Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Department of Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai 200030, China.
J Biol Chem. 2013 Jun 7;288(23):16588-16597. doi: 10.1074/jbc.M113.455121. Epub 2013 Apr 23.
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.
pVHL，即 von Hippel-Lindau（VHL）肿瘤抑制基因的产物，作为 E3-泛素连接酶复合物的底物识别成分发挥作用，该复合物靶向缺氧诱导因子α（HIF-α）进行泛素化和降解。除了 HIF-α，pVHL 还与其他蛋白质相互作用，具有多种功能。在这里，我们报告 pVHL 抑制核糖体生物发生和蛋白质合成。我们发现 pVHL 与 40S 核糖体蛋白 S3（RPS3）结合，但不将其作为靶标进行破坏。相反，pVHL-RPS3 相互作用干扰了 RPS3 和 RPS2 之间的相互作用。pVHL 的表达还导致前 40S 核糖体亚基在核内滞留，减少多核糖体和 18S rRNA 的水平。我们还证明 pVHL 抑制帽依赖性和帽非依赖性蛋白质合成。我们的发现揭示了 pVHL 的一个新功能，并深入了解了肿瘤抑制因子 pVHL 对核糖体生物发生的调节。
