A decade of research on the second messenger c-di-AMP

Yin, Wen; Cai, Xia; Ma, Hongdan; Zhu, Li; Zhang, Yuling; Chou, Shan‐Ho; Galperin, Michael Y.; He, Jin

doi:10.1093/femsre/fuaa019

Cited by 83 publications

(76 citation statements)

References 138 publications

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“…Bacteria possess a thorough toolbox of nucleotide-based second messengers to efficiently respond to diverse external cues ( Pesavento and Hengge, 2009 ; Kalia et al, 2013 ; Hengge et al, 2016 ). Among those, c-di-AMP is a signaling molecule mainly synthetized by Gram-positive bacteria ( Romling, 2008 ; da Aline Dias et al, 2020 ; He et al, 2020 ; Yin et al, 2020 ), which fulfills a pivotal role in the osmotic homeostasis ( Stulke and Kruger, 2020 ). The dynamic range of intracellular c-di-AMP is much lower than for (p)ppGpp and lies in the one-digit μM range (in B. subtilis 1.7 μM during vegetative growth to 5.1 μM 2 h after sporulation; Oppenheimer-Shaanan et al, 2011 ).…”

Section: Crosstalk Between (P)ppgpp and C-di-ampmentioning

confidence: 99%

(p)ppGpp: Magic Modulators of Bacterial Physiology and Metabolism

2020

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When bacteria experience growth-limiting environmental conditions, the synthesis of the hyperphosphorylated guanosine derivatives (p)ppGpp is induced by enzymes of the RelA/ SpoT homology (RSH)-type protein family. High levels of (p)ppGpp induce a process called "stringent response", a major cellular reprogramming during which ribosomal RNA (rRNA) and transfer RNA (tRNA) synthesis is downregulated, stress-related genes upregulated, messenger RNA (mRNA) stability and translation altered, and allocation of scarce resources optimized. The (p)ppGpp-mediated stringent response is thus often regarded as an all-ornothing paradigm induced by stress. Over the past decades, several binding partners of (p)ppGpp have been uncovered displaying dissociation constants from below one micromolar to more than one millimolar and thus coincide with the accepted intracellular concentrations of (p)ppGpp under non-stringent (basal levels) and stringent conditions. This suggests that the ability of (p)ppGpp to modulate target proteins or processes would be better characterized as an unceasing continuum over a concentration range instead of being an abrupt switch of biochemical processes under specific conditions. We analyzed the reported binding affinities of (p)ppGpp targets and depicted a scheme for prioritization of modulation by (p)ppGpp. In this ranking, many enzymes of e.g., nucleotide metabolism are among the first targets to be affected by rising (p)ppGpp while more fundamental processes such as DNA replication are among the last. This preference should be part of (p)ppGpp's "magic" in the adaptation of microorganisms while still maintaining their potential for outgrowth once a stressful condition is overcome.

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Section: Crosstalk Between (P)ppgpp and C-di-ampmentioning

confidence: 99%

(p)ppGpp: Magic Modulators of Bacterial Physiology and Metabolism

2020

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“…Given the importance of glycine betaine and proline betaine for osmoregulation of saltwater organisms, we speculate that this riboswitch candidate might respond to changes in the concentration shifts of one of these two molecules, or other osmoprotectants. Alternatively, the signalling molecule c-di-AMP is frequently used to signal osmotic distress [60][61][62], and a common riboswitch class for this compound has been reported previously [63].…”

