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Genetics, Vol. 171, 71-80, September 2005, Copyright © 2005
doi:10.1534/genetics.105.040584
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)-SfaD(ß)-GpgA(
) Is a Carbon Source Sensor Involved in Early cAMP-Dependent Germination in Aspergillus nidulans
* Unité Postulante Biologie et Pathogénicité Fongiques, INRA USC2019, Institut Pasteur, 75724 Paris Cedex 15, France and Department of Food Microbiology and Toxicology and Food Research Institute, Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin 53706
1 Corresponding author: Unité Postulante Biologie et Pathogénicité Fongiques, INRA USC2019, Département Dynamique et Structure des Génomes, Institut Pasteur, 25, rue du Docteur Roux, 75724 Paris Cedex 15, France.
E-mail: denfert{at}pasteur.fr
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ABSTRACT |
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-subunit GanB mediates a rapid and transient activation of cAMP synthesis in response to glucose during the early period of germination. Moreover, deletion of individual G-protein subunits resulted in defective trehalose mobilization and altered germination kinetics, indicating that GanB()-SfaD(ß)-GpgA(
) constitutes a functional heterotrimer and controls cAMP/PKA signaling in response to glucose as well as conidial germination. Further genetic analyses suggest that GanB plays a primary role in cAMP/PKA signaling, whereas the SfaD-GpgA (Gß) heterodimer is crucial for proper activation of GanB signaling sensitized by glucose. In addition, the RGS protein RgsA is also involved in regulation of the cAMP/PKA pathway and germination via attenuation of GanB signaling. Genetic epistatic analyses led us to conclude that all controls exerted by GanB()-SfaD(ß)-GpgA() on conidial germination are mediated through the cAMP/PKA pathway. Furthermore, GanB may function in sensing various carbon sources and subsequent activation of downstream signaling for germination.
Molecular genetic studies focused on the mechanisms regulating the successive steps of spore germination have led to the identification of key components specifically required for distinct stages (reviewed in D'ENFERT 1997; WENDLAND 2001). The primary requirement for initiation of germination and completion of the subsequent steps is the sensing of external signals. Early studies demonstrated that germination of ascospores in Saccharomyces cerevisiae is most efficient in the presence of a readily fermentable carbon source, suggesting that initiation of germination is regulated by nutrient availability (SAVARESE 1974; TINGLE et al. 1974). In this regard, glucose has been shown to be necessary and sufficient to induce activation of ascospore germination (HERMAN and RINE 1997). In S. cerevisiae, glucose sensing is mediated by the G-protein-coupled receptor (GPCR) Gpr1p that in turn activates the heterotrimeric G-protein -subunit encoded by the GPA2 gene (LORENZ and HEITMAN 1997; XUE et al. 1998; KRAAKMAN et al. 1999). The Gpr1p-Gpa2p system mediates glucose-dependent activation of the cAMP-dependent protein kinase (PKA) pathway that is associated with mobilization of trehalose, decreased stress resistance, and expression of ribosomal protein (rp) genes (KRAAKMAN et al. 1999). In S. cerevisiae, adenylate cyclase activity is also regulated by the small GTPase Ras2 that responds to intracellular acidification during transition to growth on glucose (COLOMBO et al. 1998). The nutrient-sensing GPCR-G-protein-cAMP-PKA pathway is conserved in Schizosaccharomyces pombe, where it appears to be crucial for efficient ascospore germination (WELTON and HOFFMAN 2000; HATANAKA and SHIMODA 2001).
