Roles of Candida albicans Mig1 and Mig2 in glucose repression, pathogenicity traits, and SNF1 essentiality

Autoři: Katherine Lagree aff001;  Carol A. Woolford aff001;  Manning Y. Huang aff001;  Gemma May aff001;  C. Joel McManus aff001;  Norma V. Solis aff002;  Scott G. Filler aff002;  Aaron P. Mitchell aff001
Působiště autorů: Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America aff001;  Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America aff002;  Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America aff003;  Department of Microbiology, University of Georgia, Athens, Georgia, United States of America aff004
Vyšlo v časopise: Roles of Candida albicans Mig1 and Mig2 in glucose repression, pathogenicity traits, and SNF1 essentiality. PLoS Genet 16(1): e32767. doi:10.1371/journal.pgen.1008582
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008582


Metabolic adaptation is linked to the ability of the opportunistic pathogen Candida albicans to colonize and cause infection in diverse host tissues. One way that C. albicans controls its metabolism is through the glucose repression pathway, where expression of alternative carbon source utilization genes is repressed in the presence of its preferred carbon source, glucose. Here we carry out genetic and gene expression studies that identify transcription factors Mig1 and Mig2 as mediators of glucose repression in C. albicans. The well-studied Mig1/2 orthologs ScMig1/2 mediate glucose repression in the yeast Saccharomyces cerevisiae; our data argue that C. albicans Mig1/2 function similarly as repressors of alternative carbon source utilization genes. However, Mig1/2 functions have several distinctive features in C. albicans. First, Mig1 and Mig2 have more co-equal roles in gene regulation than their S. cerevisiae orthologs. Second, Mig1 is regulated at the level of protein accumulation, more akin to ScMig2 than ScMig1. Third, Mig1 and Mig2 are together required for a unique aspect of C. albicans biology, the expression of several pathogenicity traits. Such Mig1/2-dependent traits include the abilities to form hyphae and biofilm, tolerance of cell wall inhibitors, and ability to damage macrophage-like cells and human endothelial cells. Finally, Mig1 is required for a puzzling feature of C. albicans biology that is not shared with S. cerevisiae: the essentiality of the Snf1 protein kinase, a central eukaryotic carbon metabolism regulator. Our results integrate Mig1 and Mig2 into the C. albicans glucose repression pathway and illuminate connections among carbon control, pathogenicity, and Snf1 essentiality.

Klíčová slova:

Biofilms – Candida albicans – Gene expression – Glucose – Glucose metabolism – Macrophages – Mutant strains – Saccharomyces cerevisiae


1. Passalacqua KD, Charbonneau ME, O’Riordan MX. Bacterial Metabolism Shapes the Host-Pathogen Interface. Microbiol Spectr. 2016;4(3). Epub 2016/06/24. doi: 10.1128/microbiolspec.VMBF-0027-2015 27337445.

2. Ries LNA, Beattie S, Cramer RA, Goldman GH. Overview of carbon and nitrogen catabolite metabolism in the virulence of human pathogenic fungi. Mol Microbiol. 2018;107(3):277–97. Epub 2017/12/03. doi: 10.1111/mmi.13887 29197127.

3. Nucci M, Anaissie E. Revisiting the source of candidemia: skin or gut? Clin Infect Dis. 2001;33(12):1959–67. Epub 2001/11/10. doi: 10.1086/323759 11702290.

4. Van Ende M, Wijnants S, Van Dijck P. Sugar Sensing and Signaling in Candida albicans and Candida glabrata. Front Microbiol. 2019;10:99. Epub 2019/02/15. doi: 10.3389/fmicb.2019.00099 30761119.

5. Hedges SB. The origin and evolution of model organisms. Nat Rev Genet. 2002;3(11):838–49. Epub 2002/11/05. doi: 10.1038/nrg929 12415314.

6. Ramirez MA, Lorenz MC. The transcription factor homolog CTF1 regulates {beta}-oxidation in Candida albicans. Eukaryot Cell. 2009;8(10):1604–14. Epub 2009/08/25. doi: 10.1128/EC.00206-09 19700635.

7. Askew C, Sellam A, Epp E, Hogues H, Mullick A, Nantel A, et al. Transcriptional regulation of carbohydrate metabolism in the human pathogen Candida albicans. PLoS Pathog. 2009;5(10):e1000612. Epub 2009/10/10. doi: 10.1371/journal.ppat.1000612 19816560.

