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Published in final edited form as: Curr Opin Microbiol. 2023 Oct 21;76:102398. doi: 10.1016/j.mib.2023.102398

Crosstalk between (p)ppGpp and other nucleotide second messengers

Danny K Fung 1,#, Aude E Trinquier 1,#, Jue D Wang 1,*
PMCID: PMC10842992  NIHMSID: NIHMS1936047  PMID: 37866203

Abstract

In response to environmental cues, bacteria produce intracellular nucleotide messengers to regulate a wide variety of cellular processes and physiology. Studies on individual nucleotide messengers, such as (p)ppGpp or cyclic (di)nucleotides, have established their respective regulatory themes. As research on nucleotide signaling networks expands, recent studies have begun to uncover various crosstalk mechanisms between (p)ppGpp and other nucleotide messengers, including signal conversion, allosteric regulation and target competition. The multiple layers of crosstalk implicate that (p)ppGpp is intricately linked to different nucleotide signaling pathways. From a physiological perspective, (p)ppGpp crosstalk enables fine tuning and feedback regulation with other nucleotide messengers to achieve optimal adaptation.

Keywords: ppGpp, ppApp, c-di-GMP, pGpp, pppGpp, c-di-AMP, AppppA, alarmones, second, messengers, crosstalk, stringent response

1. Introduction:

The remarkable ability of bacteria to colonize diverse habitats relies on their efficient response to environmental changes. To achieve this, bacteria have evolved a repertoire of stress sensing and response systems to regulate their cellular processes. A widely conserved mechanism is through utilization of nucleotide second messengers as stress responsive regulators. Notable examples include the classic cAMP [1], the stringent response alarmone (p)ppGpp (guanosine tetra- or penta-phosphates) [2] and putative oxidative stress alarmone AppppA [3], as well as cyclic dinucleotides c-di-AMP [4] and c-di-GMP [5]. These nucleotide second messengers are widely present in the bacterial domain of life and their turnover is controlled by specific synthetases and hydrolases. For example, (p)ppGpp is synthesized and hydrolyzed by multidomain and single-domain RSH (RelA-SpoT Homolog) enzymes [6-8]. On the other hand, c-di-GMP is produced by diguanylate cyclase enzymes [9] and degraded by phosphodiesterases [10]. Similar to c-di-GMP, c-di-AMP synthesis and hydrolysis is mediated through deadenylate cyclases and dedicated phosphodiesterases [11,12]. In addition to the established (p)ppGpp and cyclic dinucleotides, nucleotides such as cGAMP [13-16], pGpp [17] and (p)ppApp [18-21] have also emerged as new members of the nucleotide second messengers family. Recent explosion of anti-phage research has also uncovered many new cyclic nucleotides [22] such as cyclic mononucleotides cNMP produced by pyrimidine cyclases (Pycsar) [23], as well as cyclic dinucleotides produced by cyclic dinucleotide based anti-phage signaling systems (CBASS) [13,24-26] that are induced upon phage infection.

In general, regulation by nucleotide second messengers is mediated through direct interaction with target proteins which are often enzymes or transcription factors or riboswitches [27-29]. Despite the common regulatory principles, different nucleotide second messengers appear to have evolved specific regulatory roles [30]. For example, (p)ppGpp accumulates in response to stresses such as amino acid starvation [7,31], and reprograms transcription [32,33], down-regulates purine nucleotide biosynthesis [34] and curtails macromolecular biosynthesis [35,36]; c-di-AMP is inducible by high potassium and is strongly involved in cell wall homeostasis and osmoregulation [27,37]; while c-di-GMP responds to a variety of environmental cues [38,39] as well as surface sensing [40], and is best known for controlling biofilm formation and lifestyle transitions [28,41]. The diverse regulatory roles by various nucleotide messengers facilitate integrated regulation of cellular processes in biofilms [42] as well as throughout bacterial growth cycle [43]. Apart from “division of labor” by different nucleotide messengers, new studies have begun to reveal crosstalk between these signaling systems, with many notable examples involving (p)ppGpp. In terms of bacterial physiology, the central role of (p)ppGpp in stress response and cellular metabolism makes it an ideal candidate for crosstalk with other nucleotide messengers. In this brief review, we summarize mechanisms underlying (p)ppGpp crosstalk with other nucleotide second messengers and discuss their biological importance.

