Functional Genoproteome Research Centre, Konkuk University, Seoul, Korea.
Cell Death Differ. 2011 Dec;18(12):1865-75. doi: 10.1038/cdd.2011.57. Epub 2011 May 20.
Following DNA damage, p53 translocates to the cytoplasm and mitochondria, where it triggers transcription-independent apoptosis by binding to Bcl-2 family proteins. However, little is known about how this exonuclear function of p53 is regulated. Here, we identify and characterize a p53-interacting protein called Hades, an E3 ligase that interacts with p53 in the mitochondria. Hades reduces p53 stability via a mechanism that requires its RING-finger domain with ubiquitin ligase activity. Hades polyubiquitinates p53 in vitro independent of Mdm2 and targets a critical lysine residue in p53 (lysine 24) distinct from those targeted by Mdm2. Hades inhibits a p53-dependent mitochondrial cell death pathway by inhibiting p53 and Bcl-2 interactions. These findings show that Hades-mediated p53 ubiquitination is a novel mechanism for negatively regulating the exonuclear function of p53.
在 DNA 损伤后，p53 易位到细胞质和线粒体，在那里通过与 Bcl-2 家族蛋白结合触发转录独立的细胞凋亡。然而，人们对 p53 的这种核外功能如何被调节知之甚少。在这里，我们鉴定并表征了一种称为 Hades 的 p53 相互作用蛋白，它是一种 E3 连接酶，可在线粒体中与 p53 相互作用。Hades 通过一种需要其具有泛素连接酶活性的 RING 指结构域的机制降低 p53 的稳定性。Hades 在体外独立于 Mdm2 多泛素化 p53，并靶向 p53 中的一个关键赖氨酸残基（赖氨酸 24），不同于 Mdm2 靶向的残基。Hades 通过抑制 p53 和 Bcl-2 相互作用来抑制依赖 p53 的线粒体细胞死亡途径。这些发现表明，Hades 介导的 p53 泛素化是负调控 p53 核外功能的一种新机制。
