25 shared publications
Department of Biology, Concordia University, Montreal, Quebec, Canada
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(2006 - 2017)
(2006 - 2017)
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Article 0 Reads 3 Citations The Human Gut Microbial Metabolome Modulates Fungal Growth via the TOR Signaling Pathway Published: 13 December 2017
mSphere, doi: 10.1128/msphere.00555-17
Candida albicans is well known as a major human fungal pathogen, but it is also a permanent resident of healthy gastrointestinal tracts. Recent studies have shown that the human gut microbial metabolome represents an interesting source of bioactive molecules with a significant degree of chemical diversity. Some of these bioactive molecules may have useful antivirulence activities. For instance, intestinal bacterial species belonging to the Lachnospiraceae family were found to secrete molecules that attenuate Salmonella pathogenicity and repress the expression of virulence genes. Here, we have investigated whether the microbial gut metabolome (GM) contains molecules that might promote the commensal lifestyle and/or inhibit the expression of virulence of C. albicans in the intestine. We found that metabolites from human feces inhibited the growth of C. albicans and other opportunistic yeasts. A genetic screen in C. albicans suggested that TOR is the molecular target of the antifungal molecule(s) of the GM. In addition, we found that the GM metabolites inhibit both C. albicans hyphal growth and the invasion of human enterocytes. The antigrowth and antivirulence activities were partially recapitulated by secretions from Roseburia spp. and Bacteroides ovatus strains, respectively. This study demonstrates that the antimicrobial activity of the GM can be extended to a eukaryotic pathogen, C. albicans , illuminating the antagonistic interkingdom interactions between a fungus and intestinal commensal bacteria. IMPORTANCE Candida albicans is a natural component of the human microbiota but also an opportunistic pathogen that causes life-threatening infections. The human gastrointestinal tract is the main reservoir of C. albicans , from where systemic infections originate as a consequence of the disruption of the intestinal mucosal barrier. Recent studies provided convincing evidence that overgrowth of C. albicans and other related species in the gut is predominantly associated with chronic intestinal inflammatory bowel diseases. Here, we showed, for the first time, the antagonistic interkingdom interactions between C. albicans and common intestinal commensal bacteria. From a therapeutic perspective, administering a defined bacterial community, such as the one described here with anti- Candida activity, could provide potential therapeutic protection against gastrointestinal inflammatory diseases.
Article 0 Reads 9 Citations Rewiring of the Ppr1 Zinc Cluster Transcription Factor from Purine Catabolism to Pyrimidine Biogenesis in the Saccharomy... Published: 01 July 2016
Current Biology, doi: 10.1016/j.cub.2016.04.064
•Ppr1 regulates purine catabolism in C. albicans•Ppr1 rewired to regulate pyrimidine biosynthesis in S. cerevisiae•Ppr1 binds the DNA motif CGG(N6)CCG in C. albicans and S. cerevisiae•ppr1 null mutant C. albicans strains cannot utilize allantoin as a nitrogen source Metabolic pathways are largely conserved in eukaryotes, but the transcriptional regulation of these pathways can sometimes vary between species; this has been termed “rewiring.” Recently, it has been established that in the Saccharomyces lineage starting from Naumovozyma castellii, genes involved in allantoin breakdown have been genomically relocated to form the DAL cluster. The formation of the DAL cluster occurred along with the loss of urate permease (UAP) and urate oxidase (UOX), reducing the requirement for oxygen and bypassing the candidate Ppr1 inducer, uric acid. In Saccharomyces cerevisiae, this allantoin catabolism cluster is regulated by the transcription factor Dal82, which is not present in many of the pre-rearrangement fungal species. We have used ChIP-chip analysis, transcriptional profiling of an activated Ppr1 protein, bioinformatics, and nitrogen utilization studies to establish that in Candida albicans the zinc cluster transcription factor Ppr1 controls this allantoin catabolism regulon. Intriguingly, in S. cerevisiae, the Ppr1 ortholog binds the same DNA motif (CGG(N6)CCG) as in C. albicans but serves as a