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An expanded cell wall damage signaling network is comprised of the transcription factors Rlm1 and Sko1 in Candida albicans


Autoři: Marienela Y. Heredia aff001;  Mélanie A. C. Ikeh aff002;  Deepika Gunasekaran aff002;  Karen A. Conrad aff001;  Sviatlana Filimonava aff001;  Dawn H. Marotta aff001;  Clarissa J. Nobile aff002;  Jason M. Rauceo aff001
Působiště autorů: Department of Sciences, John Jay College of the City University of New York, New York, New York, United States of America aff001;  Department of Molecular and Cell Biology, School of Natural Sciences, University of California Merced, Merced, California, United States of America aff002;  Quantitative and Systems Biology Graduate Program, University of California Merced, Merced, California, United States of America aff003
Vyšlo v časopise: An expanded cell wall damage signaling network is comprised of the transcription factors Rlm1 and Sko1 in Candida albicans. PLoS Genet 16(7): e32767. doi:10.1371/journal.pgen.1008908
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008908

Souhrn

The human fungal pathogen Candida albicans is constantly exposed to environmental challenges impacting the cell wall. Signaling pathways coordinate stress adaptation and are essential for commensalism and virulence. The transcription factors Sko1, Cas5, and Rlm1 control the response to cell wall stress caused by the antifungal drug caspofungin. Here, we expand the Sko1 and Rlm1 transcriptional circuit and demonstrate that Rlm1 activates Sko1 cell wall stress signaling. Caspofungin-induced transcription of SKO1 and several Sko1-dependent cell wall integrity genes are attenuated in an rlm1Δ/Δ mutant strain when compared to the treated wild-type strain but not in a cas5Δ/Δ mutant strain. Genome-wide chromatin immunoprecipitation (ChIP-seq) results revealed numerous Sko1 and Rlm1 directly bound target genes in the presence of caspofungin that were undetected in previous gene expression studies. Notable targets include genes involved in cell wall integrity, osmolarity, and cellular aggregation, as well as several uncharacterized genes. Interestingly, we found that Rlm1 does not bind to the upstream intergenic region of SKO1 in the presence of caspofungin, indicating that Rlm1 indirectly controls caspofungin-induced SKO1 transcription. In addition, we discovered that caspofungin-induced SKO1 transcription occurs through self-activation. Based on our ChIP-seq data, we also discovered an Rlm1 consensus motif unique to C. albicans. For Sko1, we found a consensus motif similar to the known Sko1 motif for Saccharomyces cerevisiae. Growth assays showed that SKO1 overexpression suppressed caspofungin hypersensitivity in an rlm1Δ/Δ mutant strain. In addition, overexpression of the glycerol phosphatase, RHR2, suppressed caspofungin hypersensitivity specifically in a sko1Δ/Δ mutant strain. Our findings link the Sko1 and Rlm1 signaling pathways, identify new biological roles for Sko1 and Rlm1, and highlight the complex dynamics underlying cell wall signaling.

Klíčová slova:

Candida albicans – Cell walls – Gene regulation – Microarrays – Mutant strains – Osmotic shock – Stress signaling cascade – Transcriptional control


Zdroje

1. Sobel JD. Recurrent vulvovaginal candidiasis. Am J Obstet Gynecol. 2016;214(1):15–21. doi: 10.1016/j.ajog.2015.06.067 26164695.

2. Pfaller MA. Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am J Med. 2012;125(1 Suppl):S3–13. Epub 2012/01/04. doi: 10.1016/j.amjmed.2011.11.001 22196207.

3. Polke M, Hube B, Jacobsen ID. Candida survival strategies. Adv Appl Microbiol. 2015;91:139–235. doi: 10.1016/bs.aambs.2014.12.002 25911234.

4. Gow NAR, Latge JP, Munro CA. The Fungal Cell Wall: Structure, Biosynthesis, and Function. Microbiol Spectr. 2017;5(3). doi: 10.1128/microbiolspec.FUNK-0035-2016 28513415.

5. Sucher AJ, Chahine EB, Balcer HE. Echinocandins: the newest class of antifungals. Ann Pharmacother. 2009;43(10):1647–57. doi: 10.1345/aph.1M237 19724014.