8. Childers DS, Raziunaite I, Mol Avelar G, Mackie J, Budge S, Stead D, et al. The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence. PLoS Pathog. 2016;12(4):e1005566. Epub 2016/04/14. doi: 10.1371/journal.ppat.1005566 27073846.

9. Ramirez-Zavala B, Mottola A, Haubenreisser J, Schneider S, Allert S, Brunke S, et al. The Snf1-activating kinase Sak1 is a key regulator of metabolic adaptation and in vivo fitness of Candida albicans. Mol Microbiol. 2017;104(6):989–1007. Epub 2017/03/25. doi: 10.1111/mmi.13674 28337802.

10. Hong SP, Carlson M. Regulation of snf1 protein kinase in response to environmental stress. J Biol Chem. 2007;282(23):16838–45. Epub 2007/04/18. doi: 10.1074/jbc.M700146200 17438333.

11. Hedbacker K, Carlson M. SNF1/AMPK pathways in yeast. Front Biosci. 2008;13:2408–20. Epub 2007/11/06. doi: 10.2741/2854 17981722.

12. Lutfiyya LL, Johnston M. Two zinc-finger-containing repressors are responsible for glucose repression of SUC2 expression. Mol Cell Biol. 1996;16(9):4790–7. Epub 1996/09/01. doi: 10.1128/mcb.16.9.4790 8756637.

13. Lutfiyya LL, Iyer VR, DeRisi J, DeVit MJ, Brown PO, Johnston M. Characterization of three related glucose repressors and genes they regulate in Saccharomyces cerevisiae. Genetics. 1998;150(4):1377–91. Epub 1998/12/02. 9832517.

14. Westholm JO, Nordberg N, Muren E, Ameur A, Komorowski J, Ronne H. Combinatorial control of gene expression by the three yeast repressors Mig1, Mig2 and Mig3. BMC Genomics. 2008;9:601. Epub 2008/12/18. doi: 10.1186/1471-2164-9-601 19087243.

15. Kaniak A, Xue Z, Macool D, Kim JH, Johnston M. Regulatory network connecting two glucose signal transduction pathways in Saccharomyces cerevisiae. Eukaryot Cell. 2004;3(1):221–31. Epub 2004/02/12. doi: 10.1128/EC.3.1.221-231.2004 14871952.

16. Lim MK, Siew WL, Zhao J, Tay YC, Ang E, Lehming N. Galactose induction of the GAL1 gene requires conditional degradation of the Mig2 repressor. Biochem J. 2011;435(3):641–9. Epub 2011/02/18. doi: 10.1042/BJ20102034 21323640.

17. De Vit MJ, Waddle JA, Johnston M. Regulated nuclear translocation of the Mig1 glucose repressor. Mol Biol Cell. 1997;8(8):1603–18. Epub 1997/08/01. doi: 10.1091/mbc.8.8.1603 9285828.

18. Zaragoza O, Rodriguez C, Gancedo C. Isolation of the MIG1 gene from Candida albicans and effects of its disruption on catabolite repression. J Bacteriol. 2000;182(2):320–6. Epub 2000/01/12. doi: 10.1128/jb.182.2.320-326.2000 10629176.

19. Murad AM, d’Enfert C, Gaillardin C, Tournu H, Tekaia F, Talibi D, et al. Transcript profiling in Candida albicans reveals new cellular functions for the transcriptional repressors CaTup1, CaMig1 and CaNrg1. Mol Microbiol. 2001;42(4):981–93. Epub 2001/12/12. doi: 10.1046/j.1365-2958.2001.02713.x 11737641.

20. Cottier F, Tan ASM, Yurieva M, Liao W, Lum J, Poidinger M, et al. The Transcriptional Response of Candida albicans to Weak Organic Acids, Carbon Source, and MIG1 Inactivation Unveils a Role for HGT16 in Mediating the Fungistatic Effect of Acetic Acid. G3 (Bethesda). 2017;7(11):3597–604. Epub 2017/09/08. doi: 10.1534/g3.117.300238 28877970.

