1. FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts 02138, USA
2. Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, California 94720, USA
3. Present address: Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts 02139, USA.

Correspondence to: Michael T. Laub^1,3 Correspondence and requests for materials should be addressed to M.T.L. (Email: laub@mit.edu).

Abstract

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.

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