2. Mechanisms of crosstalk between (p)ppGpp and other nucleotide second messengers:

Overall, crosstalk between (p)ppGpp and other nucleotide second messengers occurs at the level of messenger metabolism as well as downstream target regulation. Here we focus on the mechanisms (Figure 1) underlying these different modes of crosstalk. In section 3, we will explain the current progress in understanding the physiological relevance of crosstalk.

Figure 1. Mechanisms of (p)ppGpp-second messengers crosstalk.

Figure 1.

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(A) Signal conversion. In B. subtilis, conversion of (p)ppGpp to pGpp by NahA changes its target regulation spectrum in which pGpp only regulates a subset of (p)ppGpp targets [17]. (B) Target competition. In C. crescentus, (p)ppGpp and c-di-GMP competes for SmbA leading to different regulation effects by either (p)ppGpp or c-di-GMP [60]. In B. subtilis, (p)ppGpp and AppppA share an overlapping binding site on IMPDH in which either interaction inhibits its activity. (C) Allosteric regulation. In B. subtilis and L. monocytogenes, c-di-AMP interacts with DarB (or CbpB in L. monocytogenes) [70,72,74] to disrupt its stimulation of (p)ppGpp synthesis by the bifunctional (p)ppGpp synthetase/hydrolase Rel. On the other hand, (p)ppGpp inhibits c-di-AMP degradation by inhibiting the c-di-AMP phosphodiesterase GdpP [69]. (D) Enzyme promiscuity. Nucleotide metabolizing enzymes such as small alarmone hydrolases can accommodate many nucleotide substrates including (p)ppGpp, pGpp, (p)ppApp and NADPH with different catalytic efficiency. In X. campestris pv. campestris, this results in competition and differential regulation according to relative levels between (p)ppGpp and other nucleotide second messengers [81].

2.1. Crosstalk through nucleotide messenger interconversion

While ppGpp and pppGpp, often referred together as (p)ppGpp, are the best studied alarmones, other chemically similar derivatives of (p)ppGpp are also present in bacteria. For example, pGpp (guanosine-5′-monophosphate-3′-diphosphate) is produced by SasB (RelQ) in Enterococcus faecalis [44], or by Rel in Clostridium difficile [45]. In addition, Nudix (Nucleoside Diphosphate linked to any moiety “X”) hydrolases MutT and NudG from Escherichia coli and Ndx8 from Thermus thermophilus have been found to hydrolyze (p)ppGpp into ppGp (guanosine-5′-diphosphate-3′-monophosphate), pGpp (guanosine-5′-monophosphate-3′-diphosphate) or pGp (guanosine 5′-monophosphate 3′-monophosphate) [46,47]. Whether these (p)ppGpp derivatives play regulatory roles remained unclear until recently when pGpp was found to be produced from (p)ppGpp hydrolysis by the Nudix hydrolase NahA in Bacillus subtilis [17]. In contrast to (p)ppGpp, pGpp regulates only a subset of (p)ppGpp protein targets [17] as well as the B. subtilis small alarmone synthetase SasB [48], thus promoting crosstalk between related nucleotide messengers (Figure 1A). Given the widespread occurrence of Nudix hydrolases in the bacteria kingdom [49], other (p)ppGpp derivatives could also be involved in crosstalk. Apart from (p)ppGpp derivatives, pGpG (5′-phosphoguanylyl-guanosine), the phosphodiesterase (PDE-A) product of c-di-GMP, has been reported to inhibit PDE-A activity [50]. Similarly, the c-di-AMP product pApA (5′-phosphadenylyl-adenosine) was also found to inhibit the c-di-AMP phosphodiesterase GdpP [51]. Intriguingly, ORFeome screen for pGpG binding proteins also revealed targets outside of PDE-A [50], suggesting that crosstalk mediated by signal conversion may also apply to cyclic dinucleotides.

