Alternative sulphur metabolism in the fungal pathogen Candida parapsilosis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
24 Oct 2024
24 Oct 2024
Historique:
received:
12
02
2024
accepted:
08
10
2024
medline:
25
10
2024
pubmed:
25
10
2024
entrez:
25
10
2024
Statut:
epublish
Résumé
Candida parapsilosis is an opportunistic fungal pathogen commonly isolated from the environment and associated with nosocomial infection outbreaks worldwide. We describe here the construction of a large collection of gene disruptions, greatly increasing the molecular tools available for probing gene function in C. parapsilosis. We use these to identify transcription factors associated with multiple metabolic pathways, and in particular to dissect the network regulating the assimilation of sulphur. We find that, unlike in other yeasts and filamentous fungi, the transcription factor Met4 is not the main regulator of methionine synthesis. In C. parapsilosis, assimilation of inorganic sulphur (sulphate) and synthesis of cysteine and methionine is regulated by Met28, a paralog of Met4, whereas Met4 regulates expression of a wide array of transporters and enzymes involved in the assimilation of organosulfur compounds. Analysis of transcription factor binding sites suggests that Met4 is recruited by the DNA-binding protein Met32, and Met28 is recruited by Cbf1. Despite having different target genes, Met4 and Met28 have partial functional overlap, possibly because Met4 can contribute to assimilation of inorganic sulphur in the absence of Met28.
Identifiants
pubmed: 39448588
doi: 10.1038/s41467-024-53442-8
pii: 10.1038/s41467-024-53442-8
doi:
Substances chimiques
Sulfur
70FD1KFU70
Fungal Proteins
0
Transcription Factors
0
Methionine
AE28F7PNPL
Cysteine
K848JZ4886
Sulfates
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9190Subventions
Organisme : Science Foundation Ireland (SFI)
ID : 19/FFP/6668
Informations de copyright
© 2024. The Author(s).
Références
Brown, G. D. et al. Hidden killers: human fungal infections. Sci. Transl. Med. 4, 165rv113 (2012).
doi: 10.1126/scitranslmed.3004404
Rauseo, A. M., Coler-Reilly, A., Larson, L. & Spec, A. Hope on the horizon: Novel fungal treatments in development. Open Forum Infect. Dis. 7, ofaa016 (2020).
pubmed: 32099843
pmcid: 7031074
doi: 10.1093/ofid/ofaa016
Tóth, R. et al. Candida parapsilosis: from genes to the bedside. Clin. Microbiol Rev. 32, e00111–e00118 (2019).
pubmed: 30814115
pmcid: 6431126
doi: 10.1128/CMR.00111-18
Bassetti, M. et al. Incidence and outcome of invasive candidiasis in intensive care units (ICUs) in Europe: results of the EUCANDICU project. Crit. Care 23, 219 (2019).
pubmed: 31200780
pmcid: 6567430
doi: 10.1186/s13054-019-2497-3
Santos, M. A. S., Gomes, A. C., Santos, M. C., Carreto, L. C. & Moura, G. R. The genetic code of the fungal CTG clade. C. R. Biol. 334, 607–611 (2011).
pubmed: 21819941
doi: 10.1016/j.crvi.2011.05.008
Perez, J. C. Fungi of the human gut microbiota: Roles and significance. Int J. Med. Microbiol. 311, 151490 (2021).
pubmed: 33676239
doi: 10.1016/j.ijmm.2021.151490
Dogen, A. et al. Candida parapsilosis in domestic laundry machines. Med. Mycol. 55, 813–819 (2017).
pubmed: 28204594
doi: 10.1093/mmy/myx008
Trofa, D., Gácser, A. & Nosanchuk, J. D. Candida parapsilosis, an Emerging Fungal Pathogen. Clin. Microbiol. Rev. 21, 606–625 (2008).
pubmed: 18854483
pmcid: 2570155
doi: 10.1128/CMR.00013-08
Daneshnia, F. et al. Determinants of fluconazole resistance and echinocandin tolerance in C. parapsilosis isolates causing a large clonal candidemia outbreak among COVID-19 patients in a Brazilian ICU. Emerg. Microbes Infect. 1–33 https://doi.org/10.1080/22221751.2022.2117093 (2022).
