State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China.
Cell. 2011 Sep 30;147(1):223-34. doi: 10.1016/j.cell.2011.08.037.
Autophagy is an important intracellular catabolic mechanism that mediates the degradation of cytoplasmic proteins and organelles. We report a potent small molecule inhibitor of autophagy named "spautin-1" for specific and potent autophagy inhibitor-1. Spautin-1 promotes the degradation of Vps34 PI3 kinase complexes by inhibiting two ubiquitin-specific peptidases, USP10 and USP13, that target the Beclin1 subunit of Vps34 complexes. Beclin1 is a tumor suppressor and frequently monoallelically lost in human cancers. Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. Since USP10 mediates the deubiquitination of p53, regulating deubiquitination activity of USP10 and USP13 by Beclin1 provides a mechanism for Beclin1 to control the levels of p53. Our study provides a molecular mechanism involving protein deubiquitination that connects two important tumor suppressors, p53 and Beclin1, and a potent small molecule inhibitor of autophagy as a possible lead compound for developing anticancer drugs.
自噬是一种重要的细胞内分解代谢机制，介导细胞质蛋白和细胞器的降解。我们报告了一种名为“spautin-1”的强效自噬小分子抑制剂，它是特异性和强效的自噬抑制剂-1。Spautin-1 通过抑制靶向 Vps34 复合物 Beclin1 亚基的两个泛素特异性肽酶 USP10 和 USP13，促进 Vps34 PI3 激酶复合物的降解。Beclin1 是一种肿瘤抑制因子，在人类癌症中经常单等位基因缺失。有趣的是，Beclin1 还通过调节其去泛素化活性来控制 USP10 和 USP13 的蛋白质稳定性。由于 USP10 介导 p53 的去泛素化，因此 Beclin1 通过调节 USP10 和 USP13 的去泛素化活性来控制 p53 的水平，这为 Beclin1 提供了一种控制 p53 水平的机制。我们的研究提供了一个涉及蛋白质去泛素化的分子机制，将两个重要的肿瘤抑制因子 p53 和 Beclin1 以及一种强效的自噬小分子抑制剂联系起来，并为开发抗癌药物提供了一种可能的先导化合物。