regulator of pyrimidine biosynthesis. This transcription factor rewiring appears to have taken place at the same phylogenetic step as the formation of the rearranged DAL cluster. This transfer of the control of allantoin degradation from Ppr1 to Dal82, together with the repositioning of Ppr1 to the regulation of pyrimidine biosynthesis, may have resulted from a switch to a metabolism that could exploit hypoxic conditions in the lineage leading to N. castellii and S. cerevisiae. IntroductionJump to SectionIntroductionResults Bioinformatic Analysis of Ppr1 Function in C. albicans Uracil Biosynthesis Direct Identification of C. albicans Ppr1 Target Genes Using ChIP-Chip Ppr1 DNA Binding Sequence in C. albicans Transcriptional Profiling Experiments Using a Ppr1 Gain-of-Function Mutant Allantoin Utilization Ppr1 Regulation of Other FunctionsDiscussionExperimental Procedures Strains, Media, Plasmids, and Transformation Immunoprecipitation ChIP-Chip Transcriptional Profiling Experiments Bioinformatics Allantoin Utilization AssayAuthor ContributionsAcknowledgmentsAccession NumbersSupplemental InformationReferencesThe regulation of gene expression is an important factor in the development of organisms, the evolution of species, and cellular adaptation to environmental changes. Although cells typically have conserved metabolic machinery, the regulation of genes encoding this machinery can vary, giving rise in part to the differences in phenotype that are observed among species [1xEvolutionary tinkering with conserved components of a transcriptional regulatory network. Lavoie, H., Hogues, H., Mallick, J., Sellam, A., Nantel, A., and Whiteway, M. PLoS Biol. 2010; 8: e1000329Crossref | PubMed | Scopus (82)See all References1]. Key components of eukaryotic gene expression control are the transcription factors (TFs), which act as transcriptional activators or repressors through binding to specific DNA sequences at the promoter regions of genes. These TFs fall into families, such as the basic helix-loop-helix (bHLH) class [2xThe basic helix-loop-helix protein family: comparative genomics and phylogenetic analysis. Ledent, V. and Vervoort, M. Genome Res. 2001; 11: 754–770Crossref | PubMed | Scopus (198)See all References2], zinc finger TFs [3xZinc finger proteins: new insights into structural and functional diversity. Laity, J.H., Lee, B.M., and Wright, P.E. Curr. Opin. Struct. Biol. 2001; 11: 39–46Crossref | PubMed | Scopus (605)See all References3], homeobox family [4xA potential role of homeobox transcription factors in osteoarthritis. Pelttari, K., Barbero, A., and Martin, I. Ann. Transl. Med. 2015; 17: 254See all References4], and leucine zipper TFs [5xThe leucine zipper domains of the transcription factors GCN4 and c-Jun have ribonuclease activity. Nikolaev, Y., Deillon, C., Hoffmann, S.R., Bigler, L., Friess, S., Zenobi, R., Pervushin, K., Hunziker, P., and Gutte, B. PLoS ONE. 2010; 5: e10765Crossref | PubMed | Scopus (11)See all References5].The zinc cluster TFs (ZCFs) are a subclass of the zinc finger proteins found exclusively in fungi. These ZCFs contain the conserved structural motif CX2CX6CX5–12CX2CX6–8C (where C represents cysteine, and X is any amino acid) [6xA fungal family of transcriptional regulators: the zinc cluster proteins. MacPherson, S., Larochelle, M., and Turcotte, B. Microbiol. Mol. Biol. Rev. 2006; 70: 583–604Crossref | PubMed | Scopus (236)See all References, 7xAnalysis of a fungus-specific transcription factor family, the Candida albicans zinc cluster proteins, by artificial activation. Schillig, R. and Morschhäuser, J. Mol. Microbiol. 2013; 89: 1003–1017Crossref | PubMed | Scopus (15)See all References, 8xThe zinc cluster transcription factor Ahr1p directs Mcm1p regulation of Candida albicans adhesion. Askew, C., Sellam, A., Epp, E., Mallick, J., Hogues, H., Mullick, A., Nantel, A., and Whiteway, M. Mol. Microbiol. 