TY - JOUR

T1 - c-di-AMP hydrolysis by the phosphodiesterase AtaC promotes differentiation of multicellular bacteria

AU - Latoscha, Andreas

AU - Drexler, David Jan

AU - Al-Bassam, Mahmoud M

AU - Bandera, Adrian M

AU - Kaever, Volkhard

AU - Findlay, Kim C

AU - Witte, Gregor

AU - Tschowri, Natalia

N1 - Funding information: ACKNOWLEDGMENTS. We are grateful to Mark J. Buttner and Fabian M. Commichau for helpful discussion and critical reading of the manuscript and thank Matt Bush for technical support with scanning electron micrographs. We thank the staff of the EMBL Hamburg beamline P12 at PETRA3 (EMBL/DESY, Hamburg, Germany) for outstanding scientific support. We also acknowledge Anna-Lena Hagemann and Annette Garbe for technical support with LC-MS/MS funded by the Deutsche Forschungsgemeinschaft (DFG) Priority Program SPP 1879 (Grant KA 730/9-1). We acknowledge the use of the Prometheus instrument in the Bioanalytics unit of the Ludwig-Maximilians-Universität München Biocen-ter and discussions with Franziska Tippel and Beate Kern (NanoTemper Technologies). Research in G.W.’s lab is funded by DFG Grant GRK1721 and the DFG Priority Program SPP 1879 (Grant WI 3717/3-1). Research in N.T.’s lab is funded by the DFG Emmy Noether Program (Grant TS 325/1-1) and the DFG Priority Program SPP 1879 (Grants TS 325/2-1 and TS 325/2-2).

PY - 2020/3/31

Y1 - 2020/3/31

N2 - 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.

AB - 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.

KW - Adenosine Monophosphate/metabolism

KW - Bacterial Proteins/metabolism

KW - Dinucleoside Phosphates/metabolism

KW - Gene Expression Regulation, Bacterial/genetics

KW - Hydrolysis

KW - Mycobacterium tuberculosis/metabolism

KW - Phosphoric Diester Hydrolases/metabolism

KW - Second Messenger Systems

KW - Signal Transduction/physiology

KW - Streptococcus pneumoniae/metabolism

KW - Streptomyces/metabolism

KW - Streptomyces

KW - Osmostress

KW - C-di-AMP

KW - Development

KW - Phosphodiesterase

UR - http://www.scopus.com/inward/record.url?scp=85082750083&partnerID=8YFLogxK

U2 - 10.1073/pnas.1917080117

DO - 10.1073/pnas.1917080117

M3 - Article

C2 - 32188788

VL - 117

SP - 7392

EP - 7400

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 13

ER -