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J Biol Chem. 2019 May 6. pii: jbc.RA119.008774. doi: 10.1074/jbc.RA119.008774. [Epub ahead of print]

Sustained sensing in potassium homeostasis: Cyclic di-AMP controls potassium uptake by KimA at the levels of expression and activity.

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University of Göttingen, Germany.
University of Göttingen.
University of Maryland, United States.
Goethe University Frankfurt, Germany.
Georg-August-Universität Göttingen.
Institut für Mikrobiologie und Genetik, University of Göttingen, Germany.


The signaling nucleotide cyclic di-AMP (c-di-AMP) is the only known essential second messenger in bacteria. Recently, c-di-AMP has been identified as being essential for controlling potassium uptake in the model organism Bacillus subtilis and several other bacteria. A B. subtilis strain lacking c-di-AMP is not viable at high potassium concentrations, unless the bacteria acquire suppressor mutations. In this study, we isolated such suppressor mutants and found mutations that reduced the activities of the potassium transporters KtrCD and KimA. Although c-di-AMP-mediated control of KtrCD has previously been demonstrated, it is unknown how c-di-AMP affects KimA activity. Using the DRaCALA screening assay, we tested for any interactions of KimA and other potential target proteins in B. subtilis with c-di-AMP. This assay identified KimA as well as the K+/H+ antiporter KhtT; the potassium exporter CpaA (YjbQ); the osmoprotectant transporter subunit OpuCA; the primary Mg2+ exporter MgtE; and DarB (YkuL), a protein of unknown function, as bona fide c-di-AMP-binding proteins. Further, binding of c-di-AMP to KimA inhibited potassium uptake. Our results indicate that c-di-AMP controls KimA-mediated potassium transport at both kimA gene expression and KimA activity levels. Moreover, the discovery that potassium exporters are c-di-AMP targets indicates that this second messenger controls potassium homeostasis in B. subtilis at a global level by binding to riboswitches and to different classes of transport proteins involved in potassium uptake and export.


Bacillus; Bacillus subtilis; bacterial genetics; cation homeostasis; cyclic di-AMP; cyclic diadenosine monophosphate (c-di-AMP); dinucleotide signaling; osmoregulation; potassium transport; prokaryotic signal-transduction; second messenger

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