6. Rauceo JM, Blankenship JR, Fanning S, Hamaker JJ, Deneault JS, Smith FJ, et al. Regulation of the Candida albicans cell wall damage response by transcription factor Sko1 and PAS kinase Psk1. Mol Biol Cell. 2008;19(7):2741–51. doi: 10.1091/mbc.e08-02-0191 18434592; PubMed Central PMCID: PMC2441657.

7. Bruno VM, Kalachikov S, Subaran R, Nobile CJ, Kyratsous C, Mitchell AP. Control of the C. albicans cell wall damage response by transcriptional regulator Cas5. PLoS Pathog. 2006;2(3):e21. doi: 10.1371/journal.ppat.0020021 16552442.

8. Xie JL, Qin L, Miao Z, Grys BT, Diaz JC, Ting K, et al. The Candida albicans transcription factor Cas5 couples stress responses, drug resistance and cell cycle regulation. Nat Commun. 2017;8(1):499. doi: 10.1038/s41467-017-00547-y 28894103; PubMed Central PMCID: PMC5593949.

9. Vasicek EM, Berkow EL, Bruno VM, Mitchell AP, Wiederhold NP, Barker KS, et al. Disruption of the transcriptional regulator Cas5 results in enhanced killing of Candida albicans by Fluconazole. Antimicrob Agents Chemother. 2014;58(11):6807–18. doi: 10.1128/AAC.00064-14 25182640; PubMed Central PMCID: PMC4249418.

10. Chamilos G, Nobile CJ, Bruno VM, Lewis RE, Mitchell AP, Kontoyiannis DP. Candida albicans Cas5, a regulator of cell wall integrity, is required for virulence in murine and toll mutant fly models. J Infect Dis. 2009;200(1):152–7. Epub 2009/05/26. doi: 10.1086/599363 19463063.

11. Levin DE. Regulation of cell wall biogenesis in Saccharomyces cerevisiae: the cell wall integrity signaling pathway. Genetics. 2011;189(4):1145–75. doi: 10.1534/genetics.111.128264 22174182; PubMed Central PMCID: PMC3241422.

12. Delgado-Silva Y, Vaz C, Carvalho-Pereira J, Carneiro C, Nogueira E, Correia A, et al. Participation of Candida albicans transcription factor RLM1 in cell wall biogenesis and virulence. PLoS One. 2014;9(1):e86270. doi: 10.1371/journal.pone.0086270 24466000; PubMed Central PMCID: PMC3900518.

13. Oliveira-Pacheco J, Alves R, Costa-Barbosa A, Cerqueira-Rodrigues B, Pereira-Silva P, Paiva S, et al. The Role of Candida albicans Transcription Factor RLM1 in Response to Carbon Adaptation. Front Microbiol. 2018;9:1127. doi: 10.3389/fmicb.2018.01127 29896184; PubMed Central PMCID: PMC5986929.

14. Capaldi AP, Kaplan T, Liu Y, Habib N, Regev A, Friedman N, et al. Structure and function of a transcriptional network activated by the MAPK Hog1. Nat Genet. 2008;40(11):1300–6. doi: 10.1038/ng.235 18931682; PubMed Central PMCID: PMC2825711.

15. Proft M, Struhl K. Hog1 kinase converts the Sko1-Cyc8-Tup1 repressor complex into an activator that recruits SAGA and SWI/SNF in response to osmotic stress. Mol Cell. 2002;9(6):1307–17. doi: 10.1016/s1097-2765(02)00557-9 12086627.

16. Marotta DH, Nantel A, Sukala L, Teubl JR, Rauceo JM. Genome-wide transcriptional profiling and enrichment mapping reveal divergent and conserved roles of Sko1 in the Candida albicans osmotic stress response. Genomics. 2013;102(4):363–71. doi: 10.1016/j.ygeno.2013.06.002 23773966; PubMed Central PMCID: PMC3907168.

17. Sellam A, van het Hoog M, Tebbji F, Beaurepaire C, Whiteway M, Nantel A. Modeling the transcriptional regulatory network that controls the early hypoxic response in Candida albicans. Eukaryot Cell. 2014;13(5):675–90. doi: 10.1128/EC.00292-13 24681685; PubMed Central PMCID: PMC4060469.

18. Alonso-Monge R, Roman E, Arana DM, Prieto D, Urrialde V, Nombela C, et al. The Sko1 protein represses the yeast-to-hypha transition and regulates the oxidative stress response in Candida albicans. Fungal Genet Biol. 2010;47(7):587–601. Epub 2010/04/15. doi: 10.1016/j.fgb.2010.03.009 20388546.