2.2. Crosstalk through interaction with the same target

Application of systematic ligand-protein interaction screens such as differential radial capillary action of ligand assay DRaCALA [52,53] or affinity pull-down using capture compounds [54,55] have greatly facilitated the identification of proteins that interact with (p)ppGpp or other nucleotide second messengers [17,47,53,55-59]. Apart from protein targets which specifically bind to one nucleotide messenger, some proteins can interact with more than one messenger leading to regulatory crosstalk (Figure 1B). This can occur competitively between two nucleotides for the same binding pocket, or separately at different sites of the protein. The small-molecule-binding protein SmbA from Caulobacter crescentus is an effector protein found to serve as a crosstalk platform for competitive (p)ppGpp or c-di-GMP binding [60]. Interaction with c-di-GMP switches SmbA from a relaxed conformation to an inactive, more compact structure. On the other hand, (p)ppGpp acts as an anti-inhibitor of c-di-GMP by competing for the same binding pocket [61]. This regulation enables SmbA to adopt distinct conformations when bound to either c-di-GMP or (p)ppGpp, leading to different regulatory effects.

Common targets of (p)ppGpp and its adenosine analog (p)ppApp have also been recently reported. In E. coli, the amidophosphoribosyl transferase PurF catalyzes the first step of de novo purine biosynthesis and was found to be a direct target of (p)ppGpp and (p)ppApp [18]. Both (p)ppGpp and (p)ppApp can individually compete with the substrate PRPP for the PurF active site in a similar manner, leading to inhibition by either alarmone [18,55]. In B. subtilis, where PurF is not known to be regulated by alarmones, the purine operon transcription regulator PurR is a target of (p)ppGpp [62] and (p)ppApp (Wang Lab, manuscript in prep). Another example of shared (p)ppGpp and (p)ppApp target is the E. coli RNA polymerase (RNAP). In E. coli, (p)ppGpp interacts with the RNAP at two unique sites to regulate transcription [63,64]. Apart from (p)ppGpp, in vitro results indicate that (p)ppApp can bind to a unique site on RNAP proximate to the catalytic center and distinct from the (p)ppGpp-specific sites 1 and 2 [21]. Although (p)ppGpp and (p)ppApp do not compete for the same site on RNAP, data suggest that binding of one or the other could prompt conformational changes on RNAP that alter binding of the other. Interestingly, contrary to the effect of (p)ppGpp, (p)ppApp was found to activate transcription of the ribosomal rrnB P1 promoter, and DksA hinders this effect [21]. Whether the interplay with the two alarmones and DksA on RNAP regulation occurs in vivo and its physiological significance requires further investigation.

AppppA (diadenosine tetraphosphate), a putative alarmone produced from ATP by aminoacyl-tRNA synthetases [3], was recently found to regulate the (p)ppGpp target inosine-5′-monophosphate dehydrogenase (IMPDH). IMPDH is a key enzyme at the branchpoint of adenosine and guanosine nucleotide biosynthesis. In Proteobacteria, IMPDH oligomerization state and activity are regulated by the balance between ATP and GTP, as those nucleotides compete for the same allosteric binding site at the CBS (cystathionine beta synthase) domain [65] within the CBS tandem also known as the Bateman regulatory domain [66]. However, this is rather an exception as all other phyla across bacteria encode an IMPDH whose CBS regulatory domain has a high affinity pocket where (p)ppGpp acts as a potent allosteric inhibitor competing with ATP for binding [66]. Interestingly, AppppA was also found to bind to B. subtilis IMPDH at the Bateman domain that partially overlaps the (p)ppGpp binding site [67], suggesting shared regulation by both alarmones.

2.3. Crosstalk through allosteric regulation of synthetases or hydrolases

Crosstalk between (p)ppGpp and other nucleotide second messengers can also occur at the level of synthetase and hydrolase regulation. A notable example is the cross-regulation between (p)ppGpp and c-di-AMP (Figure 1C). Interestingly, c-di-AMP and (p)ppGpp regulate the metabolism of each other. On one hand, c-di-AMP hydrolysis was found to be under tight (p)ppGpp control with ppGpp inhibiting (in a dose-dependent manner) the c-di-AMP hydrolysis to pApA by the c-di-AMP phosphodiesterase GdpP in B. subtilis [68] and Staphylococcus aureus [69]. The other S. aureus c-di-AMP phosphodiesterase Pde2 who preferentially converts pApA to AMP, was also found to be inhibited by ppGpp. This inhibition leads to increased pApA levels which in turn inhibit c-di-AMP hydrolysis by GdpP [51].

