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Cyclic di-AMP (c-di-AMP) is a newly discovered bacterial second messenger. However, regulation of c-di-AMP homeostasis is poorly understood. In Streptococcus pneumoniae , a sole diadenylate cyclase, CdaA, produces c-di-AMP and two phosphodiesterases, Pde1 and Pde2, cleave the signaling dinucleotide. To expand our knowledge of the pneumococcal c-di-AMP signaling network, we performed whole-genome sequencing of Δ pde1 Δ pde2 heat shock suppressors. In addition to their effects on surviving heat shock, these suppressor mutations restored general stress resistance and improved growth in rich medium. Mutations in CdaA or in the potassium transporter TrkH paired with an insertion leading to a frameshift at the C terminus of CdaA significantly reduced c-di-AMP levels. These observations indicate that the elevated c-di-AMP levels in the Δ pde1 Δ pde2 mutant enhance susceptibility of S. pneumoniae to the stress conditions. Interestingly, we have previously shown that TrkH complexes with a Trk family c-di-AMP-binding protein, CabP, to mediate potassium uptake. In this study, we found that deletion of cabP significantly reduced pneumococcal c-di-AMP levels. This is the first observation that a c-di-AMP effector protein modulates bacterial c-di-AMP homeostasis. IMPORTANCE Second messengers, including c-di-AMP, are prevalent among bacterial species. In S. pneumoniae , c-di-AMP phosphodiesterase-encoding gene null mutants are attenuated during mouse models of infection, but the role of c-di-AMP signaling in pneumococcal pathogenesis is enigmatic. In this work, we found that heat shock suppressor mutations converge on undermining c-di-AMP toxicity by changing intracellular c-di-AMP concentrations. These mutations improve the growth and restore the stress response generally in c-di-AMP phosphodiesterase-deficient pneumococci, thereby demonstrating the essentiality for tight regulation of c-di-AMP homeostasis in order to respond to stress. Likewise, this work demonstrates that a c-di-AMP effector protein, CabP, affects c-di-AMP homeostasis, which provides new perception into c-di-AMP regulation. This study has implications for c-di-AMP-producing bacteria since many species contain CabP homologs.

Stress Suppressor Screening Leads to Detection of Regulation of Cyclic di-AMP Homeostasis by a Trk Family Effector Protein in Streptococcus pneumoniae