c-di-AMP hydrolysis by the phosphodiesterase AtaC promotes differentiation of multicellular bacteria
Andreas Latoscha, David Drexler, Mahmoud M. Al‐Bassam, Adrian Maurice Bandera, Volkhard Kaever, Kim Findlay, Gregor Witte, Natalia Tschowri
Abstract
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 Mn 2+ 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 .