On the other hand, c-di-AMP inhibits the synthesis of (p)ppGpp via a c-di-AMP binding protein CbpB in Listeria monocytogenes [70] or Streptococcus agalactiae [71], or its ortholog DarB in B. subtilis [72]. In its apo form, CbpB/DarB binds to the (p)ppGpp synthetase Rel and engages it in a (p)ppGpp synthesis-promoting conformation, allowing Rel to produce (p)ppGpp in the absence of starved ribosome [70,72,73]. c-di-AMP binding to CbpB/DarB prevents the protein from binding and activating Rel [74]. As a result, c-di-AMP enables modulation of (p)ppGpp synthesis by Rel.

2.4. Crosstalk through enzyme promiscuity

Enzymes that are active in metabolism of multiple nucleotide messengers can also facilitate crosstalk. A recent example was observed for single domain RSH homologs known as small alarmone hydrolases (SAHs) that are widely present in bacteria as well as in metazoan as Mesh1 [75-77]. SAHs are phylogenetically diverse alarmone hydrolases [6], with subfamilies which specifically hydrolyze (p)ppApp [61] and many that are active against multiple substrates including (p)ppGpp, pGpp, (p)ppApp and the metabolic cofactor NADPH [20,76,78-81]. In metazoa, Mesh1 was originally found to be a (p)ppGpp hydrolase [75], but later found to have NADPH phosphatase activity [76]. In bacteria, a recently characterized example is the SAH in the gram-negative plant pathogen Xanthomonas campestris pv. campestris (Xcc) which displays a hierarchy of hydrolysis activity from pppApp to (pp)pGpp to NADPH [81]. The substrate preference of XccSAH is associated with the enzyme’s differential affinity towards the identity of nucleobase (A over G), the number of 5'-phosphates (e.g. pppGpp over pGpp), as well as 3' over 2' phosphates between alarmones and NADPH [81]. The varying activities towards different substrates provide a means to competitive cross-regulation between (p)ppApp, (p)ppGpp, pGpp and NADPH depending on their relative levels (Figure 1D).

3. Biological importance of (p)ppGpp-second messengers crosstalk:

Essentially, crosstalk between (p)ppGpp and other second messengers enables additional layers of regulation contributing to fine tuning of responses, regulation robustness, homeostatic regulation, or generation of heterogeneity. Multiple recent studies have suggested that these crosstalk regulations promote adaptation to different environments.

3.1. Diversification of regulatory responses

Fine-tuning

Crosstalk between (p)ppGpp and other nucleotide signals provides a molecular strategy to generate different regulatory responses from a limited pool of regulatory targets (Figure 2A). In Bacillus species, NahA-mediated conversion of (p)ppGpp to pGpp was reported to generate a mix of (p)ppGpp and pGpp with different target regulation spectra [17]. This enables crosstalk between chemically similar alarmones to fine tune the regulatory outcome. Specifically, the shift from (p)ppGpp to pGpp promotes relaxation of translational inhibition while maintaining purine synthesis shutdown, allowing cells to gradually transition from stringent response to growth recovery [17].

Figure 2. Biological roles of (p)ppGpp-second messengers crosstalk.

Figure 2.

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(A) Fine tuning of bacterial physiology through crosstalk. The conversion of (p)ppGpp pools to pGpp orchestrates a physiological switch from stringent response towards growth recovery in Bacillus species [17]. In C. crescentus, (p)ppGpp and c-di-GMP control cell-cycle re-entry of swarmer cells by competing for the same protein target (SmbA) and by inversely controlling glucose oxidation [60]. (B) Crosstalk ensures robust regulation of key cellular pathways. During heat shock, (p)ppGpp and AppppA both accumulate and likely regulate their shared target (IMPDH) to promote heat survival [67]. (C) Feedback regulation coordinates second messenger signaling. (p)ppGpp and c-di-AMP metabolism are coordinated through the c-di-AMP binding and Rel activating protein DarB and via the (p)ppGpp-mediated inhibition of c-di-AMP phosphodiesterase [72]. (D) Crosstalk modulates single-cell heterogeneity. Allosteric self-activation of (p)ppGpp synthetase SasB by (p)ppGpp have been reported to cause heterogenous (p)ppGpp levels in single cells [90]. In addition, the allosteric stimulation of SasB can be inhibited by pGpp [48], reducing heterogeneity in translation activity.

