Iron Regulation through the Back Door: Iron-Dependent Metabolite Levels Contribute to Transcriptional Adaptation to Iron Deprivation in Saccharomyces cerevisiae

ABSTRACTBudding yeast (Saccharomyces cerevisiae) responds to iron deprivation both by Aft1-Aft2-dependent transcriptional activation of genes involved in cellular iron uptake and by Cth1-Cth2-specific degradation of certain mRNAs coding for iron-dependent biosynthetic components. Here, we provide evidence for a novel principle of iron-responsive gene expression. This regulatory mechanism is based on the modulation of transcription through the iron-dependent variation of levels of regulatory metabolites. As an example, theLEU1gene of branched-chain amino acid biosynthesis is downregulated under iron-limiting conditions through depletion of the metabolic intermediate α-isopropylmalate, which functions as a key transcriptional coactivator of the Leu3 transcription factor. Synthesis of α-isopropylmalate involves the iron-sulfur protein Ilv3, which is inactivated under iron deficiency. As another example, decreased mRNA levels of the cytochromec-encodingCYC1gene under iron-limiting conditions involve heme-dependent transcriptional regulation via the Hap1 transcription factor. Synthesis of the iron-containing heme is directly correlated with iron availability. Thus, the iron-responsive expression of genes that are downregulated under iron-limiting conditions is conferred by two independent regulatory mechanisms: transcriptional regulation through iron-responsive metabolites and posttranscriptional mRNA degradation. Only the combination of the two processes provides a quantitative description of the response to iron deprivation in yeast.

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Arsenic Directly Binds to and Activates the Yeast AP-1-Like Transcription Factor Yap8

Molecular and Cellular Biology ◽

10.1128/mcb.00842-15 ◽

2015 ◽

Vol 36 (6) ◽

pp. 913-922 ◽

Cited By ~ 17

Author(s):

Nallani Vijay Kumar ◽

Jianbo Yang ◽

Jitesh K. Pillai ◽

Swati Rawat ◽

Carlos Solano ◽

...

Keyword(s):

Transcription Factor ◽

Transcriptional Activation ◽

Transcriptional Response ◽

Transcriptional Regulator ◽

Yeast Protein ◽

Content Type ◽

Arsenic Tolerance ◽

Arsenic Sensing

The AP-1-like transcription factor Yap8 is critical for arsenic tolerance in the yeastSaccharomyces cerevisiae. However, the mechanism by which Yap8 senses the presence of arsenic and activates transcription of detoxification genes is unknown. Here we demonstrate that Yap8 directly binds to trivalent arsenite [As(III)]in vitroandin vivoand that approximately one As(III) molecule is bound per molecule of Yap8. As(III) is coordinated by three sulfur atoms in purified Yap8, and our genetic and biochemical data identify the cysteine residues that form the binding site as Cys132, Cys137, and Cys274. As(III) binding by Yap8 does not require an additional yeast protein, and Yap8 is regulated neither at the level of localization nor at the level of DNA binding. Instead, our data are consistent with a model in which a DNA-bound form of Yap8 acts directly as an As(III) sensor. Binding of As(III) to Yap8 triggers a conformational change that in turn brings about a transcriptional response. Thus, As(III) binding to Yap8 acts as a molecular switch that converts inactive Yap8 into an active transcriptional regulator. This is the first report to demonstrate how a eukaryotic protein couples arsenic sensing to transcriptional activation.

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Arabinose-Induced Catabolite Repression as a Mechanism for Pentose Hierarchy Control inClostridium acetobutylicumATCC 824

mSystems ◽

10.1128/msystems.00064-18 ◽

2018 ◽

Vol 3 (5) ◽

Cited By ~ 2

Author(s):

Matthew D. Servinsky ◽

Rebecca L. Renberg ◽

Matthew A. Perisin ◽

Elliot S. Gerlach ◽

Sanchao Liu ◽

...

