c-di-AMP assists osmoadaptation by regulating the Listeria monocytogenes potassium transporters KimA and KtrCD

J Biol Chem. 2019 Nov 1;294(44):16020-16033. doi: 10.1074/jbc.RA119.010046. Epub 2019 Sep 9.


Many bacteria and some archaea produce the second messenger cyclic diadenosine monophosphate (c-di-AMP). c-di-AMP controls the uptake of osmolytes in Firmicutes, including the human pathogen Listeria monocytogenes, making it essential for growth. c-di-AMP is known to directly regulate several potassium channels involved in osmolyte transport in species such as Bacillus subtilis and Streptococcus pneumoniae, but whether this same mechanism is involved in L. monocytogenes, or even whether similar ion channels were present, was not known. Here, we have identified and characterized the putative L. monocytogenes' potassium transporters KimA, KtrCD, and KdpABC. We demonstrate that Escherichia coli expressing KimA and KtrCD, but not KdpABC, transport potassium into the cell, and both KimA and KtrCD are inhibited by c-di-AMP in vivo For KimA, c-di-AMP-dependent regulation requires the C-terminal domain. In vitro assays demonstrated that the dinucleotide binds to the cytoplasmic regulatory subunit KtrC and to the KdpD sensor kinase of the KdpDE two-component system, which in Staphylococcus aureus regulates the corresponding KdpABC transporter. Finally, we also show that S. aureus contains a homolog of KimA, which mediates potassium transport. Thus, the c-di-AMP-dependent control of systems involved in potassium homeostasis seems to be conserved in phylogenetically related bacteria. Surprisingly, the growth of an L. monocytogenes mutant lacking the c-di-AMP-synthesizing enzyme cdaA is only weakly inhibited by potassium. Thus, the physiological impact of the c-di-AMP-dependent control of potassium uptake seems to be less pronounced in L. monocytogenes than in other Firmicutes.

Keywords: Escherichia coli (E. coli); Gram-positive bacteria; cyclic diadenosine monophosphate (c-di-AMP); ion transport; osmoadaptation; osmoregulation; osmotic swelling; regulation; second messenger; signal transduction; transporter; turgor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Dinucleoside Phosphates / metabolism
  • Listeria monocytogenes / metabolism*
  • Membrane Transport Proteins / chemistry
  • Membrane Transport Proteins / metabolism*
  • Osmotic Pressure*
  • Potassium / metabolism*
  • Protein Domains
  • Sequence Homology, Amino Acid


  • Bacterial Proteins
  • Dinucleoside Phosphates
  • Membrane Transport Proteins
  • cyclic diadenosine phosphate
  • Potassium