Regulatory switch

Interestingly, crosstalk between (p)ppGpp and chemically dissimilar nucleotide second messengers can also constitute a regulation switch utilizing the same target. For example, C. crescentus SmbA interaction with either (p)ppGpp or c-di-GMP promotes either glucose consumption or its inhibition, resulting in growth control and redox balance modulation [60].

Synergism

Synergism could arise from regulation of complex formation between protein binding targets of (p)ppGpp and those of other nucleotide second messengers. Recently, the cAMP receptor protein (CRP) and a c-di-GMP binding target in Shewanella putrefaciens were found to interact together, when bound to their respective ligands, to synergistically promote biofilm maintenance [82]. In the case of (p)ppGpp crosstalk, synergistic effects could also arise between the (p)ppGpp-dependent allosteric regulation of Rel [83] and its interaction with apo DarB/CbpB [74], although this possibility awaits experimental exploration.

3.2. Robustness of regulatory outcomes

Crosstalk between (p)ppGpp and other signaling systems also provides an additional strategy to regulate key cellular processes to promote robustness of the regulatory outcomes. An example can be drawn from the purine biosynthesis pathways which are under tight control by (p)ppGpp [84]. (p)ppGpp regulation occurs through direct (p)ppGpp binding and inhibition of enzymes in both de novo and salvage pathways [85], as well as transcriptionally with (p)ppGpp acting as an anti-inducer of the transcription factor PurR which regulates expression of many purine biosynthesis genes [62]. The newly discovered alarmone pGpp was shown to bind to the same GTP biosynthesis enzymes as (p)ppGpp [17], exerting a redundant control on purine biosynthesis.

More dissimilar nucleotide signals were also shown to exert additional regulations with (p)ppGpp, such as in the case of IMPDH regulation (Figure 2B). This key enzyme at the branchpoint of ATP and GTP biosynthesis pathway is a common inhibition target of (p)ppGpp and AppppA [66,67]. Intriguingly, both alarmones had been independently reported to accumulate in heat-stressed B. subtilis [67,86], and are found to be critical to adapt to high temperatures. The overlapping regulations suggest that co-accumulation of (p)ppGpp and AppppA under heat stress could likely enable maximal regulation of IMPDH to enhance survival.

3.3. Feedback regulation

Another important role of (p)ppGpp crosstalk resides in the feedback regulation with synthesis and hydrolysis of other nucleotide second messengers (Figure 2C). Early report of (p)ppGpp crosstalk in S. aureus reported the presence of a positive feedback loop between c-di-AMP and (p)ppGpp metabolism [69]. The study suggested that accumulating c-di-AMP during stationary phase causes an increase in (p)ppGpp, via a still unknown mechanism, and that rising (p)ppGpp would in turn inhibit the phosphodiesterase GdpP [68], leading to increased c-di-AMP levels. Interestingly, the (p)ppGpp-mediated inhibition of c-di-AMP hydrolysis was found to impact resistance to β-lactam antibiotics [87].

The interconnection between (p)ppGpp and c-di-AMP signaling pathways is also present in other species in the form of negative feedback loops (Figure 2C). A recent study [70] showed that the essentiality of c-di-AMP in L. monocytogenes [88] relies on its prevention of (p)ppGpp overproduction through the Rel-interacting protein CbpB. Furthermore, (p)ppGpp in turn inhibits c-di-AMP synthesis, which forms a negative feedback loop contributing to homeostasis of both nucleotide second messengers. A similar feedback loop was described in B. subtilis, where low cellular potassium was found to reduce c-di-AMP levels causing the release of the CbpB ortholog DarB thereby activating (p)ppGpp synthesis by Rel [72-74]. In turn, inhibition of the c-di-AMP phosphodiesterase by (p)ppGpp is thought to promote transient induction of (p)ppGpp contributing to stress adaptation [72].