Keyword(s):

Transcriptional Regulation ◽

Genetic Engineering ◽

Catabolite Repression ◽

Clostridium Acetobutylicum ◽

Regulation Mechanism ◽

Mrna Levels ◽

Chemical Production ◽

Content Type ◽

Commodity Chemicals ◽

Pentose Utilization

ABSTRACTBacterial fermentation of carbohydrates from sustainable lignocellulosic biomass into commodity chemicals by the anaerobic bacteriumClostridium acetobutylicumis a promising alternative source to fossil fuel-derived chemicals. Recently, it was demonstrated that xylose is not appreciably fermented in the presence of arabinose, revealing a hierarchy of pentose utilization in this organism (L. Aristilde, I. A. Lewis, J. O. Park, and J. D. Rabinowitz, Appl Environ Microbiol 81:1452–1462, 2015,https://doi.org/10.1128/AEM.03199-14). The goal of the current study is to characterize the transcriptional regulation that occurs and perhaps drives this pentose hierarchy. Carbohydrate consumption rates showed that arabinose, like glucose, actively represses xylose utilization in cultures fermenting xylose. Further, arabinose addition to xylose cultures led to increased acetate-to-butyrate ratios, which indicated a transition of pentose catabolism from the pentose phosphate pathway to the phosphoketolase pathway. Transcriptome sequencing (RNA-Seq) confirmed that arabinose addition to cells actively growing on xylose resulted in increased phosphoketolase (CA_C1343) mRNA levels, providing additional evidence that arabinose induces this metabolic switch. A significant overlap in differentially regulated genes after addition of arabinose or glucose suggested a common regulation mechanism. A putative open reading frame (ORF) encoding a potential catabolite repression phosphocarrier histidine protein (Crh) was identified that likely participates in the observed transcriptional regulation. These results substantiate the claim that arabinose is utilized preferentially over xylose inC. acetobutylicumand suggest that arabinose can activate carbon catabolite repression via Crh. Furthermore, they provide valuable insights into potential mechanisms for altering pentose utilization to modulate fermentation products for chemical production.IMPORTANCEClostridium acetobutylicumcan ferment a wide variety of carbohydrates to the commodity chemicals acetone, butanol, and ethanol. Recent advances in genetic engineering have expanded the chemical production repertoire ofC. acetobutylicumusing synthetic biology. Due to its natural properties and genetic engineering potential, this organism is a promising candidate for converting biomass-derived feedstocks containing carbohydrate mixtures to commodity chemicals via natural or engineered pathways. Understanding how this organism regulates its metabolism during growth on carbohydrate mixtures is imperative to enable control of synthetic gene circuits in order to optimize chemical production. The work presented here unveils a novel mechanism via transcriptional regulation by a predicted Crh that controls the hierarchy of carbohydrate utilization and is essential for guiding robust genetic engineering strategies for chemical production.

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The Putative APSES Transcription Factor RgdA Governs Growth, Development, Toxigenesis, and Virulence in Aspergillus fumigatus

mSphere ◽

10.1128/msphere.00998-20 ◽

2020 ◽

Vol 5 (6) ◽

Author(s):

Sang-Cheol Jun ◽

Yong-Ho Choi ◽

Min-Woo Lee ◽

Jae-Hyuk Yu ◽

Kwang-Soo Shin

Keyword(s):

