进行破坏。相反，pVHL-RPS3的结合干扰了RPS3和RPS2之间的相互作用。PVHL的表达还导致40S前核糖体亚基的核滞留，减少多聚体和18S rRNA水平。我们还证明pVHL既抑制帽依赖的蛋白质合成，也抑制帽非依赖性的蛋白质合成。我们的发现揭示了pVHL的一个新功能，并为肿瘤抑制基因pVHL对核糖体生物发生的调控提供了洞察力。
Background: pVHL, a tumor suppressor, functions as the substrate recognition component of an E3-ligase complex that targets hypoxia inducible factor (HIF) 1α for destruction. Results: pVHL binds ribosomal protein RPS3, interferes with ribosome assembly, and inhibits protein synthesis. Conclusion: pVHL suppresses ribosome biogenesis and protein synthesis. Significance: The findings disclose a novel function of pVHL and provide insight into the regulation of ribosome biogenesis. pVHL, the product of von Hippel-Lindau (VHL) tumor suppressor gene, functions as the substrate recognition component of an E3-ubiquitin ligase complex that targets hypoxia inducible factor α (HIF-α) for ubiquitination and degradation. Besides HIF-α, pVHL also interacts with other proteins and has multiple functions. Here, we report that pVHL inhibits ribosome biogenesis and protein synthesis. We find that pVHL associates with the 40S ribosomal protein S3 (RPS3) but does not target it for destruction. Rather, the pVHL-RPS3 association interferes with the interaction between RPS3 and RPS2. Expression of pVHL also leads to nuclear retention of pre-40S ribosomal subunits, diminishing polysomes and 18S rRNA levels. We also demonstrate that pVHL suppresses both cap-dependent and cap-independent protein synthesis. Our findings unravel a novel function of pVHL and provide insight into the regulation of ribosome biogenesis by the tumor suppressor pVHL.