To date, no similar nutrient-sensing pathway regulating sexual or asexual spore germination has been identified in filamentous fungi. Little is known about the molecular mechanisms controlling spore germination of filamentous fungi. Several physiological changes are associated with germination, such as trehalose degradation, decreased stress resistance, and stimulation of rp gene expression, suggesting similarities with molecular mechanisms involved in growth resumption in yeasts (D'ENFERT 1997). The cAMP/PKA signal transduction cascade and heterotrimeric G-proteins have attracted growing interest in recent years, which has led to extensive information on molecular signals involved in fungal morphogenesis and virulence (reviewed in LENGELER et al. 2000). Only a few of these studies specifically investigated the spore germination process. The first unambiguous study focused on the involvement of G-proteins in spore germination was described in the dimorphic fungus Penicillium marneffei (ZUBER et al. 2003). The characterization of three G-subunits revealed that one of these, GasC, is crucial for efficient germination (ZUBER et al. 2002, 2003). The gasC deletion mutant is severely delayed in germination while a dominant-activating mutation in gasC triggers precocious germination. Surprisingly, this gain-of-function mutant strain is unable to germinate in the absence of any carbon source, suggesting that GasC does not mediate carbon source sensing during germination. In Aspergillus nidulans, the biological processes regulated by GasC in P. marneffei, i.e., conidial germination, production of secondary metabolites, and conidiation, are regulated by the cAMP/PKA pathway (SHIMIZU and KELLER 2001; FILLINGER et al. 2002) and it has therefore been proposed that GasC signals through the cAMP/PKA pathway (ZUBER et al. 2003).
Requirement of the cAMP/PKA pathway for conidial germination was proposed early on the basis of the observation that the trehalose pool in spores is rapidly mobilized at the onset of germination. Indeed, this reaction is catalyzed by neutral trehalases that are potential targets of PKA (THEVELEIN 1984; D'ENFERT et al. 1999). This model was demonstrated in A. nidulans with characterization of the genes encoding adenylate cyclase (cyaA) and PKA (pkaA) (SHIMIZU and KELLER 2001; FILLINGER et al. 2002). Deletion of cyaA causes severe defects in conidial germination, i.e., delayed germ tube formation (several hours) and a dramatic decrease in trehalose degradation. Inactivation of pkaA also leads to germination defects, indicating the involvement of the cAMP-PKA signaling pathway in activation of early events of conidial germination via carbon source sensing. Yet, germination defects of the pkaA mutant are less pronounced than those of the cyaA mutant, suggesting that cAMP might act positively not only on PkaA but also on other signaling components necessary for efficient germination. These may include additional catalytic subunits that have been revealed by sequencing of the A. nidulans genome. An additional transduction pathway is required for efficient germination in A. nidulans: Ras signaling has been proposed to control the switch from isotropic to polarized growth as overproduction of a dominant-activating form of RasA results in giant swollen conidia with multiple nuclei unable to produce a germ tube (SOM and KOLAPARTHI 1994). Whereas in S. cerevisiae cAMP signaling is regulated in part by the small GTPases Ras1 and Ras2, in A. nidulans ras and cAMP signaling control the germination process in an independent manner since overexpression of the dominant-active form of RasA blocks germ tube formation even in the absence of a functional adenylate cyclase (FILLINGER et al. 2002). Therefore, it has been proposed that activation of adenylate cyclase could be mediated by heterotrimeric G-proteins in response to glucose during early germination as described for fission and budding yeasts. Among the three G-subunits identified in A. nidulans, FadA, GanA, and GanB (YU et al. 1996; CHANG et al. 2004), on the basis of the level of sequence similarity with Gpa2 of S. cerevisiae, GanB appeared to be the most likely candidate.
Two recent studies focused on G-protein signaling components in A. nidulans have brought support to this model and established the involvement of the A. nidulans GanB and RgsA proteins in conidial germination (CHANG et al. 2004; HAN et al. 2004b). A. nidulans strains with ganB null or dominant inactivating mutations show delayed germination and decreased germination rates. In contrast, a dominant-activating form of GanB significantly accelerates germination rates and is able to induce germ tube emergence in the absence of any external carbon source. Interestingly, inactivation of the regulator of G-protein signaling (RGS) protein encoded by the rgsA gene results in phenotypes similar to those observed in a ganB gain-of-function mutant strain. Deletion of ganB fully suppresses alterations caused by deletion of rgsA, indicating that the primary role of RgsA is to downregulate GanB signaling (HAN et al. 2004b). Yet, none of these studies have addressed the link between GanB signaling and the cAMP/PKA pathway.