Thomaz, D. Y. et al. A Brazilian inter-hospital candidemia outbreak caused by fluconazole-resistant Candida parapsilosis in the COVID-19 era. J. Fungi 8, 100 (2022).
doi: 10.3390/jof8020100
Guo, W. et al. An outbreak of Candida parapsilosis fungemia among preterm infants. Genet Mol. Res. 14, 18259–18267 (2015).
pubmed: 26782473
doi: 10.4238/2015.December.23.13
Zhai, B. et al. High-resolution mycobiota analysis reveals dynamic intestinal translocation preceding invasive candidiasis. Nat. Med. 26, 59–64 (2020).
pubmed: 31907459
pmcid: 7005909
doi: 10.1038/s41591-019-0709-7
Rolling, T. et al. Haematopoietic cell transplantation outcomes are linked to intestinal mycobiota dynamics and an expansion of Candida parapsilosis complex species. Nat. Microbiol. 6, 1505–1515 (2021).
pubmed: 34764444
pmcid: 8939874
doi: 10.1038/s41564-021-00989-7
Hsu, P. C. et al. Plastic rewiring of Sef1 transcriptional networks and the potential of nonfunctional transcription factor binding in facilitating adaptive evolution. Mol. Biol. Evol. 38, 4732–4747 (2021).
pubmed: 34175931
pmcid: 8557406
doi: 10.1093/molbev/msab192
Tsong, A. E., Miller, M. G., Raisner, R. M. & Johnson, A. D. Evolution of a combinatorial transcriptional circuit: a case study in yeasts. Cell 115, 389–399 (2003).
pubmed: 14622594
doi: 10.1016/S0092-8674(03)00885-7
Nocedal, I., Mancera, E. & Johnson, A. D. Gene regulatory network plasticity predates a switch in function of a conserved transcription regulator. Elife 6, e23250 (2017).
pubmed: 28327289
pmcid: 5391208
doi: 10.7554/eLife.23250
Alves, R. et al. Adapting to survive: How Candida overcomes host-imposed constraints during human colonization. PLoS Pathog. 16, e1008478 (2020).
pubmed: 32437438
pmcid: 7241708
doi: 10.1371/journal.ppat.1008478
Ding, C. et al. Conserved and divergent roles of Bcr1 and CFEM proteins in Candida parapsilosis and Candida albicans. PLoS ONE 6, e28151 (2011).
pubmed: 22145027
pmcid: 3228736
doi: 10.1371/journal.pone.0028151
Holland, L. M. et al. Comparative phenotypic analysis of the major fungal pathogens Candida parapsilosis and Candida albicans. PLoS Pathog. 10, e1004365 (2014).
pubmed: 25233198
pmcid: 4169492
doi: 10.1371/journal.ppat.1004365
Mancera, E. et al. Evolution of the complex transcription network controlling biofilm formation in Candida species. ELife 10, e64682 (2021).
pubmed: 33825680
pmcid: 8075579
doi: 10.7554/eLife.64682
Perez, J. C. The interplay between gut bacteria and the yeast Candida albicans. Gut Microbes 13, 1979877 (2021).
pubmed: 34586038
pmcid: 8489915
doi: 10.1080/19490976.2021.1979877
Brunke, S., Mogavero, S., Kasper, L. & Hube, B. Virulence factors in fungal pathogens of man. Curr. Opin. Microbiol. 32, 89–95 (2016).
pubmed: 27257746
doi: 10.1016/j.mib.2016.05.010
Padder, S. A., Ramzan, A., Tahir, I., Rehman, R. U. & Shah, A. H. Metabolic flexibility and extensive adaptability governing multiple drug resistance and enhanced virulence in Candida albicans. Crit. Rev. Microbiol. 48, 1–20 (2022).
