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Signalling of c-di-AMP

A new phosphodiesterase targeting c-di-AMP

18.03.2020

The degradation of the bacterial nucleotide second messenger c-di-AMP is unknown for a large number of species, mainly Actinobacteria. In a joint effort, the teams of Natalia Tschowri and Gregor Witte identified and characterized a novel class of phosphodiesterases in Actinobacteria and were able to connect the role of c-di-AMP in Streptomyces to ionic stress and development.

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The nucleotide second messenger c-di-AMP is mainly present in gram-positive bacteria and fulfils a variety of important functions, such as osmolyte homeostasis, cell wall metabolism, growth, DNA integrity, biofilm formation and virulence. As it was found to be essential in many pathogens, the signalling pathway of c-di-AMP is of particular interest for drug discovery. For accurate signalling function, the levels of c-di-AMP are controlled precisely by synthesis and hydrolysis. Although three c-di-AMP hydrolysing phosphodiesterases have already been identified so far, none of them is present in the majority of a large bacterial phylum, the Actinobacteria. In a collaborative approach within the DFG priority program SPP1879, the teams of Natalia Tschowri (HU Berlin) and Gregor Witte (LMU Gene Center) uncovered an alternative degradation pathway for c-di-AMP, recently published in the journal PNAS (Proceedings of the National Academy of Sciences of the United States of America). They characterise a novel class of c-di-AMP specific phosphodiesterases, called AtaC, identify a new c-di-AMP binding protein (CpeA), and describe the effect of c-di-AMP levels on ionic stress and development in Streptomyces venezuelae. As the hydrolysis activity for c-di-AMP is also described for an AtaC homologue from the pathogen S. pneumoniae, the present discovery raises a highly interesting research topic for future studies.

Original Publication:

C-di-AMP hydrolysis by the phosphodiesterase AtaC promotes differentiation of multicellular bacteria.
Latoscha A#, Drexler DJ#, Al-Bassam MM, Kaever V, Findlay KC, Witte G*, Tschowri N.*
Proceedings of the National Academy of Sciences of the United States of America, 2020 Mar 18. https://doi.org/10.1073/pnas.1917080117 PubMed