In this study we investigated the role of heterotrimeric G-proteins in activation of the cAMP/PKA pathway at the onset of germination and shed light on the molecular mechanisms underlying the early events of conidial germination. Our findings reveal that the heterotrimeric G-protein GanB()-SfaD(ß)-GpgA() is activated by carbon source sensing and triggers a rapid and transient cAMP signal and subsequent stimulation of PKA activity critical for initiation of germination. In this model, GanB is the activating element while the primary function of the SfaD-GpgA heterodimer is to relocalize GanB to the plasma membrane and allow reactivation by carbon source sensing. Moreover, our observations provide evidence that RgsA inhibits cAMP-dependent events of spore germination through downregulation of GanB signaling.
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MATERIALS AND METHODS |
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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-protein GanB is a positive regulator of the cAMP/PKA pathway in response to glucose:-subunits during the early stages of conidial germination in A. nidulans. Trehalose breakdown, which is a direct outcome of activation of the cAMP/PKA pathway during early germination but is not a prerequisite to germ tube outgrowth (D'ENFERT et al. 1999), was monitored in A. nidulans mutant strains defective for one of the three A. nidulans G-subunits FadA, GanA, and GanB (YU et al. 1996; CHANG et al. 2004). Figure 1A shows that trehalose degradation was severely reduced in the ganB null mutant and remained unaffected in the fadA and ganA null mutants. In the wild-type strain, trehalose degradation occurred immediately after induction of germination by addition of glucose and trehalose levels were decreased to 10–20% at 90 min. In the ganB
mutant, the kinetics of degradation were altered greatly in that the pool was reduced only to 60% at 120 min after glucose addition.
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To explicitly demonstrate that GanB signaling regulates adenylate cyclase in response to glucose, we assessed cAMP levels in the resting and germinating spores of wild-type and ganB strains. Results presented in Figure 2 show that addition of glucose to dormant spores of wild type induced a rapid and transient increase in cAMP levels that was fully abolished in the ganB conidia. However, no significant difference in the steady-state levels of cAMP between the wild-type (154 ± 9 fmol/2 x 107 conidia) and ganB (178 ± 16 fmol/2 x 107conidia) dormant conidia were observed. Furthermore, levels of cAMP were below detectable limits in the A. nidulans strain defective for adenylate cyclase (data not shown). Taken together, these results suggest that GanB is responsible for regulating cAMP synthesis in response to glucose at the onset of germination but is not involved in regulating intracellular cAMP basal levels.
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) regulate the cAMP/PKA pathway during the early phase of germination:, Gpa2p, and seven-kelch domain proteins Gpb1/2p (HARASHIMA and HEITMAN 2002) and a heterotrimeric G-protein Gpa2()-Gbp1(ß)- (LORENZ and HEITMAN 1997; LANDRY and HOFFMAN 2001), respectively. We addressed whether the nutrient sensor GanB is a part of a heterotrimeric complex involved in activation of the cAMP/PKA pathway at the onset of germination. In A. nidulans, as in most fungi, one gene encoding a Gß-subunit (ROSEN et al. 1999) and one gene encoding a G-subunit have been identified (SEO et al. 2005, accompanying article in this issue). Trehalose degradation was monitored upon germination of the sfaD and gpgA mutant spores. Results presented in Figure 1B show that trehalose degradation was impaired in both mutants although to a lesser extent than when ganB is inactivated, suggesting that SfaD and GpgA positively regulate the glucose/cAMP pathway at the onset of glucose-induced germination.
RgsA/GanB signaling regulates the cAMP/PKA pathway at the onset of germination:
HAN et al. (2004b) have identified a new RGS protein (RgsA) in A. nidulans that negatively controls GanB signaling and is therefore involved in attenuating biological processes stimulated by GanB. We thereby postulated that RgsA also regulates the cAMP/PKA pathway in response to carbon source via downregulation of GanB signaling and investigated the ability of the rgsA and rgsA ganB mutants to stimulate trehalose breakdown during early germination. Deletion of rgsA triggered accelerated trehalose degradation in response to glucose. In addition, this phenotype was suppressed by ganB (Figure 1C), indicating that uncontrolled activation of GanB caused by rgsA leads to overstimulation of the cAMP/PKA pathway in response to glucose.