pubmed: 34213983
doi: 10.1080/1040841X.2021.1935447
Amich, J., Krappmann, S. & Bachhawat, A. K. Editorial: Sulphur metabolism of Fungi - implications for virulence and opportunities for therapy. Front. Microbiol. 11, 583689 (2020).
pubmed: 33117323
pmcid: 7578252
doi: 10.3389/fmicb.2020.583689
Ljungdahl, P. O. & Daignan-Fornier, B. Regulation of amino acid, nucleotide, and phosphate metabolism in Saccharomyces cerevisiae. Genetics 190, 885–929 (2012).
pubmed: 22419079
pmcid: 3296254
doi: 10.1534/genetics.111.133306
Thomas, D. & Surdin-Kerjan, Y. Metabolism of sulfur amino acids in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 61, 503–532 (1997).
pubmed: 9409150
pmcid: 232622
Lee, T. A. et al. Dissection of combinatorial control by the Met4 transcriptional complex. Mol. Biol. Cell 21, 456–469 (2010).
pubmed: 19940020
pmcid: 2814790
doi: 10.1091/mbc.e09-05-0420
Hebert, A., Casaregola, S. & Beckerich, J. M. Biodiversity in sulfur metabolism in hemiascomycetous yeasts. FEMS Yeast Res. 11, 366–378 (2011).
pubmed: 21348937
doi: 10.1111/j.1567-1364.2011.00725.x
Pacheco, D. et al. Transcription activation domains of the yeast factors Met4 and Ino2: tandem activation domains with properties similar to the yeast Gcn4 activator. Mol. Cell Biol. 38, e00038–18 (2018).
pubmed: 29507182
pmcid: 5954196
doi: 10.1128/MCB.00038-18
Kuras, L., Barbey, R. & Thomas, D. Assembly of a bZIP-bHLH transcription activation complex: formation of the yeast Cbf1-Met4-Met28 complex is regulated through Met28 stimulation of Cbf1 DNA binding. Embo j. 16, 2441–2451 (1997).
pubmed: 9171357
pmcid: 1169844
doi: 10.1093/emboj/16.9.2441
Blaiseau, P. L. & Thomas, D. Multiple transcriptional activation complexes tether the yeast activator Met4 to DNA. Embo j. 17, 6327–6336 (1998).
pubmed: 9799240
pmcid: 1170957
doi: 10.1093/emboj/17.21.6327
Shrivastava, M. et al. Modulation of the complex regulatory network for methionine biosynthesis in fungi. Genetics 217, iyaa049 (2021).
pubmed: 33724418
pmcid: 8045735
doi: 10.1093/genetics/iyaa049
Natorff, R., Sieńko, M., Brzywczy, J. & Paszewski, A. The Aspergillus nidulans metR gene encodes a bZIP protein which activates transcription of sulphur metabolism genes. Mol. Microbiol. 49, 1081–1094 (2003).
pubmed: 12890030
doi: 10.1046/j.1365-2958.2003.03617.x
Huberman, L. B. et al. Aspects of the Neurospora crassa sulfur starvation response are revealed by transcriptional profiling and DNA affinity purification sequencing. mSphere 6, e0056421 (2021). 10.1128/msphere.00564-00521.
pubmed: 34523983
doi: 10.1128/mSphere.00564-21
Lombardi, L., Oliveira-Pacheco, J. & Butler, G. Plasmid-based CRISPR-Cas9 gene editing in multiple Candida Species. mSphere 4, e00125–19 (2019).
pubmed: 30867327
pmcid: 6416365
doi: 10.1128/mSphere.00125-19
Hoot, S. J., Oliver, B. G. & White, T. C. Candida albicans UPC2 is transcriptionally induced in response to antifungal drugs and anaerobicity through Upc2p-dependent and -independent mechanisms. Microbiology 154, 2748–2756 (2008).
