Wiebusch Lüder, Bach Miriam, Uecker Ralf, Hagemeier Christian
Department of Pediatrics, Laboratory for Molecular Biology, Charité, Humboldt University, Berlin, Germany.
Cell Cycle. 2005 Oct;4(10):1435-9. doi: 10.4161/cc.4.10.2077. Epub 2005 Oct 2.
The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets regulators of the cell division cycle for degradation by the 26S proteasome. Discovered as a key regulator of mitosis, the APC/C has more recently been recognized to also play a limiting role in the control of G(0) maintenance, G(1)/S-transition and DNA-replication. Human cytomegalovirus (HCMV) has been shown to interfere with cell cycle regulation at different levels. It can induce an S phase-prone proliferation program in quiescent cells but at the same time this virus directly inhibits competitive cellular DNA replication. Here we show, that human cytomegalovirus (HCMV) inactivates the G(0)/G(1) APC/C rapidly after infection of quiescent fibroblasts, resulting in the untimely stabilization of APC/C substrates. APC/C inactivation is caused by the dissociation of its positive regulator, Cdh1. Surprisingly, this dissociation is independent from known Cdh1 inhibitors, Emi1 and Cyclin A, suggesting that APC/C-Cdh1 inhibition by HCMV is directly caused by a viral protein or an intermediate cellular factor distinct from Emi1 and Cyclin A. Thus, upon infection of quiescent cells HCMV not only activates the E2F-dependent G(1)/S transcription program but also facilitates protein accumulation of APC/C substrates by rapid Cdh1 dissociation.
后期促进复合物/细胞周期体（APC/C）是一种E3泛素连接酶，它将细胞分裂周期的调节因子作为靶点，通过26S蛋白酶体进行降解。作为有丝分裂的关键调节因子被发现后，APC/C最近还被认为在G(0)期维持、G(1)/S期转换和DNA复制的控制中发挥限制作用。人类巨细胞病毒（HCMV）已被证明在不同水平上干扰细胞周期调控。它能在静止细胞中诱导易于进入S期的增殖程序，但同时这种病毒直接抑制竞争性的细胞DNA复制。在这里我们表明，人类巨细胞病毒（HCMV）在感染静止成纤维细胞后迅速使G(0)/G(1)期的APC/C失活，导致APC/C底物过早稳定。APC/C失活是由其正向调节因子Cdh1的解离引起的。令人惊讶的是，这种解离独立于已知的Cdh1抑制剂Emi1和细胞周期蛋白A，这表明HCMV对APC/C-Cdh1的抑制是由一种病毒蛋白或不同于Emi1和细胞周期蛋白A的中间细胞因子直接引起的。因此，在感染静止细胞后，HCMV不仅激活E2F依赖的G(1)/S期转录程序，还通过快速的Cdh1解离促进APC/C底物的蛋白积累。