To further understand functional interactions between the different modules of GanB signaling, we generated the double mutant rgsA sfaD and evaluated its ability to regulate the glucose-induced cAMP/PKA signaling pathway. Our results demonstrated that deletion of sfaD resulted in suppression of the effects caused by the rgsA mutation (data not shown). The fact that the rgsA sfaD and sfaD mutants exhibit similar patterns with respect to trehalose breakdown suggests that overstimulation of the cAMP/PKA pathway by GanB requires the Gß-subunit, SfaD.
The heterotrimeric G-protein GanB()-SfaD(ß)-GpgA() is required for efficient conidial germination in A. nidulans:
Two recent studies have revealed that (i) GanB positively regulates conidial germination via carbon source sensing (CHANG et al. 2004) and (ii) RgsA is a negative regulator of germ tube formation through downregulation of GanB signaling (HAN et al. 2004b). We further investigated the role of the Gß- (SfaD) and G- (GpgA) subunits in the regulation of conidial germination. We analyzed the kinetics of germ tube emergence in the sfaD and gpgA null mutants in comparison to that in wild-type and ganB null mutant strains and observed significant defects in germination rates in both sfaD and gpgA strains similar to (but less severe than) those observed in a ganB strain (Figure 3A). These data clearly showed that the G-protein subunits G GanB, Gß SfaD, and G GpgA activate conidial germination. To define whether GanB() and SfaD(ß) regulate germ tube emergence as components of a G-protein complex, we checked germination rates of the rgsA sfaD mutant conidia. Figure 3, B and C, shows that the rgsA sfaD mutant exhibited defects in conidial germination similar to those observed in the single sfaD mutant. Therefore, the sfaD mutation suppressed germination in the absence of any external carbon source associated with the upregulation of GanB caused by the rgsA mutation (Figure 3C). These data indicated that activation of GanB-dependent germination requires the Gß subunit, as previously demonstrated for activation of the GanB-dependent cAMP/PKA pathway, suggesting that formation of the heterotrimeric ß is a prerequisite for activation of GanB signaling in response to glucose.
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)-SfaD(ß)-GpgA() is required for both activation of the glucose-dependent cAMP/PKA pathway during the early phase of germination and efficient conidial germination. These findings, in conjunction with the requirement of the cAMP/PKA pathway for efficient germ tube formation (FILLINGER et al. 2002), strongly suggest that the G-protein GanB()-SfaD(ß)-GpgA() activates conidial germination through the cAMP/PKA pathway in response to glucose. To investigate this hypothesis, we carried out genetic epistatic analyses between cyaA, rgsA, and ganB and found that cyaA is epistasic to ganB and rgsA. These mutants did not display any morphological abnormalities during conidial germination. The only defects observed were delayed/precocious emergence of germ tubes and decreased/accelerated germination rate. Viability of the cyaA and ganB mutant conidia might be partially impaired as after 20 hr of incubation, some conidia remained ungerminated (CHANG et al. 2004 and data not shown). The cyaA ganB mutant (Figure 4A and data not shown) as well as the cyaA rgsA mutant (Figure 4, B and C) displayed defects in conidial germination and in trehalose breakdown similar to those observed in the cyaA mutant. Deletion of cyaA suppressed hypergermination phenotypes associated with uncontrolled activation of GanB caused by rgsA, i.e., accelerated trehalose breakdown (Figure 4C) and ability to produce a germ tube in the absence of external carbon source (data not shown). Moreover, the cyaA mutant exhibited delayed germination more severe than that exhibited by the ganB mutant (Figure 4A). Possible interpretations for this result are described in the DISCUSSION.