Section: The Prox (Src-29-1) Motifmentioning

confidence: 99%

Comprehensive discovery of novel structured noncoding RNAs in 26 bacterial genomes

et al. 2021

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Comparative sequence analysis methods are highly effective for uncovering novel classes of structured noncoding RNAs (ncRNAs) from bacterial genomic DNA sequence datasets. Previously, we developed a computational pipeline to more comprehensively identify structured ncRNA representatives from individual bacterial genomes. This search process exploits the fact that genomic regions serving as templates for the transcription of structured RNAs tend to be present in longer than average noncoding 'intergenic regions' (IGRs) that are enriched in G and C nucleotides compared to the remainder of the genome. In the present study, we apply this computational pipeline to identify structured ncRNA candidates from 26 diverse bacterial species. Numerous novel structured ncRNA motifs were discovered, including several riboswitch candidates, one whose ligand has been identified and others that have yet to be experimentally validated. Our findings support recent predictions that hundreds of novel riboswitch classes and other ncRNAs remain undiscovered among the limited number of bacterial species whose genomes have been completely sequenced.

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“…Secondary messengers are a mechanism used by bacterial pathogens, such as B. burgdorferi , to modulate gene expression and post-transcriptional regulation in response to environmental signals by altering the function of bound proteins (Yin et al 2020; Purificação et al 2020; McDonough and Rodriguez 2011; Savage et al 2015; Ye et al 2014; Rogers et al 2009). In B. burgdorferi , the second messenger cyclic di-adenosine monophosphate (c-di-AMP) is essential for in vitro growth and the production of mammalian virulence factors (Ye et al 2014; Savage et al 2015).…”

Section: Introductionmentioning

confidence: 99%

TheBorrelia burgdorferiadenylyl cyclase, CyaB, is important for virulence factor production and mammalian infection

Ante

Farris²,

Saputra³

et al. 2021

Preprint

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Borrelia burgdorferi, the causative agent of Lyme disease, traverses through vastly distinct environments between the tick vector and the multiple phases of the mammalian infection that requires genetic adaptation for the progression of pathogenesis. Borrelial gene expression is highly responsive to changes in specific environmental signals that initiate the RpoS regulon for mammalian adaptation, but the mechanism(s) for direct detection of environmental cues has yet to be identified. Secondary messenger cyclic adenosine monophosphate (cAMP) produced by adenylate cyclase is responsive to environmental signals, such as carbon source and pH, in many bacterial pathogens to promote virulence by altering gene regulation. B. burgdorferi encodes a single non-toxin class IV adenylate cyclase (bb0723, cyaB). This study investigates cyaB expression along with its influence on borrelial virulence regulation and mammalian infectivity. Expression of cyaB was specifically induced with co-incubation of mammalian host cells that was not observed with cultivated tick cells suggesting that cyaB expression is influenced by cellular factor(s) unique to mammalian cell lines. The 3' end of cyaB also encodes a small RNA, SR0623, in the same orientation that overlaps with bb0722. The differential processing of cyaB and SR0623 transcripts may alter the ability to influence function in the form of virulence determinant regulation and infectivity. Two independent cyaB deletion B31 strains were generated in 5A4-NP1 and ML23 backgrounds and complemented with the cyaB ORF alone that truncates SR0623, cyaB with intact SR0623, or cyaB with a mutagenized full length SR0623 to evaluate the influence on transcriptional and post-transcriptional regulation of borrelial virulence factors and infectivity. In the absence of cyaB, expression and production of ospC was significantly reduced, while the protein levels for BosR and DbpA were substantially lower than parental strains. Infectivity studies with both independent cyaB mutants demonstrated an attenuated phenotype with reduced colonization of tissues during early disseminated infection. This work suggests that B. burgdorferi utilizes cyaB and potentially cAMP as a regulatory pathway to modulate borrelial gene expression and protein production to promote borrelial virulence and dissemination in the mammalian host.

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A decade of research on the second messenger c-di-AMP

Cited by 83 publications

References 138 publications

(p)ppGpp: Magic Modulators of Bacterial Physiology and Metabolism

(p)ppGpp: Magic Modulators of Bacterial Physiology and Metabolism

Comprehensive discovery of novel structured noncoding RNAs in 26 bacterial genomes

TheBorrelia burgdorferiadenylyl cyclase, CyaB, is important for virulence factor production and mammalian infection

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