Abstract
Cyclic di-GMP, an important prokaryote second messenger is used by the eukaryote Dictyostelium discoideum as a secreted signal to trigger stalk formation in fruiting bodies. Cyclic di-GMP is synthesized by a prokaryote-type diguanylate cyclase DgcA, but its mode of action was unknown. Transcriptional profiling yielded several target genes for cyclic di-GMP, which were tested for cyclic di-GMP induced expression in mutants with similar phenotypes as dgca-. A mutant with reduced PKA activity showed defective cyclic di-GMP induced stalk gene expression. Cyclic di-GMP increased cAMP levels in wild-type cells, but not in a mutant that lacked adenylate cyclase A (ACA) activity in slugs. This mutant also did not show cyclic di-GMP induced stalk gene expression. The stalk-less dgca- mutant regained its stalk by expression of a light-activated adenylate cyclase from the ACA promoter and exposure to light, indicating that cAMP is the intermediate for cyclic di-GMP in normal development. ACA is expressed at the tip of emerging fruiting bodies, where it produces the cAMP pulses that organize morphogenetic movement. The tip is also the site where stalk differentiation initiates. Our finding that cyclic di-GMP acts on tip-expressed ACA explains why the Dictyostelium stalk is always formed at the morphogenetic organizer.
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Keywords
- Dictyostelium discoideum
- Cyclic di-GMP
- Fruiting bodies
- Stalk formation
- Protein kinase A
- Adenylate cyclase A
- Organizer
1 Introduction
From an early role in activating cellulose synthesis, cyclic di-GMP is now recognized as the most ubiquitous second messenger in prokaryotes [1, 2]. The biological roles of cyclic di-GMP expanded to regulation of biofilm formation, cell motility, bacterial virulence, cell polarity, gene expression, the cell cycle and more, and the range of proteins involved in synthesis, degradation, and detection of cyclic di-GMP increased accordingly. Synthesis occurs by the diguanylate cyclase catalytic domain with conserved GGDEF motif. This domain is often combined with a range of other protein functional domains. Common combinations are with EAL or HD-GYP phosphodiesterase domains that hydrolyze cyclic di-GMP, or with the REC (receiver) endpoint of histidine–aspartate phosphorelay systems. Also small molecule or light-sensing PAS and GAF domains are often found to be associated with GGDEF domains and to regulate its cyclase activity [1]. Intracellular targets for cyclic di-GMP are manifold and include the PilZ domain, the allosteric cyclic di-GMP binding I-sites of defunct GGDEF domains, the substrate binding site of defunct EAL domains as well as many cyclic di-GMP binding sites intrinsic to transcription factors and cyclic di-GMP regulated enzymes [2, 3]. Cyclic di-GMP also binds to riboswitches in the noncoding regions of some mRNAs that control transcript stability and translation. The related molecule cyclic di-AMP was identified later, with its own di-adenylcyclase, phosphodiesterase, and cyclic di-AMP binding proteins, and, like cyclic di-GMP, controls a wide range of cellular functions [4]. The hybrid cGMP-AMP dinucleotide is synthesized by the DncV dinucleotide cyclase and has up to now more limited roles in Vibrio cholerae virulence [5] and riboswitch-mediated gene regulation in Deltaproteobacteria [6].
Cyclic dinucleotide signaling is not (entirely) confined to the prokaryote domain. The human innate immune system senses invasion of foreign DNA using a DNA-activated cGAMP synthase (cGAS), that links GMP and AMP by a 2′,-3′ linkages instead of the 3′-3′ linkage used by prokaryote dinucleotidyl cyclases. The resulting 2′3′-cGAMP binds to the STimulator of INterferon Genes (STING), causing it to recruit the protein kinase TBK1 and transcription factor IRF3, which upon phosphorylation by TBK1, translocates to the nucleus to induce expression of interferon genes [7]. Thus far unique among eukaryotes, the dictyostelid social amoebas contain a functional homolog of the bacterial diguanylate cyclases with the canonical GGDEF cyclase domain [8].
Dictyostelia are members of the Amoebozoa that display conditional multicellularity. In their unicellular stage they feed on bacteria in forest soils. Upon food depletion, the amoebas chemotactically collect into aggregates, which, after a migrating “slug” stage transform into fruiting bodies, consisting of a ball of spores, supported by a column of vacuolated stalk cells (Fig. 32.1). Deletion of the single diguanylate cyclase gene of Dictyostelium discoideum rendered cells incapable of differentiating into stalk cells, thereby preventing fruiting body formation. This chapter summarizes data on the function of cyclic di-GMP in D. discoideum, the identification of cyclic di-GMP regulated genes and the elucidation of the cyclic di-GMP signaling pathway.
