Transcriptional Control of Gluconeogenesis in <i>Aspergillus nidulans</i>

Hynes, Michael J.; Szewczyk, Edyta; Murray, Susan; Suzuki, Yumi; Davis, Meryl A.; Sealy-Lewis, Heather M.

doi:10.1534/genetics.107.070904

Cited by 43 publications

(69 citation statements)

References 62 publications

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“…Regarding the relationships between RSE2 and RSE3, the observation that the Drse2 rse3 1 , Drse3 rse2 1 , Drse2 rse3 G642 , and rse2 Y300D Drse3 strains are unable to induce the alternative oxidase unambiguously demonstrate that both proteins are required for this induction even when one of them is present in a mutated form. This result agrees with observations reported for N. crassa in which neither the aod2 nor the aod5 mutants are able to induce AOX (Descheneau et al 2005) and in A. nidulans in which neither the acuK nor the acuM mutants are able to induce PCK (Hynes et al 2007). In N. crassa, electrophoretic mobility shift assays showed that AOD2 and AOD5 act synergistically to bind an alternative oxidase induction motif (AIM) present in the promoter of the aod-1 gene, which encodes the alternative oxidase.…”

Section: G303ssupporting

confidence: 91%

“…Alternative Pathways and Senescence in P. anserinaAcuK in A. nidulans (Hynes et al 2007) act as activators of the expression of genes encoding central enzymes in the gluconeogenic pathway, in particular phosphoenolpyruvate carboxykinase (PCK) and fructose-1,6-biphosphatase (FBPase). PCK catalyzes an early step in gluconeogenesis and converts oxaloacetate to phosphoenolpyruvate, and FBPase catalyzes the final step in hexose monophosphate formation by dephosphorylating fructose-1,6-biphosphate to yield fructose-6-phosphate.…”

Section: Y300dmentioning

confidence: 99%

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Mutations in Two Zinc-Cluster Proteins Activate Alternative Respiratory and Gluconeogenic Pathways and Restore Senescence in Long-Lived Respiratory Mutants ofPodospora anserina

et al. 2009

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In Podospora anserina, inactivation of the respiratory chain results in a spectacular life-span extension. This inactivation is accompanied by the induction of the alternative oxidase. Although the functional value of this response is evident, the mechanism behind it is far from understood. By screening suppressors able to reduce the life-span extension of cytochrome-deficient mutants, we identified mutations in two zinc-cluster proteins, RSE2 and RSE3, which are conserved in other ascomycetes. These mutations led to the overexpression of the genes encoding the alternative oxidase and the gluconeogenic enzymes, fructose-1, 6 biphosphatase, and pyruvate carboxykinase. Both RSE2 and RSE3 are required for the expression of these genes. We also show that, even in the absence of a respiratory deficiency, the wild-type RSE2 and RSE3 transcription factors are involved in life-span control and their inactivation retards aging. These data are discussed with respect to aging, the regulation of the alternative oxidase, and carbon metabolism.

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Section: G303ssupporting

confidence: 91%

Section: Y300dmentioning

confidence: 99%

Mutations in Two Zinc-Cluster Proteins Activate Alternative Respiratory and Gluconeogenic Pathways and Restore Senescence in Long-Lived Respiratory Mutants ofPodospora anserina

et al. 2009

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“…In A. nidulans, the AcuM and AcuK transcription factors form a heterodimer that is a key regulator of metabolic reprogramming in response to gluconeogenic carbon sources (15,16). Previously, we found that in A. fumigatus, AcuM governs not only gluconeogenesis but also iron acquisition (14).…”

Section: Discussionmentioning

confidence: 99%

“…Deletion of sreA in the ⌬acuM mutant restored siderophore production and iron uptake in vitro, suggesting that the virulence defect of the ⌬acuM mutant may be due in part to reduced iron acquisition (14). AcuM is also present in Aspergillus nidulans, in which it governs gluconeogenesis but not iron acquisition (14,15). In A. nidulans, AcuM forms a heterodimer with a related transcription factor, AcuK (16).…”

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confidence: 99%

Divergent Targets of Aspergillus fumigatus AcuK and AcuM Transcription Factors during Growth In Vitro versus Invasive Disease

