Advances in bacterial c-di-AMP-specific phosphodiesterase

Cyclic dimeric adenosine 3′,5′-monophosphate (c-di-AMP) is an emerging second messenger with multiple functions in Archaea, Gram-positive bacteria, Mycoplasma, Chlamydia, Cyanobacteria, and some other Gram-negative bacteria. C-di-AMP-specific phosphodiesterase (PDE) maintains the balance of c-di-AMP metabolism in bacteria. PDEs in bacteria have a vibrant structure and can be classified into three categories based on their functional domains. The first characterized PDE includes GdpP and DhhP homologs. GdpP has two transmembrane helices, a PAS (Per-Arnt-Sim) domain, a degenerate GGDEF domain, and the catalytic domains DHH and DHHA1. DhhP is a stand-alone DHH-DHHA1 domain protein compared with GdpP. Both DhhP and GdpP homologs degrade c-di-AMP via DHH/DHHA1 (Asp-His-His) domain. The second involves PgpH homologs, HD (Asp-His) is the main functional domain of hydrolyzing c-di-AMP. The HD domain structure remains conserved, although the amino acid sequence identity is low in certain bacteria. The newly discovered bacterial extracellular nucleosidases contain CdnP and AtaC and are sensitive to pH and metal ions. However, their catalytic domain for enzymatic activity and specific hydrolysis mechanism needs improvement. C-di-AMP-specific PDE could degrade c-di-AMP to one pApA molecule or two AMP molecules. Some PDEs hydrolyze in two steps, while others only hydrolyze in one, which could be due to conserved metal ion centers and unique substrate binding sites found in different PDEs. However, some c-di-AMP-specific PDEs, such as DhhP, can hydrolyze not only c-di-AMP and pApA but also c-di-GMP and pGpG. Most c-di-AMP-containing bacteria encode two or more PDEs simultaneously, which sense different signals or display distinct substrate preferences to perform diverse cellular functions individually or cooperatively. PDEs are important for maintaining the physiological function of bacteria and eliciting the immune response of host cells by regulating the bacterial c-di-AMP level. Recent studies suggest that PDE deletion or mutation affects multiple physiological functions including bacterial growth, virulence, and sensitivity to the external environment. GdpP leads to a dramatic increase of c-di-AMP in Staphylococcus aureus, thus reducing bacterial metabolic activity and growth. PDE absence in Lactococcus lactis improves bacterial heat tolerance and increases susceptibility to osmotic stress. PDE deletion could inhibit the overall virulence of particle pathogenic bacteria such as Streptococcus. Thus, PDE can be concluded as a potential virulence factor of pathogenic bacteria. Meanwhile, PDE also mediates bacterial biofilm formation via modulating c-di-AMP, which may be a key element in microbial drug resistance. Furthermore, c-di-AMP can effectively activate key molecules of the host cell immune response during pathogen infection; however, its levels are strictly regulated by PDE. This indicates the PDE’s importance in bacterial physiological function and host immune response. Therefore, c-di-AMP-specific PDEs have great significance in the field of antibacterial drugs as a target for preventing and treating pathogenic infections. This paper reviews the types, structures, and biological functions of PDE, aiming to provide references for related research.