19. Skrzypek MS, Binkley J, Binkley G, Miyasato SR, Simison M, Sherlock G. The Candida Genome Database (CGD): incorporation of Assembly 22, systematic identifiers and visualization of high throughput sequencing data. Nucleic Acids Res. 2017;45(D1):D592–D6. doi: 10.1093/nar/gkw924 27738138; PubMed Central PMCID: PMC5210628.

20. Teytelman L, Thurtle DM, Rine J, van Oudenaarden A. Highly expressed loci are vulnerable to misleading ChIP localization of multiple unrelated proteins. Proc Natl Acad Sci U S A. 2013;110(46):18602–7. doi: 10.1073/pnas.1316064110 24173036; PubMed Central PMCID: PMC3831989.

21. Plaine A, Walker L, Da Costa G, Mora-Montes HM, McKinnon A, Gow NA, et al. Functional analysis of Candida albicans GPI-anchored proteins: roles in cell wall integrity and caspofungin sensitivity. Fungal Genet Biol. 2008;45(10):1404–14. doi: 10.1016/j.fgb.2008.08.003 18765290; PubMed Central PMCID: PMC2649418.

22. Park D, Lee Y, Bhupindersingh G, Iyer VR. Widespread misinterpretable ChIP-seq bias in yeast. PLoS One. 2013;8(12):e83506. doi: 10.1371/journal.pone.0083506 24349523; PubMed Central PMCID: PMC3857294.

23. 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. doi: 10.1128/mBio.00986-15 26220968; PubMed Central PMCID: PMC4551979.

24. Dodou E, Treisman R. The Saccharomyces cerevisiae MADS-box transcription factor Rlm1 is a target for the Mpk1 mitogen-activated protein kinase pathway. Mol Cell Biol. 1997;17(4):1848–59. doi: 10.1128/mcb.17.4.1848 9121433; PubMed Central PMCID: PMC232032.

25. de Boer CG, Hughes TR. YeTFaSCo: a database of evaluated yeast transcription factor sequence specificities. Nucleic Acids Res. 2012;40(Database issue):D169–79. doi: 10.1093/nar/gkr993 22102575; PubMed Central PMCID: PMC3245003.

26. Prelich G. Gene overexpression: uses, mechanisms, and interpretation. Genetics. 2012;190(3):841–54. doi: 10.1534/genetics.111.136911 22419077; PubMed Central PMCID: PMC3296252.

27. Hohmann S. Osmotic stress signaling and osmoadaptation in yeasts. Microbiol Mol Biol Rev. 2002;66(2):300–72. Epub 2002/06/01. doi: 10.1128/mmbr.66.2.300-372.2002 12040128; PubMed Central PMCID: PMC120784.

28. Fan J, Whiteway M, Shen SH. Disruption of a gene encoding glycerol 3-phosphatase from Candida albicans impairs intracellular glycerol accumulation-mediated salt-tolerance. FEMS Microbiol Lett. 2005;245(1):107–16. doi: 10.1016/j.femsle.2005.02.031 15796987.

29. Garcia R, Rodriguez-Pena JM, Bermejo C, Nombela C, Arroyo J. The high osmotic response and cell wall integrity pathways cooperate to regulate transcriptional responses to zymolyase-induced cell wall stress in Saccharomyces cerevisiae. J Biol Chem. 2009;284(16):10901–11. Epub 2009/02/24. M808693200 [pii] doi: 10.1074/jbc.M808693200 19234305; PubMed Central PMCID: PMC2667776.

30. Gelis S, de Groot PW, Castillo L, Moragues MD, Sentandreu R, Gomez MM, et al. Pga13 in Candida albicans is localized in the cell wall and influences cell surface properties, morphogenesis and virulence. Fungal Genet Biol. 2012;49(4):322–31. doi: 10.1016/j.fgb.2012.01.010 22343036.

31. Pardini G, De Groot PW, Coste AT, Karababa M, Klis FM, de Koster CG, et al. The CRH family coding for cell wall glycosylphosphatidylinositol proteins with a predicted transglycosidase domain affects cell wall organization and virulence of Candida albicans. J Biol Chem. 2006;281(52):40399–411. doi: 10.1074/jbc.M606361200 17074760.