Pongpom

Liu

et al. 2015

Infect Immun

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eIn Aspergillus nidulans, the AcuK and AcuM transcription factors form a complex that regulates gluconeogenesis. In Aspergillus fumigatus, AcuM governs gluconeogenesis and iron acquisition in vitro and virulence in immunosuppressed mice. However, the function of AcuK was previously unknown. Through in vitro studies, we found that A. fumigatus ⌬acuK single and ⌬acuK ⌬acuM double mutants had impaired gluconeogenesis and iron acquisition, similar to the ⌬acuM mutant. Also, the ⌬acuK, ⌬acuM, and ⌬acuK ⌬acuM mutants had similar virulence defects in mice. However, the ⌬acuK mutant had a milder defect in extracellular siderophore activity and induction of epithelial cell damage in vitro than did the ⌬acuM mutant. Moreover, overexpression of acuM in the ⌬acuK mutant altered expression of 3 genes and partially restored growth under iron-limited conditions, suggesting that AcuM can govern some genes independently of AcuK. Although the ⌬acuK and ⌬acuM mutants had very similar transcriptional profiles in vitro, their transcriptional profiles during murine pulmonary infection differed both from their in vitro profiles and from each other. While AcuK and AcuM governed the expression of only a few iron-responsive genes in vivo, they influenced the expression of other virulence-related genes, such as hexA and dvrA. Therefore, in A. fumigatus, while AcuK and AcuM likely function as part of the same complex, they can also function independently of each other. Furthermore, AcuK and AcuM have different target genes in vivo than in vitro, suggesting that in vivo infection stimulates unique transcriptional regulatory pathways in A. fumigatus. Aspergillus fumigatus causes a variety of diseases, including allergic bronchopulmonary aspergillosis, aspergilloma, invasive pulmonary aspergillosis, and hematogenously disseminated aspergillosis (1, 2). The incidence of invasive aspergillosis is rising due to the increasing number of immunocompromised patients, who are at risk for this disease (3, 4). Furthermore, because invasive aspergillosis remains difficult to diagnose and treat, this infection is still associated with significant mortality (5). One approach to developing new strategies to treat this frequently deadly infection is to target the factors that enable A. fumigatus to survive and proliferate within the host.Iron is an essential trace element for most living organisms, including pathogenic microorganisms. Consequently, sequestration of free iron by the host is a key factor for inhibiting the virulence of microbial pathogens (6-8). Furthermore, most successful pathogens have evolved mechanisms to obtain iron while inside the host. For example, A. fumigatus acquires iron from the host by both reductive iron assimilation and secretion of siderophores (9-11). Siderophore secretion is more important for growth within the host, because A. fumigatus mutants with defects in siderophore synthesis have dramatically attenuated virulence, whereas those with defects in reductive iron assimilation do not (11-13).Previously, we determined tha...

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“…In the presence of long-chain fatty acids, this induction is mediated by FarA and FarB, homologous transcription factors, while a third protein, ScfA, responds to short-chain fatty acids (24). Two other transcription factors, AcuK and AcuM, also regulate gluconeogenic genes and are required for growth on nonfermentable carbon sources (26). AmdX, the closest A. nidulans sequence homolog to ADR1, regulates the acetamidase AmdS, but is not required for growth on a variety of nitrogen or carbon sources (39).…”

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confidence: 99%

The Transcription Factor Homolog CTF1 Regulates β-Oxidation in Candida albicans

Ramírez

Lorenz

2009

Eukaryot Cell

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Carbon starvation is one of the many stresses to which microbial pathogens are subjected while in the host. Pathways necessary for the utilization of alternative carbon sources, such as gluconeogenesis, the glyoxylate cycle, and ␤-oxidation of fatty acids, have been shown to be required for full virulence in several systems, including the fungal pathogen Candida albicans. We have investigated the regulatory network governing alternative carbon metabolism in this organism through characterization of transcriptional regulators identified based on the model fungi, Saccharomyces cerevisiae and Aspergillus nidulans. C. albicans has homologs of the ScCAT8/AnFacB and ScADR1/AnAmdX transcription factors that regulate induction of genes encoding the proteins of gluconeogenesis, the glyoxylate cycle, and ethanol utilization. Surprisingly, C. albicans mutants lacking CAT8 or ADR1 have no apparent phenotypes and do not regulate genes for key enzymes of these pathways. Fatty acid degradation and peroxisomal biogenesis are controlled by nonhomologous regulators, OAF1/PIP2 in S. cerevisiae and FarA/FarB in A. nidulans; C. albicans is missing OAF1 and PIP2 and, instead, has a single homolog of the Far proteins, CTF1. We have shown that CTF1 is required for growth on lipids and for expression of genes necessary for ␤-oxidation, such as FOX2. ctf1⌬/ctf1⌬ (ctf1⌬/⌬) strains do not, however, show the pleiotropic phenotypes observed for fox2⌬/⌬ mutants. The ctf1⌬/⌬ mutant confers a mild attenuation in virulence, like the fox2⌬/⌬ mutant. Thus, phenotypic and genotypic observations highlight important differences in the regulatory network for alternative carbon metabolism in C. albicans compared to the paradigms developed in other model fungi.Candida albicans is both a ubiquitous commensal of the human microbial flora and the most important fungal pathogen of humans (9, 43). While C. albicans can infect nearly any site in the body, the most serious manifestation, disseminated bloodstream infections, particularly affects immunocompromised individuals and is fatal in about 40% of cases (67). Candida species are responsible for ϳ9% of cases of hospitalacquired sepsis and up to 12% of central line-associated bloodstream infections, with C. albicans causing about half of these infections (23,67). Studying the biology of C. albicans in its natural niche, the mammalian host, provides insights into how this intriguing species has adapted to become such a successful pathogen and, as a result, is crucial to the development of new drug targets and treatment strategies.An increasing body of literature indicates that some host niches are carbon limited and that mutations that abrogate utilization of nonfermentable carbon sources are compromised in virulence models for many (but not all) fungal pathogens of both plants and animals, including C. albicans, Magnaporthe grisea, Leptosphaeria maculans, Stagonospora nodorum, and Colletotrichum lagenarium (2,5,27,33,46,48,59,66). In particular, studies have focused on the pathways of gluconeogenesis, the g...

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Transcriptional Control of Gluconeogenesis in Aspergillus nidulans

Cited by 43 publications

References 62 publications

Mutations in Two Zinc-Cluster Proteins Activate Alternative Respiratory and Gluconeogenic Pathways and Restore Senescence in Long-Lived Respiratory Mutants ofPodospora anserina

Mutations in Two Zinc-Cluster Proteins Activate Alternative Respiratory and Gluconeogenic Pathways and Restore Senescence in Long-Lived Respiratory Mutants ofPodospora anserina

Divergent Targets of Aspergillus fumigatus AcuK and AcuM Transcription Factors during Growth In Vitro versus Invasive Disease

The Transcription Factor Homolog CTF1 Regulates β-Oxidation in Candida albicans

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