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conidia was monitored in the presence of various carbon sources. Results presented in Figure 5 show that germination was impaired in the ganB null mutant independent of carbon sources, suggesting that GanB signaling might mediate activation of the cAMP/PKA pathway in response to various carbon sources.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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-subunit closely related to Gpa2p GanB mediates activation of the cAMP/PKA pathway in response to glucose. These observations suggest that this nutrient-sensing pathway has been conserved through evolution to regulate processes linked to growth resumption such as diauxic growth and spore germination. To date, no functional homolog of the nutrient sensor Gpr1p has been identified in A. nidulans or in any filamentous fungus. However, the recent identification of nine putative seven-transmembrane-spanning GPCRs in the genome of A. nidulans will open a new direction for the study of signal transduction mediated by G-proteins in filamentous fungi (HAN et al. 2004a).
Our data provide evidence that SfaD (Gß) and GpgA (G) are upstream positive regulators of the cAMP/PKA pathway in response to glucose. These are also consistent with a model in which the G-subunit GanB constitutes the primary signaling element of the cascade while the SfaD(ß)-GpgA() dimer acts to reassociate with and relocalize GanB to its hypothetical cognate receptor and allow reactivation by carbon source sensing (Figure 6). Activation of G-proteins is classically based on dissociation of the heterotrimeric complex (ß) into two functional units, the ß-dimer and the GTP-bound G-subunit. In filamentous fungi, the G-subunit acts usually as the primary signaling element (LENGELER et al. 2000) whereas the Gß-complex from yeasts frequently plays an active role in signaling cascades. For example, in the budding yeast, the Gß-dimer initiates the pheromone response pathway whereas the G-subunit, Gpa1, plays a negative role by repressing Gß (WHITEWAY et al. 1989). In the basidiomycetous yeast Cryptococcus neoformans, the Gbp1Gß-subunit regulates mating via a MAP kinase cascade in parallel with the Gpa1G-subunit, which signals via a cAMP cascade (WANG et al. 2000). Another unusual feature specific to the budding and fission yeasts is the existence of a monomeric G-protein that functions without a genuine ß-dimer (LENGELER et al. 2000). In S. pombe, the G-protein Gpa1 plays an active role in the pheromone-activated MAPK signaling pathway (OBARA et al. 1991; XU et al. 1994); Git5, the only Gß-subunit present in S. pombe, is not coupled to Gpa1 (LANDRY et al. 2000). In S. cerevisiae, the glucose/cAMP signaling pathway is regulated by the monomeric G-protein Gpa2p and atypical proteins, namely Gpb1/2p and Gpg1p, that act as structural mimics of a ß-dimer to prevent activation of adenylate cyclase by Gpa2p (HARASHIMA and HEITMAN 2002). This unusual regulation, additionally with the absence of any homolog of Gpb1/2p or Gpg1p proteins in the genome of A. nidulans, might explain the inability of GanB to functionally complement the gpa2 null mutant of S. cerevisiae (our unpublished data). Although the modules of the G-protein/cAMP/PKA pathway are highly conserved, their contribution to signaling pathways appears to have diverged during evolution between filamentous fungi and yeasts: filamentous fungi share a "classical" mode of action similar to that observed in mammalian cells, whereas yeasts may have adopted novel strategies for signal transduction.