2 Secreted Cyclic di-GMP Triggers Formation of the Fruiting Body Stalk
Comparative sequence analysis across the Dictyostelium phylogeny highlighted conserved orthologous proteins with high similarity to prokaryote diguanylate cyclases. Disruption of the diguanylate cyclase-like gene dgcA in the model D. discoideum generated cells that developed normally into migrating slugs, but then failed to form fruiting bodies [8]. Fruiting body formation was restored by mixing dgca- cells with 10% wild-type cells, indicating that the dgca- mutant lacked a secreted molecule that was produced by wild-type cells. The dgca- slugs also formed fruiting bodies when submerged in 1 mM cyclic di-GMP, indicating that the missing signal was cyclic di-GMP. Purified DgcA was confirmed by mass spectrometry to be able to synthesize cyclic di-GMP from GTP, validating that Dictyostelium DgcA is a diguanylate cyclase.
DgcA is first expressed after aggregates have formed and expression is highly enriched in the anterior prestalk cells of slugs (Fig. 32.3) and later the stalk of fruiting bodies. The dgca- mutant normally expressed prestalk and prespore genes in slugs, but did not express stalk or spore genes that are normally upregulated during fruiting body formation. Stalk genes could be induced by cyclic di-GMP in dgca- cells in suspension, and cyclic di-GMP also induced the vacuolated stalk phenotype in V12M2, a strain that readily differentiates into mature stalk cells in vitro, when incubated with DIF-1, a stalk-inducing factor that was identified earlier [9]. However, unlike the PKA activator 8Br-cAMP, cyclic di-GMP was not able to induce spore differentiation in vitro.
Combined, these data indicated that D. discoideum diguanylate cyclase synthesized cyclic di-GMP in the prestalk region. cyclic di-GMP was subsequently secreted to induce formation of the stalk, which initiates fruiting body formation. The lack of spore formation in the dgca- mutant is likely a secondary defect, since spores are only formed after the prespore mass has been carried aloft by the stalk [8].
3 Interactions Between Cyclic di-GMP and DIF-1
As mentioned above, cyclic di-GMP is not the only signal capable of inducing stalk cell differentiation in Dictyostelium. DIF-1 was purified from developing cells in the 1980s and identified as a chlorinated hexanone [9]. While DIF-1 is very effective in inducing stalk cell differentiation and expression of the (pre)stalk genes ecmA and ecmB in vitro, its role in normal development is restricted. Knockouts of individual genes in its biosynthetic pathway, encoding the polyketide synthase stlB, the DIF chlorinase chlA, and the desmethyltransferase dmtA yield mutants that form elongated fragile slugs and fruiting bodies with thin, but otherwise normal stalks, that lack the basal disc and lower cup [10,11,12]. The basal disc is a structure that anchors the stalk to the substratum and, like the stalk, consists of vacuolated cells with cellulose walls. The lower cup anchors the spore mass to the stalk and consists of amoeboid cells (see Fig. 32.1). Both basal disc and lower cup cells differentiate from a subpopulation of so-called prestalk B cells that are formed by dedifferentiation of prespore cells at the slug posterior. Due to lack of the lower cup, the spore heads of stlb-, chla- and dmta- do no fully ascend the stalk.
While these data suggest that DIF-1 and cyclic di-GMP regulate different subsets of stalk-like cells, in vitro studies indicate that the interactions between cyclic di-GMP and DIF-1 are more complex [13]. In the ura- strain DH1, both DIF-1 and cyclic di-GMP induce vacuolated cells in vitro and strongly promote each other’s effects. Mutants in talin, dhkM, and iplA that do not respond to DIF-1, still respond to cyclic di-GMP, indicating that DIF-1 and cyclic di-GMP use separate signal transduction pathways. However, in the talin, dhkM, and iplA null mutants, DIF-1 still promotes the effects of cyclic di-GMP. This suggests that the pathway used by DIF-1 in synergy with cyclic di-GMP is distinct from the pathway used by DIF-1 alone. In the DIF-less stlb- mutant, cyclic di-GMP could not induce vacuolization on its own, suggesting that DIF-1 is essential for cyclic di-GMP induced vacuolization in vitro [13].
Further studies measuring the effects of increasing cyclic di-GMP concentrations on stalk gene expression showed that the stlb- mutants required approximately tenfold higher concentrations of cyclic di-GMP than wild-type cells to achieve the same level of gene expression. This suggests that DIF-1 contributes to rendering cells competent to respond to cyclic di-GMP by, e.g., inducing expression of an as yet unknown cyclic di-GMP receptor [14].