Transcription Factor ◽

Aspergillus Fumigatus ◽

Molecular Mechanisms ◽

Pathogenic Fungus ◽

Mrna Levels ◽

Transcript Levels ◽

Content Type ◽

Asexual Sporulation ◽

Human Pathogenic Fungus ◽

Growth Development

ABSTRACT The APSES transcription factor (TF) in Aspergillus species is known to govern diverse cellular processes, including growth, development, and secondary metabolism. Here, we investigated functions of the rgdA gene (Afu3g13920) encoding a putative APSES TF in the opportunistic human-pathogenic fungus Aspergillus fumigatus. The rgdA deletion resulted in significantly decreased hyphal growth and asexual sporulation. Consistently, transcript levels of the key asexual developmental regulators abaA, brlA, and wetA were decreased in the ΔrgdA mutant compared to those in the wild type (WT). Moreover, ΔrgdA resulted in reduced spore germination rates and elevated transcript levels of genes associated with conidium dormancy. The conidial cell wall hydrophobicity and architecture were changed, and levels of the RodA protein were decreased in the ΔrgdA mutant. Comparative transcriptomic analyses revealed that the ΔrgdA mutant showed higher mRNA levels of gliotoxin (GT)-biosynthetic genes and GT production. While the ΔrgdA mutant exhibited elevated production of GT, ΔrgdA strains showed reduced virulence in the mouse model. In addition, mRNA levels of genes associated with the cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway and the SakA mitogen-activated protein (MAP) kinase pathway were increased in the ΔrgdA mutant. In summary, RgdA plays multiple roles in governing growth, development, GT production, and virulence which may involve attenuation of PKA and SakA signaling. IMPORTANCE Immunocompromised patients are susceptible to infections with the opportunistic human-pathogenic fungus Aspergillus fumigatus. This fungus causes systemic infections such as invasive aspergillosis (IA), which is one of the most life-threatening fungal diseases. To control this serious disease, it is critical to identify new antifungal drug targets. In fungi, the transcriptional regulatory proteins of the APSES family play crucial roles in controlling various biological processes, including mating, asexual sporulation and dimorphic growth, and virulence traits. This study found that a putative APSES transcription factor, RgdA, regulates normal growth, asexual development, conidium germination, spore wall architecture and hydrophobicity, toxin production, and virulence in A. fumigatus. Better understanding the molecular mechanisms of RgdA in human-pathogenic fungi may reveal a novel antifungal target for future drug development.

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Functional Dissection of a Candida albicans Zinc Cluster Transcription Factor, the Multidrug Resistance Regulator Mrr1

Eukaryotic Cell ◽

10.1128/ec.05100-11 ◽

2011 ◽

Vol 10 (8) ◽

pp. 1110-1121 ◽

Cited By ~ 18

Author(s):

Sabrina Schubert ◽

Christina Popp ◽

P. David Rogers ◽

Joachim Morschhäuser

Keyword(s):

Transcription Factor ◽

Candida Albicans ◽

Transcriptional Activation ◽

Efflux Pump ◽

Major Facilitator Superfamily ◽

Constitutive Activity ◽

Activation Domain ◽

Pathogenic Yeast ◽

Content Type ◽

Zinc Cluster

ABSTRACTThe overexpression of theMDR1gene, which encodes a multidrug efflux pump of the major facilitator superfamily, is a frequent cause of resistance to the widely used antimycotic agent fluconazole and other toxic compounds in the pathogenic yeastCandida albicans. The zinc cluster transcription factor Mrr1 controlsMDR1expression in response to inducing chemicals, and gain-of-function mutations inMRR1are responsible for the constitutiveMDR1upregulation in fluconazole-resistantC. albicansstrains. To understand how Mrr1 activity is regulated, we identified functional domains of this transcription factor. A hybrid protein consisting of the N-terminal 106 amino acids of Mrr1 and the transcriptional activation domain of Gal4 fromSaccharomyces cerevisiaeconstitutively inducedMDR1expression, demonstrating that the DNA binding domain is sufficient to target Mrr1 to theMDR1promoter. Using a series of C-terminal truncations and systematic internal deletions, we could show that Mrr1 contains multiple activation and inhibitory domains. One activation domain (AD1) is located in the C terminus of Mrr1. When fused to the tetracycline repressor TetR, this distal activation domain induced gene expression from a TetR-dependent promoter. The deletion of an inhibitory region (ID1) located near the distal activation domain resulted in constitutive activity of Mrr1. The additional removal of AD1 abolished the constitutive activity, but the truncated Mrr1 still could activate theMDR1promoter in response to the inducer benomyl. These results demonstrate that the activity of Mrr1 is regulated in multiple ways and provide insights into the function of an important mediator of drug resistance inC. albicans.

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Regulatory factors controlling transcription of Saccharomyces cerevisiae IXR1 by oxygen levels: a model of transcriptional adaptation from aerobiosis to hypoxia implicating ROX1 and IXR1 cross-regulation

Biochemical Journal ◽

10.1042/bj20091500 ◽

2009 ◽

Vol 425 (1) ◽

pp. 235-243 ◽

Cited By ~ 13

Author(s):

Raquel Castro-Prego ◽

Mónica Lamas-Maceiras ◽

Pilar Soengas ◽

Isabel Carneiro ◽

Isabel González-Siso ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Oxygen Availability ◽

