Mrr1 Regulation of Methylglyoxal Catabolism and Methylglyoxal-induced Fluconazole Resistance in Candida Lusitaniae

Overview

Journal Mol Microbiol

Specialties Microbiology
Molecular Biology

Date 2020 Dec 15

PMID 33319423

Citations 10

Authors

Amy R Biermann

Elora G Demers

Deborah A Hogan

Affiliations

Soon will be listed here.

Abstract

Transcription factor Mrr1, best known for its regulation of Candida azole resistance genes such as MDR1, regulates other genes that are poorly characterized. Among the other Mrr1-regulated genes are putative methylglyoxal reductases. Methylglyoxal (MG) is a toxic metabolite that is elevated in diabetes, uremia, and sepsis, which are diseases that increase the risk for candidiasis, and MG serves as a regulatory signal in diverse organisms. Our studies in Clavispora lusitaniae, also known as Candida lusitaniae, showed that Mrr1 regulates expression of two paralogous MG reductases, MGD1 and MGD2, and that both participate in MG resistance and MG catabolism. Exogenous MG increased Mrr1-dependent expression of MGD1 and MGD2 as well as expression of MDR1, which encodes an efflux pump that exports fluconazole. MG improved growth in the presence of fluconazole and this was largely Mrr1-dependent with contributions from a secondary transcription factor, Cap1. Increased fluconazole resistance was also observed in mutants lacking Glo1, a Mrr1-independent MG catabolic enzyme. Isolates from other Candida species displayed heterogeneity in MG resistance and MG stimulation of azole resistance. We propose endogenous and host-derived MG can induce MDR1 and other Mrr1-regulated genes causing increased drug resistance, which may contribute to some instances of fungal treatment failure.

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References

Lapolla A, Flamini R, Lupo A, Arico N, Rugiu C, Reitano R . Evaluation of glyoxal and methylglyoxal levels in uremic patients under peritoneal dialysis. Ann N Y Acad Sci. 2005; 1043:217-24. DOI: 10.1196/annals.1333.027. View

Zuin A, Vivancos A, Sanso M, Takatsume Y, Ayte J, Inoue Y . The glycolytic metabolite methylglyoxal activates Pap1 and Sty1 stress responses in Schizosaccharomyces pombe. J Biol Chem. 2005; 280(44):36708-13. DOI: 10.1074/jbc.M508400200. View

Letunic I, Bork P . Interactive Tree Of Life (iTOL): an online tool for phylogenetic tree display and annotation. Bioinformatics. 2006; 23(1):127-8. DOI: 10.1093/bioinformatics/btl529. View

Maeta K, Izawa S, Okazaki S, Kuge S, Inoue Y . Activity of the Yap1 transcription factor in Saccharomyces cerevisiae is modulated by methylglyoxal, a metabolite derived from glycolysis. Mol Cell Biol. 2004; 24(19):8753-64. PMC: 516737. DOI: 10.1128/MCB.24.19.8753-8764.2004. View

Znaidi S, Weber S, Zin Al-Abdin O, Bomme P, Saidane S, Drouin S . Genomewide location analysis of Candida albicans Upc2p, a regulator of sterol metabolism and azole drug resistance. Eukaryot Cell. 2008; 7(5):836-47. PMC: 2394978. DOI: 10.1128/EC.00070-08. View

Lu J, Randell E, Han Y, Adeli K, Krahn J, Meng Q . Increased plasma methylglyoxal level, inflammation, and vascular endothelial dysfunction in diabetic nephropathy. Clin Biochem. 2010; 44(4):307-11. DOI: 10.1016/j.clinbiochem.2010.11.004. View

Li R, Kumar R, Tati S, Puri S, Edgerton M . Candida albicans flu1-mediated efflux of salivary histatin 5 reduces its cytosolic concentration and fungicidal activity. Antimicrob Agents Chemother. 2013; 57(4):1832-9. PMC: 3623299. DOI: 10.1128/AAC.02295-12. View

Yamauchi S, Kiyosawa N, Ando Y, Watanabe K, Niino N, Ito K . Hepatic transcriptome and proteome responses against diethyl maleate-induced glutathione depletion in the rat. Arch Toxicol. 2010; 85(9):1045-56. DOI: 10.1007/s00204-010-0632-7. View

Enkvetchakul B, Bottje W . Influence of diethyl maleate and cysteine on tissue glutathione and growth in broiler chickens. Poult Sci. 1995; 74(5):864-73. DOI: 10.3382/ps.0740864. View

10.

Karg E, Papp F, Tassi N, Janaky T, Wittmann G, Turi S . Enhanced methylglyoxal formation in the erythrocytes of hemodialyzed patients. Metabolism. 2009; 58(7):976-82. DOI: 10.1016/j.metabol.2009.02.032. View

11.

Inoue Y, Kimura A . Identification of the structural gene for glyoxalase I from Saccharomyces cerevisiae. J Biol Chem. 1996; 271(42):25958-65. View

12.

Masterjohn C, Park Y, Lee J, Noh S, Koo S, Bruno R . Dietary fructose feeding increases adipose methylglyoxal accumulation in rats in association with low expression and activity of glyoxalase-2. Nutrients. 2013; 5(8):3311-28. PMC: 3775256. DOI: 10.3390/nu5083311. View

13.

Grahl N, Demers E, Crocker A, Hogan D . Use of RNA-Protein Complexes for Genome Editing in Non- Species. mSphere. 2017; 2(3). PMC: 5480035. DOI: 10.1128/mSphere.00218-17. View

14.

Brenner T, Fleming T, Uhle F, Silaff S, Schmitt F, Salgado E . Methylglyoxal as a new biomarker in patients with septic shock: an observational clinical study. Crit Care. 2014; 18(6):683. PMC: 4301657. DOI: 10.1186/s13054-014-0683-x. View

15.

Stewart B, Navid A, Kulp K, Knaack J, Bench G . D-Lactate production as a function of glucose metabolism in Saccharomyces cerevisiae. Yeast. 2013; 30(2):81-91. PMC: 3569098. DOI: 10.1002/yea.2942. View

16.

Morschhauser J, Barker K, Liu T, BlaB-Warmuth J, Homayouni R, Rogers P . The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. PLoS Pathog. 2007; 3(11):e164. PMC: 2048531. DOI: 10.1371/journal.ppat.0030164. View

17.

Basenko E, Pulman J, Shanmugasundram A, Harb O, Crouch K, Starns D . FungiDB: An Integrated Bioinformatic Resource for Fungi and Oomycetes. J Fungi (Basel). 2018; 4(1). PMC: 5872342. DOI: 10.3390/jof4010039. View

18.

Hoehamer C, Cummings E, Hilliard G, Morschhauser J, Rogers P . Proteomic analysis of Mrr1p- and Tac1p-associated differential protein expression in azole-resistant clinical isolates of Candida albicans. Proteomics Clin Appl. 2010; 3(8):968-78. PMC: 4694560. DOI: 10.1002/prca.200800252. View

19.

Basso Jr L, Bartiss A, Mao Y, Gast C, Coelho P, Snyder M . Transformation of Candida albicans with a synthetic hygromycin B resistance gene. Yeast. 2010; 27(12):1039-48. PMC: 4243612. DOI: 10.1002/yea.1813. View

20.

Sievers F, Wilm A, Dineen D, Gibson T, Karplus K, Li W . Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011; 7:539. PMC: 3261699. DOI: 10.1038/msb.2011.75. View