32. Moreno-Ruiz E, Ortu G, de Groot PW, Cottier F, Loussert C, Prevost MC, et al. The GPI-modified proteins Pga59 and Pga62 of Candida albicans are required for cell wall integrity. Microbiology. 2009;155(Pt 6):2004–20. Epub 2009/04/23. doi: 10.1099/mic.0.028902-0 19383685.

33. Fonzi WA. PHR1 and PHR2 of Candida albicans encode putative glycosidases required for proper cross-linking of beta-1,3- and beta-1,6-glucans. J Bacteriol. 1999;181(22):7070–9. 10559174; PubMed Central PMCID: PMC94183.

34. Munro CA, Selvaggini S, de Bruijn I, Walker L, Lenardon MD, Gerssen B, et al. The PKC, HOG and Ca2+ signalling pathways co-ordinately regulate chitin synthesis in Candida albicans. Mol Microbiol. 2007;63(5):1399–413. doi: 10.1111/j.1365-2958.2007.05588.x 17302816; PubMed Central PMCID: PMC2649417.

35. Jones LA, Sudbery PE. Spitzenkorper, exocyst, and polarisome components in Candida albicans hyphae show different patterns of localization and have distinct dynamic properties. Eukaryot Cell. 2010;9(10):1455–65. doi: 10.1128/EC.00109-10 20693302; PubMed Central PMCID: PMC2950421.

36. Segal ES, Gritsenko V, Levitan A, Yadav B, Dror N, Steenwyk JL, et al. Gene Essentiality Analyzed by In Vivo Transposon Mutagenesis and Machine Learning in a Stable Haploid Isolate of Candida albicans. mBio. 2018;9(5). doi: 10.1128/mBio.02048-18 30377286; PubMed Central PMCID: PMC6212825.

37. Zarzov P, Mazzoni C, Mann C. The SLT2(MPK1) MAP kinase is activated during periods of polarized cell growth in yeast. EMBO J. 1996;15(1):83–91. 8598209; PubMed Central PMCID: PMC449920.

38. Gomez A, Perez J, Reyes A, Duran A, Roncero C. Slt2 and Rim101 contribute independently to the correct assembly of the chitin ring at the budding yeast neck in Saccharomyces cerevisiae. Eukaryot Cell. 2009;8(9):1449–59. doi: 10.1128/EC.00153-09 19633265; PubMed Central PMCID: PMC2747826.

39. Johnson C, Kweon HK, Sheidy D, Shively CA, Mellacheruvu D, Nesvizhskii AI, et al. The yeast Sks1p kinase signaling network regulates pseudohyphal growth and glucose response. PLoS Genet. 2014;10(3):e1004183. doi: 10.1371/journal.pgen.1004183 24603354; PubMed Central PMCID: PMC3945295.

40. 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. doi: 10.1016/j.cell.2011.10.048 22265407; PubMed Central PMCID: PMC3266547.

41. Enjalbert B, Smith DA, Cornell MJ, Alam I, Nicholls S, Brown AJ, 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. 2006;17(2):1018–32. doi: 10.1091/mbc.e05-06-0501 16339080.

42. Enjalbert B, Moran GP, Vaughan C, Yeomans T, Maccallum DM, Quinn J, et al. Genome-wide gene expression profiling and a forward genetic screen show that differential expression of the sodium ion transporter Ena21 contributes to the differential tolerance of Candida albicans and Candida dubliniensis to osmotic stress. Mol Microbiol. 2009;72(1):216–28. doi: 10.1111/j.1365-2958.2009.06640.x 19239621.

43. Mavrianos J, Desai C, Chauhan N. Two-component histidine phosphotransfer protein Ypd1 is not essential for viability in Candida albicans. Eukaryot Cell. 2014;13(4):452–60. doi: 10.1128/EC.00243-13 24489039; PubMed Central PMCID: PMC4000104.

44. Day AM, Smith DA, Ikeh MA, Haider M, Herrero-de-Dios CM, Brown AJ, et al. Blocking two-component signalling enhances Candida albicans virulence and reveals adaptive mechanisms that counteract sustained SAPK activation. PLoS Pathog. 2017;13(1):e1006131. doi: 10.1371/journal.ppat.1006131 28135328; PubMed Central PMCID: PMC5300278.