3.4. Modulation of single cell heterogeneity through crosstalk

Nucleotide second messengers have been implicated in the generation of phenotypic heterogeneity in isogenic bacterial populations (Figure 2D). For example, heterogeneity in (p)ppGpp levels has been shown to lead to generation of subpopulations with different translation activity [89] and antibiotic survival [90] in B. subtilis. While heterogeneity of nucleotide second messenger could be attributed to factors such as stochastic gene expression [91], recent study also suggested the involvement of crosstalk through allosteric regulation. In B. subtilis, allosteric stimulation of (p)ppGpp synthetase SasB by ppGpp contributes to heterogenous (p)ppGpp levels [90]. Similarly, recent report of allosteric stimulation of Rel by (p)ppGpp [83] also likely promote (p)ppGpp heterogeneity. In addition, it is also proposed that the allosteric stimulation of SasB is inhibited by pGpp, which in turn influence protein synthesis heterogeneity in B. subtilis population [48]. This suggests a role of second messenger crosstalk in cell-to-cell variability, at least at the level of second messenger synthesis regulation. Apart from (p)ppGpp, levels of other nucleotides such as c-di-GMP have also been reported to vary within isogenic B. subtilis [92] and C. crescentus populations [93,94]. Whether heterogeneity of these other nucleotide messengers also involve crosstalk requires future investigation.

4. Conclusions and future directions:

Recent studies have revealed multiple mechanisms of crosstalk between (p)ppGpp and other nucleotide second messengers. With respect to (p)ppGpp, its crosstalk with different second messengers would allow integration of central dogma control with processes regulated by other nucleotide messengers. In addition, since (p)ppGpp levels respond to nutritional and metabolic stresses, crosstalk with (p)ppGpp would also provide an additional checkpoint to regulate developmental decisions or major physiological changes. As more nucleotide second messenger targets are being discovered, more examples of (p)ppGpp crosstalk and its physiological importance are likely to be revealed.

The discovery of many novel cyclic nucleotides [22,24,25] from the expanding field of anti-phage research also give rise to the possibility that these phage-induced signals may crosstalk with intrinsic second messenger pathways. Since (p)ppGpp plays a key role on central dogma regulation and growth arrest, (p)ppGpp signaling could contribute to disruption of phage production or to shutdown host processes to enable coordinated protection against phage infection. Recently, CapRelSJ46, a RSH consisting of a fused toxin-antitoxin system, has been found to protect bacteria against phage infection [95] by blocking translation through pyrophosphorylation of tRNAs. Interestingly, multiple families of (p)ppGpp or (p)ppApp-producing small alarmone synthetases also belongs to the large family of toxin-antitoxin systems [20]. Although CapRelSJ46 doesn’t make (p)ppGpp, it is tempting to speculate that RSHs which produces (p)ppGpp or (p)ppApp may act in concert or crosstalk with phage-induced cyclic nucleotides for phage defense.

From a practical standpoint, as knowledge on (p)ppGpp-second messenger crosstalk accumulates, key interactions between (p)ppGpp and other nucleotide second messengers may be exploited to disrupt bacterial regulation. Compared to agents which disrupt the entire second messenger signaling pathway, crosstalk inhibitors would likely impose less selection pressure thus reducing the likelihood of resistance development.

Highlights:

  • Bacteria utilize nucleotide second messengers such as (p)ppGpp as stress regulators.

  • Crosstalk exists between nucleotide second messenger signaling pathways.

  • (p)ppGpp crosstalk with other second messenger pathways through signal conversion, target competition, and allosteric interaction.

  • (p)ppGpp crosstalk enables fine tuning and feedback regulation to optimize stress adaptation.

Acknowledgements:

Work in the authors’ laboratory discussed in this review was supported by an NIH public service grant R35GM127088 and HHMI Emergent Pathogen Initiative Consortium (to JDW). We apologize to colleagues whose work is not directly cited due to space limitations.

Footnotes

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Declaration of Competing Interest

The authors declare no conflict of interest

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