21. Petter R, Chang YC, Kwon-Chung KJ. A gene homologous to Saccharomyces cerevisiae SNF1 appears to be essential for the viability of Candida albicans. Infect Immun. 1997;65(12):4909–17. Epub 1997/12/11. 9393775.

22. Enloe B, Diamond A, Mitchell AP. A single-transformation gene function test in diploid Candida albicans. J Bacteriol. 2000;182(20):5730–6. Epub 2000/09/27. doi: 10.1128/jb.182.20.5730-5736.2000 11004171.

23. Blankenship JR, Fanning S, Hamaker JJ, Mitchell AP. An extensive circuitry for cell wall regulation in Candida albicans. PLoS Pathog. 2010;6(2):e1000752. Epub 2010/02/09. doi: 10.1371/journal.ppat.1000752 20140194.

24. Vyas VK, Barrasa MI, Fink GR. A Candida albicans CRISPR system permits genetic engineering of essential genes and gene families. Sci Adv. 2015;1(3):e1500248. Epub 2015/05/16. doi: 10.1126/sciadv.1500248 25977940.

25. Woolford CA, Lagree K, Xu W, Aleynikov T, Adhikari H, Sanchez H, et al. Bypass of Candida albicans Filamentation/Biofilm Regulators through Diminished Expression of Protein Kinase Cak1. PLoS Genet. 2016;12(12):e1006487. Epub 2016/12/10. doi: 10.1371/journal.pgen.1006487 27935965.

26. Mottola A, Morschhauser J. An Intragenic Recombination Event Generates a Snf4-Independent Form of the Essential Protein Kinase Snf1 in Candida albicans. mSphere. 2019;4(3). Epub 2019/06/21. doi: 10.1128/mSphere.00352-19 31217306.

27. Lorenz MC, Bender JA, Fink GR. Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot Cell. 2004;3(5):1076–87. Epub 2004/10/08. doi: 10.1128/EC.3.5.1076-1087.2004 15470236.

28. Tucey TM, Verma J, Harrison PF, Snelgrove SL, Lo TL, Scherer AK, et al. Glucose Homeostasis Is Important for Immune Cell Viability during Candida Challenge and Host Survival of Systemic Fungal Infection. Cell Metab. 2018;27(5):988–1006.e7. Epub 2018/05/03. doi: 10.1016/j.cmet.2018.03.019 29719235.

29. Bruno VM, Wang Z, Marjani SL, Euskirchen GM, Martin J, Sherlock G, et al. Comprehensive annotation of the transcriptome of the human fungal pathogen Candida albicans using RNA-seq. Genome Res. 2010;20(10):1451–8. Epub 2010/09/03. doi: 10.1101/gr.109553.110 20810668.

30. Nobile CJ, Fox EP, Nett JE, Sorrells TR, Mitrovich QM, Hernday AD, et al. A recently evolved transcriptional network controls biofilm development in Candida albicans. Cell. 2012;148(1–2):126–38. Epub 2012/01/24. doi: 10.1016/j.cell.2011.10.048 22265407.

31. Xu W, Solis NV, Ehrlich RL, Woolford CA, Filler SG, Mitchell AP. Activation and alliance of regulatory pathways in C. albicans during mammalian infection. PLoS Biol. 2015;13(2):e1002076. Epub 2015/02/19. doi: 10.1371/journal.pbio.1002076 25693184.

32. Sellam A, Chaillot J, Mallick J, Tebbji F, Richard Albert J, Cook MA, et al. The p38/HOG stress-activated protein kinase network couples growth to division in Candida albicans. PLoS Genet. 2019;15(3):e1008052. Epub 2019/03/29. doi: 10.1371/journal.pgen.1008052 30921326.

33. Min K, Ichikawa Y, Woolford CA, Mitchell AP. Candida albicans Gene Deletion with a Transient CRISPR-Cas9 System. mSphere. 2016;1(3). Epub 2016/06/25. doi: 10.1128/mSphere.00130-16 27340698.

34. Murad AM, Lee PR, Broadbent ID, Barelle CJ, Brown AJ. CIp10, an efficient and convenient integrating vector for Candida albicans. Yeast. 2000;16(4):325–7. Epub 2000/02/12. 10669870.