pubmed: 18757808
doi: 10.1099/mic.0.2008/017475-0
Homann, O. R., Dea, J., Noble, S. M. & Johnson, A. D. A phenotypic profile of the Candida albicans regulatory network. PLoS Genet. 5, e1000783 (2009).
pubmed: 20041210
pmcid: 2790342
doi: 10.1371/journal.pgen.1000783
Enjalbert, B. et al. Role of the Hog1 stress-activated protein kinase in the global transcriptional response to stress in the fungal pathogen Candida albicans. Mol. Biol. Cell 17, 1018–1032 (2006).
pubmed: 16339080
pmcid: 1356608
doi: 10.1091/mbc.e05-06-0501
Alonso-Monge, R. et al. The Hog1 mitogen-activated protein kinase is essential in the oxidative stress response and chlamydospore formation in Candida albicans. Eukaryot. Cell 2, 351–361 (2003).
pubmed: 12684384
pmcid: 154845
doi: 10.1128/EC.2.2.351-361.2003
Arana, D. M., Nombela, C., Alonso-Monge, R. & Pla, J. The Pbs2 MAP kinase kinase is essential for the oxidative-stress response in the fungal pathogen Candida albicans. Microbiology 151, 1033–1049 (2005).
pubmed: 15817773
doi: 10.1099/mic.0.27723-0
Jiang, L. et al. Cadmium-induced activation of high osmolarity glycerol pathway through its Sln1 branch is dependent on the MAP kinase kinase kinase Ssk2, but not its paralog Ssk22, in budding yeast. FEMS Yeast Res. 14, 1263–1272 (2014).
pubmed: 25331360
doi: 10.1111/1567-1364.12220
Kitanovic, A. et al. Phosphatidylinositol 3-kinase VPS34 of Candida albicans is involved in filamentous growth, secretion of aspartic proteases, and intracellular detoxification. FEMS Yeast Res. 5, 431–439 (2005).
pubmed: 15691748
doi: 10.1016/j.femsyr.2004.11.005
Blankenship, J. R., Fanning, S., Hamaker, J. J. & Mitchell, A. P. An extensive circuitry for cell wall regulation in Candida albicans. PLoS Pathog. 6, e1000752 (2010).
pubmed: 20140194
pmcid: 2816693
doi: 10.1371/journal.ppat.1000752
Rai, M. N., Sharma, V., Balusu, S. & Kaur, R. An essential role for phosphatidylinositol 3-kinase in the inhibition of phagosomal maturation, intracellular survival and virulence in Candida glabrata. Cell Microbiol. 17, 269–287 (2015).
pubmed: 25223215
doi: 10.1111/cmi.12364
Turner, S. A., Ma, Q., Ola, M., Martinez de San Vicente, K. & Butler, G. Dal81 Regulates expression of arginine metabolism genes in Candida parapsilosis. mSphere 3, e00028–18 (2018).
pubmed: 29564399
pmcid: 5853489
doi: 10.1128/mSphere.00028-18
Liao, W. L., Ramón, A. M. & Fonzi, W. A. GLN3 encodes a global regulator of nitrogen metabolism and virulence of C. albicans. Fungal Genet. Biol. 45, 514–526 (2008).
pubmed: 17950010
doi: 10.1016/j.fgb.2007.08.006
Tebung, W. A., Choudhury, B. I., Tebbji, F., Morschhäuser, J. & Whiteway, M. Rewiring of the Ppr1 zinc cluster transcription factor from purine catabolism to pyrimidine biogenesis in the saccharomycetaceae. Curr. Biol. 26, 1677–1687 (2016).
pubmed: 27321996
doi: 10.1016/j.cub.2016.04.064
Ghosh, S., Kebaara, B. W., Atkin, A. L. & Nickerson, K. W. Regulation of aromatic alcohol production in Candida albicans. Appl. Environ. Microbiol. 74, 7211–7218 (2008).