Mrna Levels ◽

Mobility Shift ◽

Hypoxic Conditions ◽

Cross Links ◽

Mobility Shift Assay ◽

Transcriptional Adaptation

Ixr1p from Saccharomyces cerevisiae has been previously studied because it binds to DNA containing intrastrand cross-links formed by the anticancer drug cisplatin. Ixr1p is also a transcriptional regulator of anaerobic/hypoxic genes, such as SRP1/TIR1, which encodes a stress-response cell wall manoprotein, and COX5B, which encodes the Vb subunit of the mitochondrial complex cytochrome c oxidase. However, factors controlling IXR1 expression remained unexplored. In the present study we show that IXR1 mRNA levels are controlled by oxygen availability and increase during hypoxia. In aerobiosis, low levels of IXR1 expression are maintained by Rox1p repression through the general co-repressor complex Tup1–Ssn6. Ixr1p itself is necessary for full IXR1 expression under hypoxic conditions. Deletion analyses have identified the region in the IXR1 promoter responsible for this positive auto-control (nucleotides −557 to −376). EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation) assays show that Ixr1p binds to the IXR1 promoter both in vitro and in vivo. Ixr1p is also required for hypoxic repression of ROX1 and binds to its promoter. UPC2 deletion has opposite effects on IXR1 and ROX1 transcription during hypoxia. Ixr1p is also necessary for resistance to oxidative stress generated by H2O2. IXR1 expression is moderately activated by H2O2 and this induction is Yap1p-dependent. A model of IXR1 regulation as a relay for sensing different signals related to change in oxygen availability is proposed. In this model, transcriptional adaptation from aerobiosis to hypoxia depends on ROX1 and IXR1 cross-regulation.

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Put3 Positively Regulates Proline Utilization in Candida albicans

mSphere ◽

10.1128/msphere.00354-17 ◽

2017 ◽

Vol 2 (6) ◽

Cited By ~ 9

Author(s):

Walters Aji Tebung ◽

Raha Parvizi Omran ◽

Debra L. Fulton ◽

Joachim Morschhäuser ◽

Malcolm Whiteway

Keyword(s):

Saccharomyces Cerevisiae ◽

Transcription Factor ◽

Candida Albicans ◽

Nitrogen Source ◽

Opportunistic Pathogen ◽

Baker's Yeast ◽

Null Mutant ◽

Multiple Sources ◽

Content Type ◽

Proline Catabolism

ABSTRACT Candida albicans poses a significant threat to the lives of immunocompromised people. Historically, knowledge has been drawn from studies on Saccharomyces cerevisiae to understand the pathogen, and many Candida albicans genes are named after their S. cerevisiae orthologs. Direct studies on the pathogen have, however, revealed differences in the roles of some orthologous proteins in the two yeasts. We show that the Put3 transcription factor allows the pathogen to completely degrade proline to usable nitrogen and carbon by evading regulatory restrictions imposed on its S. cerevisiae ortholog, which mandates conditional use of proline only as a nitrogen source in the baker’s yeast. The ability of Candida albicans to freely obtain nutrients from multiple sources may help it thrive as a commensal and opportunistic pathogen. The zinc cluster transcription factor Put3 was initially characterized in Saccharomyces cerevisiae as the transcriptional activator of PUT1 and PUT2, two genes acting early in the proline assimilation pathway. We have used phenotypic studies, transcription profiling, and chromatin immunoprecipitation with microarray technology (ChIP-chip) to establish that unlike S. cerevisiae, which only uses proline as a nitrogen source, Candida albicans can use proline as a nitrogen source, a carbon source, or a source of both nitrogen and carbon. However, a C. albicans put3 null mutant cannot grow on proline, suggesting that as in S. cerevisiae, C. albicans Put3 (CaPut3) is required for proline catabolism, and because the C. albicans put3 null mutant grew efficiently on glutamate as the sole carbon or nitrogen source, it appears that CaPut3 also regulates the early genes of the pathway. CaPut3 showed direct binding to the CaPUT1 promoter, and both PUT1 and PUT2 were upregulated in response to proline addition in a Put3-dependent manner, as well as in a C. albicans strain expressing a hyperactive Put3. CaPut3 directs proline degradation even in the presence of a good nitrogen source such as ammonia, which contrasts with S. cerevisiae Put3 (ScPut3)-regulated proline catabolism, which only occurs in the absence of a rich nitrogen source. Thus, while overall proline regulatory circuitry differs between S. cerevisiae and C. albicans, the specific role of Put3 appears fundamentally conserved. IMPORTANCE Candida albicans poses a significant threat to the lives of immunocompromised people. Historically, knowledge has been drawn from studies on Saccharomyces cerevisiae to understand the pathogen, and many Candida albicans genes are named after their S. cerevisiae orthologs. Direct studies on the pathogen have, however, revealed differences in the roles of some orthologous proteins in the two yeasts. We show that the Put3 transcription factor allows the pathogen to completely degrade proline to usable nitrogen and carbon by evading regulatory restrictions imposed on its S. cerevisiae ortholog, which mandates conditional use of proline only as a nitrogen source in the baker’s yeast. The ability of Candida albicans to freely obtain nutrients from multiple sources may help it thrive as a commensal and opportunistic pathogen.