4 Identification of Cyclic di-GMP Target Genes and Elucidation of Its Mode of Action
Transcriptomic profiling of dgca- and wild-type structures at the stage of wild-type fruiting body formation yielded ~150 genes that were over tenfold downregulated in the dgca- mutants and could therefore be potential target genes for cyclic di-GMP. About half of these genes where spore related, and many of the remaining genes were expressed in cup cells, with relatively few being specifically expressed in the stalk [14]. The latter set was enriched in extracellular matrix- and cellulose-binding proteins and contained known stalk genes such as ecmB, but no other DIF-1-regulated stalk genes, such as ecmA, staA(pDd26), and staB [15, 16]. The cup genes were, like the stalk-specific genes, upregulated by cyclic di-GMP in vitro, but required at least 30-fold higher cyclic di-GMP concentrations than stalk genes for optimal expression.
A screen for cyclic di-GMP target proteins was initiated by analyzing cyclic di-GMP induced expression of the newly identified stalk genes abcG18 and staC in mutants defective in fruiting body formation. One such mutant overexpresses a dominant negative inhibitor of cAMP-dependent protein kinase (PKA) from a prestalk-specific promoter [17]. These PkaRm cells showed strongly reduced cyclic di-GMP induction of abcG18 and staC transcription, suggesting PKA mediates the effects of cyclic di-GMP [14]. This was substantiated by observations that the PKA activator 8Br-cAMP could replace cyclic di-GMP in abcG18 and staC gene induction experiments, and that cyclic di-GMP induced a persistent cAMP increase in slug cells (Fig. 32.2a), but not in pre-aggregative cells.
In D.discoideum, cAMP is synthesized by three adenylate cyclases ACA, ACG, and ACR, and degraded intracellularly by the cAMP phosphodiesterase RegA. Null mutants in acg, acr, and regA still showed the cyclic di-GMP induced increase in cAMP levels. Aca- mutants cannot aggregate and involvement of ACA was therefore tested in an aca- mutant transformed with a temperature-sensitive variant of ACA. This mutant formed slugs at the permissive temperature of 22 °C and then showed cyclic di-GMP induced cAMP synthesis at 22 °C, but not at the restrictive temperature of 28 °C (Fig. 32.2b). The aca-/tsACA mutant also lost cyclic di-GMP induced stalk gene expression (Fig. 32.2c), indicating that at least in vitro cyclic di-GMP induces stalk gene expression by successively activating ACA and PKA.
In slugs, ACA is expressed at the anterior tip of the structure, which is also the site where stalk formation initiates (Figs. 32.1 and 32.3). To demonstrate that localized cAMP production and PKA activation at the tip are sufficient to induce stalk formation, the light-inducible cyanobacterial adenylate cyclase mPAC [18, 19] was fused to the tip-specific ACA promoter and transformed into dgca- cells. When transformants were kept in the dark, they remained in the slug stage, but when exposed to light they formed fruiting bodies with normal stalks [14]. These experiments showed that local activation of cAMP synthesis at the slug tip (by cyclic di-GMP) activates stalk formation during normal development.
5 Cyclic di-GMP Acting on ACA Links Morphogenetic Movement with Stalk Formation
While the role of cyclic di-GMP in D. discoideum is thus far restricted to stalk differentiation, ACA has an additional well-documented role in producing the cAMP pulses that coordinate aggregation [20] and upregulate the expression of aggregation-specific genes [21], and in coordinating post-aggregative morphogenesis by initiating cAMP waves from the slug and fruiting body tip [22]. In this role, ACA activity is under both positive and negative feedback by secreted cAMP acting on G-protein coupled cAMP receptors (cARs). A complex mechanism that involves activation of ACA activity, desensitization of cARs, and hydrolysis of both intracellular and extracellular cAMP, enables starving cells to initiate cAMP oscillations and to relay the pulses as propagating waves [23]. Cells respond with chemotaxis toward the highest cAMP concentration and stream together in aggregates. While ACA is first expressed in all cells, after aggregation it is predominantly expressed at the tip [24], which continues to emit cAMP pulses and to attract the cells behind it [25]. In this manner the tip functions as a typical embryonic organizer [26], i.e., as a small group of cells that emit signals that control the behavior of a much larger group [27].
