Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea.
College of Medicine, Hanyang University, Seoul 04763, Korea.
Int J Mol Sci. 2020 Nov 28;21(23):9076. doi: 10.3390/ijms21239076.
Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by the dysfunction of the enzyme phenylalanine hydroxylase (PAH). Alterations in the level of PAH leads to the toxic accumulation of phenylalanine in the blood and brain. Protein degradation mediated by ubiquitination is a principal cellular process for maintaining protein homeostasis. Therefore, it is important to identify the E3 ligases responsible for PAH turnover and proteostasis. Here, we report that anaphase-promoting complex/cyclosome-Cdh1 (APC/C) is an E3 ubiquitin ligase complex that interacts and promotes the polyubiquitination of PAH through the 26S proteasomal pathway. Cdh1 destabilizes and declines the half-life of PAH. In contrast, the CRISPR/Cas9-mediated knockout of stabilizes PAH expression and enhances phenylalanine metabolism. Additionally, our current study demonstrates the clinical relevance of PAH and Cdh1 correlation in hepatocellular carcinoma (HCC). Overall, we show that PAH is a prognostic marker for HCC and Cdh1 could be a potential therapeutic target to regulate PAH-mediated physiological and metabolic disorders.
苯丙酮尿症（PKU）是一种常染色体隐性代谢疾病，由苯丙氨酸羟化酶（PAH）的功能障碍引起。PAH 水平的改变导致苯丙氨酸在血液和大脑中有毒积累。泛素化介导的蛋白质降解是维持蛋白质内稳态的主要细胞过程。因此，识别负责 PAH 周转和蛋白稳态的 E3 连接酶至关重要。在这里，我们报告说，后期促进复合物/细胞周期蛋白-Cdh1（APC/C）是一种 E3 泛素连接酶复合物，通过 26S 蛋白酶体途径相互作用并促进 PAH 的多泛素化。Cdh1 使 PAH 失稳并降低其半衰期。相比之下，CRISPR/Cas9 介导的敲除 稳定了 PAH 的表达并增强了苯丙氨酸代谢。此外，我们的研究还证明了 PAH 和 Cdh1 在肝细胞癌（HCC）中的相关性具有临床意义。总的来说，我们表明 PAH 是 HCC 的预后标志物，Cdh1 可能是调节 PAH 介导的生理和代谢紊乱的潜在治疗靶点。