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Transcriptional Regulation of CLN3Expression by Glucose in Saccharomyces cerevisiae

Journal of Bacteriology ◽

10.1128/jb.180.17.4508-4515.1998 ◽

1998 ◽

Vol 180 (17) ◽

pp. 4508-4515 ◽

Cited By ~ 32

Author(s):

Fereshteh Parviz ◽

Duane D. Hall ◽

David D. Markwardt ◽

Warren Heideman

Keyword(s):

Saccharomyces Cerevisiae ◽

Transcriptional Activation ◽

Mitotic Cycle ◽

Specific Interaction ◽

Point Mutations ◽

Yeast Cells ◽

Mrna Levels ◽

Glucose Medium ◽

Constant Size ◽

Promoter Mutations

ABSTRACT In Saccharomyces cerevisiae, the transition from the G1 phase of the mitotic cycle into S phase is controlled by a set of G1 cyclins that regulate the activity of the protein kinase encoded by CDC28. Yeast cells regulate progress through the G1/S boundary in response to nutrients, moving quickly through G1 in glucose medium and more slowly in poorer medium. We have examined connections between glucose and the level of the message encoding Cln3, a G1cyclin. We found that glucose positively regulates CLN3mRNA levels through a set of repeated AAGAAAAA (A2GA5) elements within theCLN3 promoter. Mutations in these sequences reduce both transcriptional activation and specific interaction betweenCLN3 promoter elements and proteins in yeast extracts. Creation of five point mutations, replacing the G’s within these repeats with T’s, in the CLN3 promoter substantially reduces CLN3 expression in glucose medium and inhibits the ability of the cells to maintain a constant size when shifted into glucose.

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Adenovirus transcriptional regulatory regions are conserved in mammalian cells and Saccharomyces cerevisiae

Molecular and Cellular Biology ◽

10.1128/mcb.8.9.3717-3725.1988 ◽

1988 ◽

Vol 8 (9) ◽

pp. 3717-3725

Author(s):

M Kornuc ◽

R Altman ◽

D Harrich ◽

J Garcia ◽

J Chao ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Transcription Factor ◽

Transcriptional Regulation ◽

Binding Sites ◽

Mammalian Cells ◽

Yeast Cells ◽

Binding Domains ◽

Cell Extracts ◽

Dnase I Footprinting ◽

Transactivator Protein

The adenovirus early region 3 (E3) promoter is an early viral promoter which is strongly induced by the adenovirus transactivator protein E1A. DNase I footprinting with HeLa cell extracts has identified four factor-binding domains which appear to be involved in basal and E1A-induced transcriptional regulation. These binding domains may bind TATA region-binding factors (site I), the CREB/ATF protein (site II), the AP-1 protein (site III), and nuclear factor I/CTF (site IV). Recently, it has been shown that the DNA-binding domain of transcription factor AP-1 has homology with the yeast transcription factor GCN4 and that the yeast transactivator protein GAL4 is able to stimulate transcription in HeLa cells from promoters containing GAL4-binding sites. These results suggest an evolutionary conservation of both transcription factors and the mechanisms responsible for transcriptional activation in Saccharomyces cerevisiae and higher eucaryotic organisms. To determine whether similar patterns of transcriptional regulation were seen with the E3 promoter in HeLa and yeast cells, the E3 promoter fused to the chloramphenicol acetyltransferase (cat) gene was cloned into a high-copy-number plasmid and stably introduced into yeast cells. S1 analysis revealed that similar E3 promoter mRNA start sites were found in yeast and HeLa cells. DNase I footprinting with partially purified yeast extracts revealed that four regions of the E3 promoter were protected. Several of these regions were similar to binding sites determined by using HeLa cell extracts. Oligonucleotide mutagenesis of these binding domains indicated their importance in the transcriptional regulation of the E3 promoter in yeast cells. These results suggest that similar cellular transcription factor-binding sites may be involved in the regulation of promoters in both yeast and mammalian cells.

