Biondi Emanuele G, Reisinger Sarah J, Skerker Jeffrey M, Arif Muhammad, Perchuk Barrett S, Ryan Kathleen R, Laub Michael T
FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Nature. 2006 Dec 14;444(7121):899-904. doi: 10.1038/nature05321. Epub 2006 Nov 29.
How bacteria regulate cell cycle progression at a molecular level is a fundamental but poorly understood problem. In Caulobacter crescentus, two-component signal transduction proteins are crucial for cell cycle regulation, but the connectivity of regulators involved has remained elusive and key factors are unidentified. Here we identify ChpT, an essential histidine phosphotransferase that controls the activity of CtrA, the master cell cycle regulator. We show that the essential histidine kinase CckA initiates two phosphorelays, each requiring ChpT, which lead to the phosphorylation and stabilization of CtrA. Downregulation of CckA activity therefore results in the dephosphorylation and degradation of CtrA, which in turn allow the initiation of DNA replication. Furthermore, we show that CtrA triggers its own destruction by promoting cell division and inducing synthesis of the essential regulator DivK, which feeds back to downregulate CckA immediately before S phase. Our results define a single integrated circuit whose components and connectivity can account for the cell cycle oscillations of CtrA in Caulobacter.
细菌如何在分子水平上调节细胞周期进程是一个基本但却知之甚少的问题。在新月柄杆菌中，双组分信号转导蛋白对细胞周期调控至关重要，但所涉及的调节因子之间的联系仍不明确，关键因子也尚未确定。在此，我们鉴定出ChpT，一种控制主要细胞周期调节因子CtrA活性的必需组氨酸磷酸转移酶。我们发现，必需组氨酸激酶CckA启动两个磷酸化信号传递途径，每个途径都需要ChpT参与，从而导致CtrA的磷酸化和稳定。因此，CckA活性的下调会导致CtrA的去磷酸化和降解，进而允许DNA复制的起始。此外，我们表明CtrA通过促进细胞分裂和诱导必需调节因子DivK的合成来触发自身的降解，DivK在S期之前立即反馈下调CckA。我们的结果定义了一个单一的集成电路，其组件和连接方式可以解释新月柄杆菌中CtrA的细胞周期振荡。