The tip is also the site where stalk formation initiates and until recently it was unclear how these two roles were connected. The observation that cyclic di-GMP acts on ACA to induce stalk formation suggests a model that links stalk formation with organizer function (Fig. 32.3). DgcA is widely expressed throughout the slug prestalk region (Fig. 32.3a), under at least partial control of the transcription factor gtaG, that is also exclusively expressed in prestalk cells [28]. However, cyclic di-GMP can only exert its function in the extreme tip where ACA is expressed (Fig. 32.3b). The persistently elevated cAMP levels at the tip then activate PKA to induce stalk gene expression (Fig. 32.3c). The interaction between cyclic di-GMP and ACA explains why the stalk is always formed from the organizing tip.
6 Open Questions
6.1 Unknown Signal Transduction Components
There are still several missing components in the pathway linking cyclic di-GMP to stalk gene expression. Firstly, it is unknown how cyclic di-GMP activates ACA. Preliminary data using a temperature-sensitive mutant in the single G-protein β-subunit of D. discoideum show that a heterotrimeric G-protein is not involved (Schilde and Schaap, unpublished results). Also knockout of several G-protein coupled receptors (GPCRs) that are expressed after aggregation in prestalk cells did not yield a cyclic di-GMP insensitive mutant (Chen and Schaap, unpublished result). The activation of ACA by cyclic di-GMP is also not direct, since it occurs only in slug cells and not in aggregating cells where ACA is most highly expressed. It may, therefore, involve a transmembrane receptor that is not a GPCR, or a transporter that carries cyclic di-GMP into the cell.
The target for PKA is also not known. Cells defective in the transcription factors cudA and statA show, like dgca-, a cell autonomous defect in fruiting body formation [29, 30]. However, statA- cells showed normal cyclic di-GMP induced stalk gene expression, and it was reduced, but not absent in cudA- cells (Chen and Schaap, unpublished results).
6.2 Cell-Type Specificity
PKA activation not only induces terminal stalk cell differentiation, but also spore maturation and expression of cup genes [14, 17, 31]. This means that cyclic di-GMP only selectively induces stalk gene expression, because both dgcA and ACA are selectively expressed in prestalk cells. The stalk fate of these cells must already have been determined earlier. The primary candidate for prestalk specification is DIF-1, which is produced by prespore cells and induces expression of several prestalk genes in vitro [32]. However, because loss of DIF-1 does not prevent stalk formation [10,11,12], an additional, as yet unknown, factor has to be present to direct cells to a stalk fate.
6.3 Evolutionary Conservation
D. discoideum is a member of one of the four major groups of Dictyostelia, which themselves are members of Amoebozoa. Among Amoebozoa, there are other taxa, such as the myxogastrids and the protostelids that make stalked fruiting structures. However, while diguanylate cyclase genes were conserved in all four major taxon groups of Dictyostelia, none were found in the proteomes of Protostelium fungivorum [33], the myxogastrid Physarum polycephalum [34] or other Amoebozoa, such as Acanthamoeba castellani [35] and Entamoeba histolytica [36]. Phylogenetic analysis indicated that dgcA most likely entered Dictyostelid genomes by lateral gene transfer from bacteria [37], probably aided by the fact that Dictyostelia feed on bacteria. Three other developmentally essential genes, chlA, iptA, and dokA uniquely entered Dictyostelia by LGT [37]. Like, dgcA, two of those, chlA [11] and iptA [38], synthesize secreted signals that regulate cell-type specialization. This suggests that these foreign genes became fixed during early (pre)dictyostelid multicellularity, because they met a need for intercellular communication to direct cell specialization.
No genes encoding the EAL or HD-GYP phosphodiesterases, or any of the prokaryote cyclic di-GMP binding proteins have been detected in Dictyostelium genomes (unpublished results), nor homologs of the mammalian dinucleotide cyclase cGAS or the cGAMP or cyclic di-GMP binding protein STING [39]. Apparently, with ACA and PKA as downstream cyclic di-GMP targets, Dictyostelia have evolved their own unique cyclic di-GMP signaling pathway.
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Acknowledgment
Research reported in this study was funded by Leverhulme Trust grants RPG-2012-746 and RPG-2016-220, Wellcome Trust grant 100293/Z/12/Z and European Research Council grant 742288.
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Chen, Zh., Schilde, C., Schaap, P. (2020). Cyclic di-GMP Activates Adenylate Cyclase A and Protein Kinase A to Induce Stalk Formation in Dictyostelium . In: Chou, SH., Guiliani, N., Lee, V., Römling, U. (eds) Microbial Cyclic Di-Nucleotide Signaling. Springer, Cham. https://doi.org/10.1007/978-3-030-33308-9_32
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