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Pho85 Kinase, a Cyclin-Dependent Kinase, Regulates Nuclear Accumulation of the Rim101 Transcription Factor in the Stress Response of Saccharomyces cerevisiae

Eukaryotic Cell ◽

10.1128/ec.00247-09 ◽

2010 ◽

Vol 9 (6) ◽

pp. 943-951 ◽

Cited By ~ 13

Author(s):

Masafumi Nishizawa ◽

Mirai Tanigawa ◽

Michio Hayashi ◽

Tatsuya Maeda ◽

Yoshiaki Yazaki ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Transcription Factor ◽

Cellular Response ◽

Proteolytic Processing ◽

Yeast Cells ◽

Nuclear Accumulation ◽

Alkaline Stress ◽

Content Type ◽

Its Gene ◽

Alkaline Conditions

ABSTRACT The budding yeast Saccharomyces cerevisiae alters its gene expression profile in response to changing environmental conditions. The Pho85 kinase, one of the yeast cyclin-dependent kinases (CDK), is known to play an important role in the cellular response to alterations in parameters such as nutrient levels and salinity. Several genes whose expression is regulated, either directly or indirectly, by the Rim101 transcription factor become constitutively activated when Pho85 function is absent,. Because Rim101 is responsible for adaptation to alkaline conditions, this observation suggests an interaction between Pho85 and Rim101 in the response to alkaline stress. We have found that Pho85 affects neither RIM101 transcription, the proteolytic processing that is required for Rim101 activation, nor Rim101 stability. Rather, Pho85 regulates the nuclear accumulation of active Rim101, possibly via phosphorylation. Additionally, we report that Pho85 and the transcription factor Pho4 are necessary for adaptation to alkaline conditions and that PTK2 activation by Pho4 is involved in this process. These findings illustrate novel roles for the regulators of the PHO system when yeast cells cope with various environmental stresses potentially threatening their survival.

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Transcriptional regulation of the transforming growth factor beta 1 promoter by v-src gene products is mediated through the AP-1 complex.

Molecular and Cellular Biology ◽

10.1128/mcb.10.9.4978 ◽

1990 ◽

Vol 10 (9) ◽

pp. 4978-4983 ◽

Cited By ~ 73

Author(s):

M C Birchenall-Roberts ◽

F W Ruscetti ◽

J Kasper ◽

H D Lee ◽

R Friedman ◽

...

Keyword(s):

Transcriptional Regulation ◽

Growth Factor ◽

Transforming Growth Factor Beta ◽

Transcriptional Activation ◽

Transforming Growth Factor ◽

Mrna Levels ◽

Tgf Beta ◽

Precursor Cell Line ◽

Src Gene ◽

Growth Factor Beta

Growth factor-independent 32D-src and 32D-abl cell lines, established by infecting the interleukin-3-dependent myeloid precursor cell line (32D-123) with retroviruses containing the src or abl oncogene, were used to study transcriptional regulation of transforming growth factor beta 1 (TGF-beta 1) mRNA. Analysis of different TGF-beta 1 promoter constructs regulated by pp60v-src indicated that sequences responsive to high levels of src induction contain binding sites for AP-1. Both src and serum induced expression of the c-fos and c-jun genes in myeloid cells, resulting in transcriptional activation of the TGF-beta 1 gene. We found that serum treatment increased TGF-beta 1 mRNA levels in 32D-123 cells and that the v-Src protein could replace the serum requirement by stimulating binding to the AP-1 complex of the TGF-beta 1 promoter, thereby mediating the induction of TGF-beta 1 transcription.

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