c-di-AMP hydrolysis by the phosphodiesterase AtaC promotes differentiation of multicellular bacteria

Proc Natl Acad Sci U S A. 2020 Mar 31;117(13):7392-7400. doi: 10.1073/pnas.1917080117. Epub 2020 Mar 18.


Antibiotic-producing Streptomyces use the diadenylate cyclase DisA to synthesize the nucleotide second messenger c-di-AMP, but the mechanism for terminating c-di-AMP signaling and the proteins that bind the molecule to effect signal transduction are unknown. Here, we identify the AtaC protein as a c-di-AMP-specific phosphodiesterase that is also conserved in pathogens such as Streptococcus pneumoniae and Mycobacterium tuberculosis AtaC is monomeric in solution and binds Mn2+ to specifically hydrolyze c-di-AMP to AMP via the intermediate 5'-pApA. As an effector of c-di-AMP signaling, we characterize the RCK_C domain protein CpeA. c-di-AMP promotes interaction between CpeA and the predicted cation/proton antiporter, CpeB, linking c-di-AMP signaling to ion homeostasis in Actinobacteria. Hydrolysis of c-di-AMP is critical for normal growth and differentiation in Streptomyces, connecting ionic stress to development. Thus, we present the discovery of two components of c-di-AMP signaling in bacteria and show that precise control of this second messenger is essential for ion balance and coordinated development in Streptomyces.

Keywords: Streptomyces; c-di-AMP; development; osmostress; phosphodiesterase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / metabolism
  • Bacterial Proteins / metabolism
  • Dinucleoside Phosphates / metabolism*
  • Gene Expression Regulation, Bacterial / genetics
  • Hydrolysis
  • Mycobacterium tuberculosis / metabolism
  • Phosphoric Diester Hydrolases / metabolism*
  • Second Messenger Systems
  • Signal Transduction / physiology
  • Streptococcus pneumoniae / metabolism
  • Streptomyces / metabolism*


  • Bacterial Proteins
  • Dinucleoside Phosphates
  • cyclic diadenosine phosphate
  • Adenosine Monophosphate
  • Phosphoric Diester Hydrolases