pubmed: 18836025
pmcid: 2592902
doi: 10.1128/AEM.01614-08
Masselot, M. & De Robichon-Szulmajster, H. Methionine biosynthesis in Saccharomyces cerevisiae. I. Genetical analysis of auxotrophic mutants. Mol. Gen. Genet. 139, 121–132 (1975).
pubmed: 1101032
doi: 10.1007/BF00264692
Yoo, S. J., Sohn, M. J., Jeong, D. M. & Kang, H. A. Short bZIP homologue of sulfur regulator Met4 from Ogataea parapolymorpha does not depend on DNA-binding cofactors for activating genes in sulfur starvation. Environ. Microbiol. 22, 310–328 (2020).
pubmed: 31680403
doi: 10.1111/1462-2920.14849
Kuras, L. & Thomas, D. Functional analysis of Met4, a yeast transcriptional activator responsive to S-adenosylmethionine. Mol. Cell Biol. 15, 208–216 (1995).
pubmed: 7799928
pmcid: 231936
doi: 10.1128/MCB.15.1.208
Byrne, K. P. & Wolfe, K. H. The Yeast Gene Order Browser: combining curated homology and syntenic context reveals gene fate in polyploid species. Genome Res. 15, 1456–1461 (2005).
pubmed: 16169922
pmcid: 1240090
doi: 10.1101/gr.3672305
Maguire, S. L. et al. Comparative genome analysis and gene finding in Candida species using CGOB. Mol. Biol. Evol. 30, 1281–1291 (2013).
pubmed: 23486613
pmcid: 3649674
doi: 10.1093/molbev/mst042
Gouy, M., Guindon, S. & Gascuel, O. SeaView version 4: A multiplatform graphical user interface for sequence alignment and phylogenetic tree building. Mol. Biol. Evol. 27, 221–224 (2010).
pubmed: 19854763
doi: 10.1093/molbev/msp259
Huang, M. Y., Woolford, C. A., May, G., McManus, C. J. & Mitchell, A. P. Circuit diversification in a biofilm regulatory network. PLOS Pathog. 15, e1007787 (2019).
pubmed: 31116789
pmcid: 6530872
doi: 10.1371/journal.ppat.1007787
Do, E. et al. Collaboration between antagonistic cell type regulators governs natural variation in the Candida albicans biofilm and hyphal gene expression network. mBio 13, e0193722 (2022).
pubmed: 35993746
doi: 10.1128/mbio.01937-22
Cravener, M. V. et al. Reinforcement amid genetic diversity in the Candida albicans biofilm regulatory network. PLoS Pathog. 19, e1011109 (2023).
pubmed: 36696432
pmcid: 9901766
doi: 10.1371/journal.ppat.1011109
Bergin, S. A. et al. Systematic analysis of copy number variations in the pathogenic yeast Candida parapsilosis identifies a gene amplification in RTA3 that is associated with drug resistance. mBio 0, e01777–01722 (2022).
Holt, S. et al. Major sulfonate transporter Soa1 in Saccharomyces cerevisiae and considerable substrate diversity in its fungal family. Nat. Commun. 8, 14247 (2017).
pubmed: 28165463
pmcid: 5303821
doi: 10.1038/ncomms14247
Isnard, A. D., Thomas, D. & Surdin-Kerjan, Y. The study of methionine uptake in Saccharomyces cerevisiae reveals a new family of amino acid permeases. J. Mol. Biol. 262, 473–484 (1996).
pubmed: 8893857
doi: 10.1006/jmbi.1996.0529
Linder, T. Genomics of alternative sulfur utilization in ascomycetous yeasts. Microbiology 158, 2585–2597 (2012).
pubmed: 22790398
doi: 10.1099/mic.0.060285-0
Linder, T. Assimilation of alternative sulfur sources in fungi. World J. Microbiol. Biotechnol. 34, 51 (2018).
pubmed: 29550883
pmcid: 5857272
doi: 10.1007/s11274-018-2435-6
Bailey, T. L., Johnson, J., Grant, C. E. & Noble, W. S. The MEME Suite. Nucleic Acids Res. 43, W39–W49 (2015).