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-subunit GanB (HAN et al. 2004b). RgsA is similar to ScRgs2 of S. cerevisiae, which is responsible for downregulation of the GanB-related G-subunit, Gpa2p (VERSELE et al. 1999). As described for deletion of RGS2, our results reveal that inactivation of rgsA leads to stimulation of the cAMP/PKA signaling pathway, evidenced by accelerated trehalose breakdown kinetics. Moreover, the double mutant rgsA ganB displays defects in trehalose breakdown similar to those displayed by the ganB mutant. These results indicate that RgsA modulates the cAMP/PKA pathway through downregulation of GanB signaling at the onset of germination (Figure 6). Whereas RgsA appears to be differentially expressed during the developmental cycle of A. nidulans (HAN et al. 2004b), the mechanisms underlying its regulation remain to be uncovered. However, an elevated level of transcriptional expression is reported for rgsA in ascospores of A. nidulans (HAN et al. 2004b). This, in combination with the requirement of GanB for efficient ascospore and conidial germination (CHANG et al. 2004), suggests that RgsA plays a crucial role in preventing germination under inappropriate environmental conditions via downregulation of GanB signaling in dormant spores. Furthermore, our epistatic analysis between the sfaD and rgsA genes demonstrates that deletion of sfaD suppresses germination defects associated with the upregulation of GanB, resulting from inactivation of rgsA. These data are in good agreement with our model (Figure 6) in which one of the functions of the ß-dimer within the heterotrimeric G-protein GanB-SfaD-GpgA is to reassociate with and to redirect GanB to its cognate GPCR for reactivation by glucose.
A very recent report has revealed the requirement of the G-subunit GanB for efficient spore germination in response to glucose sensing (CHANG et al. 2004). In our study, we provide evidence that GanB regulates conidial germination within the heterotrimeric G-protein GanB()-SfaD(ß)-GpgA() through activation of the cAMP/PKA pathway in response to glucose (Figure 6). Our observations revealed that the cyaA mutant shows a germination defect more severe than that of the ganB mutant. To explain these observations, one attractive hypothesis could be the existence of additional upstream regulators of the cAMP/PKA pathway. Two possible candidates are the G-subunits, FadA and GanA: although the fadA and ganA mutants showed no defect in activation of the cAMP/PKA pathway in response to glucose, functional redundancy between them cannot be excluded. In N. crassa, whereas inactivation of the G-subunit Gna-2 does not yield detectable phenotype, simultaneous inactivation of gna-2 and gna-1 resulted in synthetic defects, suggesting overlapping functions (BAASIRI et al. 1997). A complementary hypothesis involves the maintenance of a basal level of cellular cAMP to ensure efficient germination. Previous studies in several plant pathogens revealed interconnections between cAMP signaling and MAPK pathways. In both Magnoporthe grisea and Ustilago maydis, cAMP appears to regulate positively the MAPK pathway involved in appressorium formation and pheromone response, respectively (XU and HAMER 1996; LEE et al. 2003). In Sclerotinia sclerotiorum, cAMP inhibits the MAPK pathway responsible for sclerotial development (CHEN and DICKMAN 2005). A previous study revealed that RasA from A. nidulans regulates conidial germination via an undefined signaling pathway in parallel to the cAMP/PKA pathway (FILLINGER et al. 2002). Since signaling pathways often operate in interconnecting networks, it can be hypothesized that in A. nidulans, cAMP might act positively on Ras signaling, maybe through a MAPK pathway. Indeed, germination defects of the cyaA mutant could be due to inactivation of both cAMP/PKA and Ras signaling pathways.
In A. nidulans, activation of the cAMP/PKA pathway at the onset of germination can be induced by various carbon sources such as fructose, ethanol, or acetate with specific kinetics of trehalose breakdown for each energy source (FILLINGER et al. 2002). Our data suggest that, regardless of the carbon source, sensing and subsequent activation of the cAMP/PKA pathway is mediated by GanB signaling. These results are in contrast with those of S. cerevisiae in which Gpa2p is associated with a GPCR specifically sensitized by glucose and sucrose, Gpr1p (KRAAKMAN et al. 1999; LEMAIRE et al. 2004). Our studies suggest that either the receptor associated with GanB is able to perceive many carbon sources or GanB can interact with various GPCRs. This last hypothesis is in good agreement with phylogenetic studies of nine putative GPCRs in the A. nidulans genome, where three of them appeared to share the highest similarity with the glucose sensor of S. cerevisiae, Gpr1p, suggesting potential functional redundancy of GPCRs (HAN et al. 2004a). Interestingly, deletion of gprD triggers a delay in germ tube formation—
3 hr—indicating that GprD is required for proper germination.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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