Riboswitches in eubacteria sense the second messenger c-di-AMP

Nelson, Jelani; Sudarsan, Narasimhan; Furukawa, Kazuhiro; Weinberg, Zasha; Wang, Joy X.; Breaker, Ronald R.

doi:10.1038/nchembio.1363

Cited by 259 publications

(370 citation statements)

References 62 publications

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“…The cyclic dinucleotide content of Geobacter bacteria has not been analyzed previously, although bioinformatics analyses have predicted the presence of enzymes related to cdiG and cdiA signaling (19,20) and corresponding GEMM-I and ydaO class riboswitches (15,21). Our current results strongly suggest that these organisms also produce cAG as an endogenous signaling molecule, even though their genomes do not harbor any homologs of DncV.…”

supporting

confidence: 51%

GEMM-I riboswitches from Geobacter sense the bacterial second messenger cyclic AMP-GMP

Kellenberger¹,

Wilson²,

Hickey³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

117

146

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Cyclic dinucleotides are an expanding class of signaling molecules that control many aspects of bacterial physiology. A synthase for cyclic AMP-GMP (cAG, also referenced as 3′-5′, 3′-5′ cGAMP) called DncV is associated with hyperinfectivity of Vibrio cholerae but has not been found in many bacteria, raising questions about the prevalence and function of cAG signaling. We have discovered that the environmental bacterium Geobacter sulfurreducens produces cAG and uses a subset of GEMM-I class riboswitches (GEMM-Ib, Genes for the Environment, Membranes, and Motility) as specific receptors for cAG. GEMM-Ib riboswitches regulate genes associated with extracellular electron transfer; thus cAG signaling may control aspects of bacterial electrophysiology. These findings expand the role of cAG beyond organisms that harbor DncV and beyond pathogenesis to microbial geochemistry, which is important to environmental remediation and microbial fuel cell development. Finally, we have developed an RNA-based fluorescent biosensor for live-cell imaging of cAG. This selective, genetically encodable biosensor will be useful to probe the biochemistry and cell biology of cAG signaling in diverse bacteria.

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supporting

confidence: 51%

GEMM-I riboswitches from Geobacter sense the bacterial second messenger cyclic AMP-GMP

Kellenberger¹,

Wilson²,

Hickey³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

117

146

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“…Our results reveal that the large abundance and redundancy of GGDEF genes in bacterial genomes have allowed this enzyme family to diverge and evolve toward new synthase activity; the distribution of HD-GYP and EAL phosphodiesterase domains also are expanded in Deltaproteobacteria (9), and at least one variant HD-GYP domain has been shown to degrade cAG (34). Besides synthesizing cAG, we also showed that GGDEF domains can make cdiA, an activity that had been speculated (43), but only now proven. We conceive that larger distortions of the substrate-binding pocket, including in the signature GGDEF motif, could accommodate synthesis of pyrimidine-containing CDNs, which would expand the palette of CDN signaling molecules in nature.…”

Section: Whereas Previous Ggdef Enzymes Were Uniformly Assigned As Dgmentioning

confidence: 70%

Hybrid promiscuous (Hypr) GGDEF enzymes produce cyclic AMP-GMP (3′, 3′-cGAMP)

Hallberg

Wang

Wright

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

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Over 30 years ago, GGDEF domain-containing enzymes were shown to be diguanylate cyclases that produce cyclic di-GMP (cdiG), a second messenger that modulates the key bacterial lifestyle transition from a motile to sessile biofilm-forming state. Since then, the ubiquity of genes encoding GGDEF proteins in bacterial genomes has established the dominance of cdiG signaling in bacteria. However, the observation that proteobacteria encode a large number of GGDEF proteins, nearing 1% of coding sequences in some cases, raises the question of why bacteria need so many GGDEF enzymes. In this study, we reveal that a subfamily of GGDEF enzymes synthesizes the asymmetric signaling molecule cyclic AMP-GMP (cAG or 3′, 3′-cGAMP). This discovery is unexpected because GGDEF enzymes function as symmetric homodimers, with each monomer binding to one substrate NTP. Detailed analysis of the enzyme from Geobacter sulfurreducens showed it is a dinucleotide cyclase capable of switching the major cyclic dinucleotide (CDN) produced based on ATP-to-GTP ratios. We then establish through bioinformatics and activity assays that hybrid CDN-producing and promiscuous substrate-binding (Hypr) GGDEF enzymes are found in other deltaproteobacteria. Finally, we validated the predictive power of our analysis by showing that cAG is present in surface-grown Myxococcus xanthus. This study reveals that GGDEF enzymes make alternative cyclic dinucleotides to cdiG and expands the role of this widely distributed enzyme family to include regulation of cAG signaling.bacterial signaling | surface sensing | second messengers | cyclic dinucleotides | fluorescent biosensor

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“…Five riboswitch classes are known that respond to c-di-GMP (two classes) (Sudarsan et al 2008;Lee et al 2010), c-di-AMP (Nelson et al 2013), c-AMP-GMP (Kellenberger et al 2015;Nelson et al 2015), and ZTP (Kim et al 2015). These observations again suggest that modern cells still carry traces of ancient RNA World signaling partnerships between riboswitches and small-molecule signals formed from ribonucleotide components (Breaker 2010;.…”

Section: Rna-derived Compounds Are the Most Prevalent Ligands For Thementioning

confidence: 75%

“…Notably, riboswitches for the signaling compounds c-di-AMP and c-AMP-GMP were discovered before these molecules were known to exist. Specifically, the ydaO orphan riboswitch class ) was reported several years before c-di-AMP was first discovered (Witte et al 2008), followed thereafter by confirmation of c-di-AMP as the riboswitch ligand (Nelson et al 2013). Similarly, cdi-GMP riboswitch variants (Sudarsan et al 2008) were in hand, but remained unlinked to their natural ligand until after their ligand, c-AMP-GMP, had been discovered by other means (Davies et al 2012).…”

Section: Rna-derived Compounds Are the Most Prevalent Ligands For Thementioning

confidence: 99%

Riboswitch diversity and distribution

McCown

Corbino

Stav

et al. 2017

RNA

392

516

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Riboswitches are commonly used by bacteria to detect a variety of metabolites and ions to regulate gene expression. To date, nearly 40 different classes of riboswitches have been discovered, experimentally validated, and modeled at atomic resolution in complex with their cognate ligands. The research findings produced since the first riboswitch validation reports in 2002 reveal that these noncoding RNA domains exploit many different structural features to create binding pockets that are extremely selective for their target ligands. Some riboswitch classes are very common and are present in bacteria from nearly all lineages, whereas others are exceedingly rare and appear in only a few species whose DNA has been sequenced. Presented herein are the consensus sequences, structural models, and phylogenetic distributions for all validated riboswitch classes. Based on our findings, we predict that there are potentially many thousands of distinct bacterial riboswitch classes remaining to be discovered, but that the rarity of individual undiscovered classes will make it increasingly difficult to find additional examples of this RNA-based sensory and gene control mechanism.

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Riboswitches in eubacteria sense the second messenger c-di-AMP

Cited by 259 publications

References 62 publications

GEMM-I riboswitches from Geobacter sense the bacterial second messenger cyclic AMP-GMP

GEMM-I riboswitches from Geobacter sense the bacterial second messenger cyclic AMP-GMP

Hybrid promiscuous (Hypr) GGDEF enzymes produce cyclic AMP-GMP (3′, 3′-cGAMP)

Riboswitch diversity and distribution

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