2011; 79: 940–953Crossref | PubMed | Scopus (21)See all References, 9xGAL4 transcription factor is not a “zinc finger” but forms a Zn(II)2Cys6 binuclear cluster. Pan, T. and Coleman, J.E. Proc. Natl. Acad. Sci. USA. 1990; 87: 2077–2081Crossref | PubMedSee all References, 10xFunctional dissection and sequence of yeast HAP1 activator. Pfeifer, K., Kim, K.S., Kogan, S., and Guarente, L. Cell. 1989; 56: 291–301Abstract | Full Text PDF | PubMed | Scopus (190)See all References]. This cysteine-rich sequence is generally located at the N terminus of the TF, and consists of six cysteines with typically a lysine residue between the second and third cysteines [11xA linker region of the yeast zinc cluster protein Leu3p specifies binding to everted repeat DNA. Mamane, Y., Hellauer, K., Rochon, M.H., and Turcotte, B. J. Biol. Chem. 1998; 273: 18556–18561Crossref | PubMed | Scopus (11)See all References, 12xCrystal structure of a PPR1-DNA complex: DNA recognition by proteins containing a Zn2Cys6 binuclear cluster. Marmorstein, R. and Harrison, S.C. Genes Dev. 1994; 8: 2504–2512Crossref | PubMedSee all References, 13xDNA recognition by GAL4: structure of a protein-DNA complex. Marmorstein, R., Carey, M., Ptashne, M., and Harrison, S.C. Nature. 1992; 356: 408–414Crossref | PubMed | Scopus (0)See all References]. The entire DNA binding domain of the transcription factor consists of the zinc finger, a linker region, and a dimerization domain. Typically, ZCFs bind as homodimers, using their zinc finger motif to generate hydrogen-bonding major-groove interactions to CGG nucleotide triplets that are oriented in everted, inverted, or direct repeats [6xA fungal family of transcriptional regulators: the zinc cluster proteins. MacPherson, S., Larochelle, M., and Turcotte, B. Microbiol. Mol. Biol. Rev. 2006; 70: 583–604Crossref | PubMed | Scopus (236)See all References, 12xCrystal structure of a PPR1-DNA complex: DNA recognition by proteins containing a Zn2Cys6 binuclear cluster. Marmorstein, R. and Harrison, S.C. Genes Dev. 1994; 8: 2504–2512Crossref | PubMedSee all References]. The spacing of the CGG sequences is important for binding specificity, which is controlled by the number of generally non-conserved amino acids specifying both the ZCF’s linker length and its folding [6xA fungal family of transcriptional regulators: the zinc cluster proteins. MacPherson, S., Larochelle, M., and Turcotte, B. Microbiol. Mol. Biol. Rev. 2006; 70: 583–604Crossref | PubMed | Scopus (236)See all References, 11xA linker region of the yeast zinc cluster protein Leu3p specifies binding to everted repeat DNA. Mamane, Y., Hellauer, K., Rochon, M.H., and Turcotte, B. J. Biol. Chem. 1998; 273: 18556–18561Crossref | PubMed | Scopus (11)See all References, 14xMolecular architecture of a Leu3p-DNA complex in solution: a biochemical approach. Remboutsika, E. and Kohlhaw, G.B. Mol. Cell. Biol. 1994; 14: 5547–5557Crossref | PubMedSee all References, 15xDNA sequence preferences of GAL4 and PPR1: how a subset of Zn2Cys6 binuclear cluster proteins recognizes DNA. Liang, S.D., Marmorstein, R., Harrison, S.C., and Ptashne, M. Mol. Cell. Biol. 1996; 16: 3773–3780Crossref | PubMedSee all References]. The conserved cysteines serve to complex two zinc ions that are important in facilitating the DNA binding of the protein [10xFunctional dissection and sequence of yeast HAP1 activator. Pfeifer, K., Kim, K.S., Kogan, S., and Guarente, L. Cell. 1989; 56: 291–301Abstract | Full Text PDF | PubMed | Scopus (190)See all References, 13xDNA recognition by GAL4: structure of a protein-DNA complex. Marmorstein, R., Carey, M., Ptashne, M., and Harrison, S.C. Nature. 1992; 356: 408–414Crossref | PubMed | Scopus (0)See all References].These zinc cluster transcription factors are major components of fungal-specific regulatory circuits, and are known to control a multitude of processes as varied as metabolism, meiosis, virulence, and antifungal drug resistance [6xA fungal family of transcriptional regulators: the zinc cluster proteins. MacPherson, S., Larochelle, M., and Turcotte, B. Microbiol. Mol. Biol. Rev. 2006; 70: 583–604Crossref | PubMed | Scopus (236)See all References, 7xAnalysis of a fungus-specific transcription factor family, the Candida albicans zinc cluster proteins, by artificial activation. Schillig, R. and Morschhäuser, J. Mol. Microbiol. 2013; 89: 1003–1017Crossref | PubMed | Scopus (15)See all References, 16xIn vivo systematic analysis of Candida albicans Zn2-Cys6 transcription factors mutants for mice organ colonization. Vandeputte, P., Ischer, F., Sanglard, D., and Coste, A.T. PLoS ONE. 2011; 6: e26962Crossref | PubMed | Scopus (15)See all References]. A cl
Article 0 Reads 13 Citations A Functional Portrait of Med7 and the Mediator Complex in Candida albicans Published: 06 November 2014
PLoS Genetics, doi: 10.1371/journal.pgen.1004770