pubmed: 25953851
pmcid: 4489269
doi: 10.1093/nar/gkv416
Thomas, P. D. et al. PANTHER: Making genome-scale phylogenetics accessible to all. Protein Sci. 31, 8–22 (2022).
pubmed: 34717010
doi: 10.1002/pro.4218
Lavoie, H. et al. Evolutionary tinkering with conserved components of a transcriptional regulatory network. PLOS Biol. 8, e1000329 (2010).
pubmed: 20231876
pmcid: 2834713
doi: 10.1371/journal.pbio.1000329
Schrevens, S. et al. Methionine is required for cAMP-PKA-mediated morphogenesis and virulence of Candida albicans. Mol. Microbiol. 108, 258–275 (2018).
pubmed: 29453849
doi: 10.1111/mmi.13933
Siggers, T., Duyzend, M. H., Reddy, J., Khan, S. & Bulyk, M. L. Non-DNA-binding cofactors enhance DNA-binding specificity of a transcriptional regulatory complex. Mol. Syst. Biol. 7, 555 (2011).
pubmed: 22146299
pmcid: 3737730
doi: 10.1038/msb.2011.89
Autry, A. R. & Fitzgerald, J. W. Sulfonate S: A major form of forest soil organic sulfur. Biol. Fertil. Soils 10, 50–56 (1990).
doi: 10.1007/BF00336124
Hall, C., Brachat, S. & Dietrich, F. S. Contribution of horizontal gene transfer to the evolution of Saccharomyces cerevisiae. Eukaryot. Cell 4, 1102–1115 (2005).
pubmed: 15947202
pmcid: 1151995
doi: 10.1128/EC.4.6.1102-1115.2005
Hogan, D. A., Auchtung, T. A. & Hausinger, R. P. Cloning and characterization of a sulfonate/alpha-ketoglutarate dioxygenase from saccharomyces cerevisiae. J. Bacteriol. 181, 5876–5879 (1999).
pubmed: 10482536
pmcid: 94115
doi: 10.1128/JB.181.18.5876-5879.1999
Teigen, L. M. et al. Dietary factors in sulfur metabolism and pathogenesis of Ulcerative Colitis. Nutrients 11, 931 (2019).
pubmed: 31027194
pmcid: 6521024
doi: 10.3390/nu11040931
Peng, D. & Tarleton, R. EuPaGDT: a web tool tailored to design CRISPR guide RNAs for eukaryotic pathogens. Micro. Genom. 1, e000033 (2015).
Lombardi, L. & Butler, G. Plasmid-based CRISPR-Cas9 editing in multiple Candida species. Methods Mol. Biol. 2542, 13–40 (2022).
pubmed: 36008654
doi: 10.1007/978-1-0716-2549-1_2
Cravener, M. V. & Mitchell, A. P. Candida albicans culture, cell harvesting, and total RNA extraction. Bio Protoc. 10, e3803 (2020).
pubmed: 33659457
pmcid: 7854013
doi: 10.21769/BioProtoc.3803
Guida, A. et al. Using RNA-seq to determine the transcriptional landscape and the hypoxic response of the pathogenic yeast Candida parapsilosis. BMC Genomics 12, 628 (2011).
pubmed: 22192698
pmcid: 3287387
doi: 10.1186/1471-2164-12-628
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
pubmed: 23104886
doi: 10.1093/bioinformatics/bts635
Kuhn, D. M., Chandra, J., Mukherjee, P. K. & Ghannoum, M. A. Comparison of biofilms formed by Candida albicans and Candida parapsilosis on bioprosthetic surfaces. Infect. Immun. 70, 878–888 (2002).
pubmed: 11796623
pmcid: 127692
doi: 10.1128/IAI.70.2.878-888.2002
Anders, S. & Huber, W. Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010).
pubmed: 20979621
pmcid: 3218662
doi: 10.1186/gb-2010-11-10-r106