Bacteria that synthesize c-di-AMP also encode several mechanisms for controlling c-di-AMP levels within the cytoplasm. One major class of phosphodiesterases comprises GdpP and DhhP homologs, which degrade c-di-AMP into the linear molecule 5'-pApA or AMP by the DHH-DHHA1 domain. The other major class comprises PgpH homologs, which degrade c-di-AMP by the HD domain. Both GdpP and PgpH harbor sensory domains, likely to regulate c-di-AMP hydrolysis activity in response to signal input. As another possible mechanism for controlling cytoplasmic c-di-AMP levels, bacteria also secrete c-di-AMP via multidrug resistance transporters, as demonstrated for Listeria monocytogenes. Mutants that accumulate high c-di-AMP levels, by deletion of phosphodiesterases or multidrug resistance transporters, exhibit aberrant physiology, growth defects, and attenuated virulence in infection.
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