RESEARCH HIGHLIGHTS

B AC T E R I A L P H Y S I O LO GY

Linking cell differentiation and growth

c‑di‑GMP controls cell cycle progression by regulating the activity of CckA

To ensure their survival, bacteria need to tune cell division with dynamic developmental responses, but the molecular mechanisms that couple these processes are unknown. Now, Lori, Ozaki et al. show that Caulobacter crescentus uses oscil‑ lating levels of cyclic diguanylate (c‑di‑GMP) to regulate both cell morphogenesis and chromosome replication, providing a novel link between cell growth and differentiation in bacteria. C. crescentus is an aquatic bac‑ terium that divides asymmetrically into a stalked cell (which is a sessile, proliferative cell) and a swarmer cell (which is motile and does not repli‑ cate). Swarmer cells can differentiate into stalked cells in a process that was previously shown to be dependent on c‑di‑GMP. Furthermore, c‑di‑GMP levels are known to oscillate during the bacterial cell cycle, with levels being low in swarmer cells and peak‑ ing in stalked cells, but whether such oscillations contribute to cell cycle progression was unknown. The authors performed a genetic screen for synthetic lethal mutants in a C. crescentus strain that lacks all diguanylate cyclases and is therefore unable to synthesize c‑di‑GMP. They identified the response regulator

DivK, suggesting that DivK and c‑di‑GMP co-regulate cell cycle progression. DivK is known to regulate the activity of CckA, a bifunctional protein with both kinase and phosphatase activities that regulates the activity of the response regulator CtrA via a phosphorelay; CtrA is phosphorylated in swarmer cells and prevents chromosome replication by binding to the origin of replication, whereas in stalked cells CtrA is dephosphorylated, which promotes replication initiation. Thus, the authors analysed the effects of c‑di‑GMP on the CckA–CtrA phospho­relay and found that c‑di‑GMP inhibits CckA kinase activity and stimulates its phos‑ phatase activity. Furthermore, the authors showed that c-di-GMP binds to the catalytic ATP-binding domain of CckA, and a single mutation in CckA (Y514D) strongly diminished c-di-GMP binding. Moreover, the mutant CckA was unable to switch from the kinase state to the phosphatase state, demonstrating that c‑di‑GMP binding to CckA is required to induce a change in its activity. To confirm that c‑di‑GMP controls cell cycle progression by regulating the activity of CckA, the authors

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introduced a mutation into divK in the CckA Y514D mutant, with the expectation that this mutant should be unable to differentiate from swarmer cells into stalked cells even in the presence of c‑di‑GMP. Consistent with this, the mutant showed severe growth defects and increased binding of CtrA to the origin of replication, and was arrested in the swarmer state, even in the presence of c‑di‑GMP. The authors propose a model in which DivK and c‑di‑GMP control the activity of CckA, which in turn regulates the ability of CtrA to control chromosome replication and promote cell cycle progression. Notably, this mechanism is similar to the use of cyclins and cyclin-dependent kinases in eukaryotes as it relies on oscillat‑ ing levels of c‑di‑GMP to regulate a c‑di‑GMP-dependent kinase for control of cell cycle progression in C. crescentus. Finally, this model establishes c‑di‑GMP as a key regulator of both cell morphology and bacterial replication, providing a novel mechanistic link between these two processes. Cláudio Nunes-Alves ORIGINAL RESEARCH PAPER Lori, C., Ozaki, S. et al. Cyclic di-GMP acts as a cell cycle oscillator to drive chromosome replication. Nature http://dx.doi.org/10.1038/nature14473 (2015)

VOLUME 13 | JULY 2015 © 2015 Macmillan Publishers Limited. All rights reserved

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Nature Reviews Microbiology | AOP, published online 26 May 2015; doi:10.1038/nrmicro3505

Bacterial physiology. Linking cell differentiation and growth.

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