35. Huang MY, Woolford CA, Mitchell AP. Rapid Gene Concatenation for Genetic Rescue of Multigene Mutants in Candida albicans. mSphere. 2018;3(2). Epub 2018/04/27. doi: 10.1128/mSphere.00169-18 29695626.

36. Monteiro PT, Pais P, Costa C, Manna S, Sa-Correia I, Teixeira MC. The PathoYeastract database: an information system for the analysis of gene and genomic transcription regulation in pathogenic yeasts. Nucleic Acids Res. 2016;45(D1):D597–D603. Epub 2016/09/15. doi: 10.1093/nar/gkw817 27625390.

37. Fan J, Chaturvedi V, Shen SH. Identification and phylogenetic analysis of a glucose transporter gene family from the human pathogenic yeast Candida albicans. J Mol Evol. 2002;55(3):336–46. Epub 2002/08/21. doi: 10.1007/s00239-002-2330-4 12187386.

38. Brown V, Sexton JA, Johnston M. A glucose sensor in Candida albicans. Eukaryot Cell. 2006;5(10):1726–37. Epub 2006/10/13. doi: 10.1128/EC.00186-06 17030998.

39. Sexton JA, Brown V, Johnston M. Regulation of sugar transport and metabolism by the Candida albicans Rgt1 transcriptional repressor. Yeast. 2007;24(10):847–60. Epub 2007/07/03. doi: 10.1002/yea.1514 17605131.

40. Piekarska K, Hardy G, Mol E, van den Burg J, Strijbis K, van Roermund C, et al. The activity of the glyoxylate cycle in peroxisomes of Candida albicans depends on a functional beta-oxidation pathway: evidence for reduced metabolite transport across the peroxisomal membrane. Microbiology. 2008;154(Pt 10):3061–72. Epub 2008/10/04. doi: 10.1099/mic.0.2008/020289-0 18832312.

41. Fernandez-Cid A, Riera A, Herrero P, Moreno F. Glucose levels regulate the nucleo-mitochondrial distribution of Mig2. Mitochondrion. 2012;12(3):370–80. Epub 2012/02/23. doi: 10.1016/j.mito.2012.02.001 22353369.

42. Treitel MA, Kuchin S, Carlson M. Snf1 protein kinase regulates phosphorylation of the Mig1 repressor in Saccharomyces cerevisiae. Mol Cell Biol. 1998;18(11):6273–80. Epub 1998/10/17. doi: 10.1128/mcb.18.11.6273 9774644.

43. Celenza JL, Carlson M. A yeast gene that is essential for release from glucose repression encodes a protein kinase. Science. 1986;233(4769):1175–80. Epub 1986/09/12. doi: 10.1126/science.3526554 3526554.

44. Ene IV, Adya AK, Wehmeier S, Brand AC, MacCallum DM, Gow NA, et al. Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen. Cell Microbiol. 2012;14(9):1319–35. Epub 2012/05/17. doi: 10.1111/j.1462-5822.2012.01813.x 22587014.

45. Ene IV, Walker LA, Schiavone M, Lee KK, Martin-Yken H, Dague E, et al. Cell Wall Remodeling Enzymes Modulate Fungal Cell Wall Elasticity and Osmotic Stress Resistance. MBio. 2015;6(4):e00986. Epub 2015/07/30. doi: 10.1128/mBio.00986-15 26220968.

46. Sabina J, Brown V. Glucose sensing network in Candida albicans: a sweet spot for fungal morphogenesis. Eukaryot Cell. 2009;8(9):1314–20. Epub 2009/07/21. doi: 10.1128/EC.00138-09 19617394.

47. Desai JV, Mitchell AP, Andes DR. Fungal biofilms, drug resistance, and recurrent infection. Cold Spring Harb Perspect Med. 2014;4(10). Epub 2014/10/03. doi: 10.1101/cshperspect.a019729 25274758.

48. Barelle CJ, Priest CL, Maccallum DM, Gow NA, Odds FC, Brown AJ. Niche-specific regulation of central metabolic pathways in a fungal pathogen. Cell Microbiol. 2006;8(6):961–71. Epub 2006/05/10. doi: 10.1111/j.1462-5822.2005.00676.x 16681837.

49. Westman J, Moran G, Mogavero S, Hube B, Grinstein S. Candida albicans Hyphal Expansion Causes Phagosomal Membrane Damage and Luminal Alkalinization. MBio. 2018;9(5). Epub 2018/09/13. doi: 10.1128/mBio.01226-18 30206168.

