Editors' ChoiceMicrobiology

Cyclin-like function of bacterial c-di-GMP

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Sci. Signal.  21 Jul 2015:
Vol. 8, Issue 386, pp. ec195
DOI: 10.1126/scisignal.aad0291

Bacteria lack the cyclins and cyclin-dependent kinases (CDKs) that control cell cycle progression and balance proliferation with differentiation in eukaryotes. In the marine bacterium Caulobacter crescentus, the dual kinase and phosphatase CckA controls the phosphorylation status of the master cell cycle regulator CtrA. When CtrA is phosphorylated, it binds to the origin of replication to prevent initiation of DNA replication; dephosphorylation of CtrA relieves this repression. Proliferating C. crescentus cells are asymmetric rods, with one pole attached to the substrate by a stalk and the other pole bearing a flagellum. The cells divide asymmetrically to generate one sessile stalked cell from the stalk pole, which can continue to proliferate, and one motile swarmer cell, which must subsequently attach to a surface and differentiate into a stalked cell to divide. The abundance of the second messenger 3',5'-cyclic-di-guanosine monophosphate (c-di-GMP) is low in swarmer cells, increases during the transition to the stalked form, and reaches a maximum in the differentiated stalked cell. Lori et al. found that c-di-GMP controlled cell cycle progression in C. crescentus by affecting the activity CtrA. In vitro assays using purified proteins showed that c-di-GMP bound directly to CckA, inhibited its kinase activity, and stimulated its phosphatase activity. In vivo experiments were consistent with the rise in c-di-GMP abundance during the G1-to-S (motile-to-sessile) transition promoting cell cycle progression by shifting the balance of CckA activity. During the division of C. crescentus, the kinase activity of CckA predominates at the flagellated pole, and its phosphatase activity predominates at the stalk pole, resulting in a heritable phenomenon called replicative asymmetry in which chromosome duplication preferentially occurs at the stalk pole. Replicative asymmetry also required c-di-GMP, and the authors propose that spatially restricted biosynthesis and metabolism of c-di-GMP contributes to creating or maintaining the two functionally distinct pools of CckA. Thus, like cyclins in eukaryotes, c-di-GMP coordinates cell division with cell differentiation in bacteria.

C. Lori, S. Ozaki, S. Steiner, R. Böhm, S. Abel, B. N. Dubey, T. Schirmer, S. Hiller, U. Jenal, Cyclic di-GMP acts as a cell cycle oscillator to drive chromosome replication. Nature 523, 236–239 (2015). [PubMed]