Abstract
Bacteria often use cyclic dinucleotides as second messengers for signal transduction. While the classical molecule c-di-GMP is involved in lifestyle selection, the functions of the more recently discovered signaling nucleotide cyclic di-AMP are less defined. For many Gram-positive bacteria, c-di-AMP is essential for growth suggesting its involvement in a key cellular function. We have analyzed c-di-AMP signaling in the genome-reduced pathogenic bacterium Mycoplasma pneumoniae. Our results demonstrate that these bacteria produce c-di-AMP, and we could identify the diadenylate cyclase CdaM (MPN244). This enzyme is the founding member of a novel family of diadenylate cyclases. Of two potential c-di-AMP degrading phosphodiesterases, only PdeM (MPN549) is active in c-di-AMP degradation, whereas NrnA (MPN140) was reported to degrade short oligoribonucleotides. As observed in other bacteria, both the c-di-AMP synthesizing and the degrading enzymes are essential for M. pneumoniae suggesting control of a major homeostatic process. To obtain more insights into the nature of this process, we have identified a c-di-AMP-binding protein from M. pneumoniae, KtrC. KtrC is the cytoplasmic regulatory subunit of the low affinity potassium transporter KtrCD. It is established that binding of c-di-AMP inhibits the KtrCD activity resulting in a limitation of potassium uptake. Our results suggest that the control of potassium homeostasis is the essential function of c-di-AMP in M. pneumoniae.
Highlights
To respond to changes in their environment, bacteria have evolved a large set of signal detection and transduction systems
C-di-AMP Signaling in M. pneumoniae cAMP is the paradigmatic second messenger, and this nucleotide is involved in coordinating carbon and nitrogen metabolism and in carbon catabolite repression in Escherichia coli and related bacteria (Görke and Stülke, 2008; You et al, 2013). (p)ppGpp is formed upon starvation and triggers a reduction of cellular house-keeping activities (Steinchen and Bange, 2016)
All Firmicutes studied so far produce c-di-AMP, and in most of them, this second messenger is essential for the growth of these bacteria (Commichau et al, 2015)
Summary
To respond to changes in their environment, bacteria have evolved a large set of signal detection and transduction systems. Cyclic di-GMP is in many bacteria involved in the choice between sessile and motile lifestyles (Hengge, 2009) While these second messengers have been intensively studied in a large number of different bacteria, cyclic di-AMP has been discovered only less than a decade ago (Witte et al, 2008). This nucleotide was found in the crystal structure of the so-called DNA integrity scanning protein DisA, which exhibits diadenylate cyclase activity (Witte et al, 2008). To control the intracellular levels of c-di-AMP, the bacteria that produce cyclic di-AMP do possess phosphodiesterases to degrade this molecule (Rao et al, 2010; Corrigan et al, 2011; Commichau et al, 2015; Huynh and Woodward, 2016)
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