50. Sanchez AA, Johnston DA, Myers C, Edwards JE Jr, Mitchell AP, Filler SG. Relationship between Candida albicans virulence during experimental hematogenously disseminated infection and endothelial cell damage in vitro. Infect Immun. 2004;72(1):598–601. Epub 2003/12/23. doi: 10.1128/IAI.72.1.598-601.2004 14688143.

51. Hiltunen JK, Mursula AM, Rottensteiner H, Wierenga RK, Kastaniotis AJ, Gurvitz A. The biochemistry of peroxisomal beta-oxidation in the yeast Saccharomyces cerevisiae. FEMS Microbiol Rev. 2003;27(1):35–64. Epub 2003/04/17. doi: 10.1016/S0168-6445(03)00017-2 12697341.

52. Veenhuis M, Mateblowski M, Kunau WH, Harder W. Proliferation of microbodies in Saccharomyces cerevisiae. Yeast. 1987;3(2):77–84. Epub 1987/06/01. doi: 10.1002/yea.320030204 3332968.

53. Rodaki A, Bohovych IM, Enjalbert B, Young T, Odds FC, Gow NA, et al. Glucose promotes stress resistance in the fungal pathogen Candida albicans. Mol Biol Cell. 2009;20(22):4845–55. Epub 2009/09/18. doi: 10.1091/mbc.E09-01-0002 19759180.

54. Gola S, Martin R, Walther A, Dunkler A, Wendland J. New modules for PCR-based gene targeting in Candida albicans: rapid and efficient gene targeting using 100 bp of flanking homology region. Yeast. 2003;20(16):1339–47. Epub 2003/12/10. doi: 10.1002/yea.1044 14663826.

55. Noble SM, French S, Kohn LA, Chen V, Johnson AD. Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity. Nat Genet. 2010;42(7):590–8. Epub 2010/06/15. doi: 10.1038/ng.605 20543849.

56. Huang MY, Woolford CA, May G, McManus CJ, Mitchell AP. Circuit diversification in a biofilm regulatory network. PLoS Pathog. 2019;15(5):e1007787. Epub 2019/05/23. doi: 10.1371/journal.ppat.1007787 31116789

57. Trapnell C, Pachter L, Salzberg SL. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009;25(9):1105–11. Epub 2009/03/18. doi: 10.1093/bioinformatics/btp120 19289445.

58. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25(16):2078–9. Epub 2009/06/10. doi: 10.1093/bioinformatics/btp352 19505943.

59. Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26(6):841–2. Epub 2010/01/30. doi: 10.1093/bioinformatics/btq033 20110278.

60. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. Epub 2014/12/18. doi: 10.1186/s13059-014-0550-8 25516281.

61. Lagree K, Desai JV, Finkel JS, Lanni F. Microscopy of fungal biofilms. Curr Opin Microbiol. 2018;43:100–7. Epub 2018/02/08. doi: 10.1016/j.mib.2017.12.008 29414442.

62. Vylkova S, Lorenz MC. Modulation of phagosomal pH by Candida albicans promotes hyphal morphogenesis and requires Stp2p, a regulator of amino acid transport. PLoS Pathog. 2015;10(3):e1003995. Epub 2014/03/15. doi: 10.1371/journal.ppat.1003995 24626429.

63. Filler SG, Swerdloff JN, Hobbs C, Luckett PM. Penetration and damage of endothelial cells by Candida albicans. Infect Immun. 1995;63(3):976–83. Epub 1995/03/01. 7868270.

Článek vyšel v časopise

PLOS Genetics

2020 Číslo 1
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Třikrát z interní medicíny
nový kurz
Autoři: MUDr. Jana Kubátová

Pokročilá Parkinsonova nemoc − úskalí a možnosti léčby
Autoři: doc. MUDr. Marek Baláž, Ph.D.

Léčba diabetes mellitus 2. typu pomocí GLP- 1 RA

Depresivní porucha a zánětlivé procesy
Autoři: MUDr. Juraj Tkáč

Methotrexát a jeho formy podávání v revmatologii
Autoři: MUDr. Liliana Šedová

Všechny kurzy
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se