Mediator is a multi-subunit protein complex that regulates gene expression in eukaryotes by integrating physiological and developmental signals and transmitting them to the general RNA polymerase II machinery. We examined, in the fungal pathogen Candida albicans, a set of conditional alleles of genes encoding Mediator subunits of the head, middle, and tail modules that were found to be essential in the related ascomycete Saccharomyces cerevisiae. Intriguingly, while the Med4, 8, 10, 11, 14, 17, 21 and 22 subunits were essential in both fungi, the structurally highly conserved Med7 subunit was apparently non-essential in C. albicans. While loss of CaMed7 did not lead to loss of viability under normal growth conditions, it dramatically influenced the pathogen's ability to grow in different carbon sources, to form hyphae and biofilms, and to colonize the gastrointestinal tracts of mice. We used epitope tagging and location profiling of the Med7 subunit to examine the distribution of the DNA sites bound by Mediator during growth in either the yeast or the hyphal form, two distinct morphologies characterized by different transcription profiles. We observed a core set of 200 genes bound by Med7 under both conditions; this core set is expanded moderately during yeast growth, but is expanded considerably during hyphal growth, supporting the idea that Mediator binding correlates with changes in transcriptional activity and that this binding is condition specific. Med7 bound not only in the promoter regions of active genes but also within coding regions and at the 3′ ends of genes. By combining genome-wide location profiling, expression analyses and phenotyping, we have identified different Med7p-influenced regulons including genes related to glycolysis and the Filamentous Growth Regulator family. In the absence of Med7, the ribosomal regulon is de-repressed, suggesting Med7 is involved in central aspects of growth control.
Article 0 Reads 80 Citations Global Gene Deletion Analysis Exploring Yeast Filamentous Growth Published: 13 September 2012
Science, doi: 10.1126/science.1224339
Article 0 Reads 16 Citations A novel role for the transcription factor Cwt1p as a negative regulator of nitrosative stress in Candida albicans. Published: 29 August 2012
PLOS ONE, doi: 10.1371/journal.pone.0043956
The ability of Candida albicans to survive in the presence of nitrosative stress during the initial contact with the host immune system is crucial for its ability to colonize mammalian hosts. Thus, this fungus must activate robust mechanisms to neutralize and repair nitrosative-induced damage. Until now, very little was known regarding the regulatory circuits associated with reactive nitrogen species detoxification in fungi. To gain insight into the transcriptional regulatory networks controlling nitrosative stress response (NRS) in C. albicans a compilation of transcriptional regulator-defective mutants were screened. This led to the identification of Cwt1p as a negative regulator of NSR. By combining genome-wide location and expression analyses, we have characterized the Cwt1p regulon and demonstrated that Cwt1p is directly required for proper repression of the flavohemoglobin Yhb1p, a key NO-detoxification enzyme. Furthermore, Cwt1p operates both by activating and repressing genes of specific functions solicited upon NSR. Additionally, we used Gene Set Enrichment Analysis to reinvestigate the C. albicans NSR-transcriptome and demonstrate a significant similarity with the transcriptional profiles of C. albicans interacting with phagocytic host-cells. In summary, we have characterized a novel negative regulator of NSR and bring new insights into the transcriptional regulatory network governing fungal NSR.
Article 0 Reads 38 Citations Pho85, Pcl1, and Hms1 Signaling Governs Candida albicans Morphogenesis Induced by High Temperature or Hsp90 Compromise Published: 01 March 2012
Current Biology, doi: 10.1016/j.cub.2012.01.062
Temperature exerts powerful control over development and virulence of diverse pathogens. In the leading human fungal pathogen, Candida albicans, temperature governs morphogenesis, a key virulence trait. Many cues that induce the yeast to filament transition are contingent on a minimum of 37°C, whereas further elevation to 39°C serves as an independent inducer. The molecular chaperone Hsp90 is a key regulator of C. albicans temperature-dependent morphogenesis. Compromise of Hsp90 function genetically, pharmacologically, or by elevated temperature induces filamentation in a manner that depends on protein kinase A signaling but is independent of the terminal transcription factor, Efg1.