45. Su C, Lu Y, Liu H. Reduced TOR signaling sustains hyphal development in Candida albicans by lowering Hog1 basal activity. Mol Biol Cell. 2013;24(3):385–97. doi: 10.1091/mbc.E12-06-0477 23171549; PubMed Central PMCID: PMC3564525.

46. Proft M, Gibbons FD, Copeland M, Roth FP, Struhl K. Genomewide identification of Sko1 target promoters reveals a regulatory network that operates in response to osmotic stress in Saccharomyces cerevisiae. Eukaryot Cell. 2005;4(8):1343–52. doi: 10.1128/EC.4.8.1343-1352.2005 16087739.

47. Caplan T, Polvi EJ, Xie JL, Buckhalter S, Leach MD, Robbins N, et al. Functional Genomic Screening Reveals Core Modulators of Echinocandin Stress Responses in Candida albicans. Cell Rep. 2018;23(8):2292–8. doi: 10.1016/j.celrep.2018.04.084 29791841.

48. El-Kirat-Chatel S, Beaussart A, Alsteens D, Jackson DN, Lipke PN, Dufrene YF. Nanoscale analysis of caspofungin-induced cell surface remodelling in Candida albicans. Nanoscale. 2013;5(3):1105–15. doi: 10.1039/c2nr33215a 23262781; PubMed Central PMCID: PMC3564254.

49. Gregori C, Glaser W, Frohner IE, Reinoso-Martin C, Rupp S, Schuller C, et al. Efg1 Controls caspofungin-induced cell aggregation of Candida albicans through the adhesin Als1. Eukaryot Cell. 2011;10(12):1694–704. Epub 2011/11/01. doi: 10.1128/EC.05187-11 22037180; PubMed Central PMCID: PMC3232723.

50. Finkel JS, Xu W, Huang D, Hill EM, Desai JV, Woolford CA, et al. Portrait of Candida albicans adherence regulators. PLoS pathogens. 2012;8(2):e1002525. Epub 2012/02/24. doi: 10.1371/journal.ppat.1002525 22359502; PubMed Central PMCID: PMC3280983.

51. Desai JV, Bruno VM, Ganguly S, Stamper RJ, Mitchell KF, Solis N, et al. Regulatory role of glycerol in Candida albicans biofilm formation. mBio. 2013;4(2):e00637–12. doi: 10.1128/mBio.00637-12 23572557; PubMed Central PMCID: PMC3622937.

52. Davis D, Edwards JE Jr., Mitchell AP, Ibrahim AS. Candida albicans RIM101 pH response pathway is required for host-pathogen interactions. Infect Immun. 2000;68(10):5953–9. doi: 10.1128/iai.68.10.5953-5959.2000 10992507; PubMed Central PMCID: PMC101559.

53. Wilson RB, Davis D, Mitchell AP. Rapid hypothesis testing with Candida albicans through gene disruption with short homology regions. J Bacteriol. 1999;181(6):1868–74. 10074081.

54. Walther A, Wendland J. An improved transformation protocol for the human fungal pathogen Candida albicans. Curr Genet. 2003;42(6):339–43. doi: 10.1007/s00294-002-0349-0 12612807.

55. Nobile CJ, Solis N, Myers CL, Fay AJ, Deneault JS, Nantel A, et al. Candida albicans transcription factor Rim101 mediates pathogenic interactions through cell wall functions. Cell Microbiol. 2008;10(11):2180–96. doi: 10.1111/j.1462-5822.2008.01198.x 18627379; PubMed Central PMCID: PMC2701370.

56. Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 2009;55(4):611–22. Epub 2009/02/28. doi: 10.1373/clinchem.2008.112797 19246619.

57. Lohse MB, Kongsomboonvech P, Madrigal M, Hernday AD, Nobile CJ. Genome-Wide Chromatin Immunoprecipitation in Candida albicans and Other Yeasts. Methods Mol Biol. 2016;1361:161–84. doi: 10.1007/978-1-4939-3079-1_10 26483022; PubMed Central PMCID: PMC4773921.

58. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30(15):2114–20. doi: 10.1093/bioinformatics/btu170 24695404; PubMed Central PMCID: PMC4103590.

59. Langmead B, Trapnell C, Pop M, Salzberg SL. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009;10(3):R25. doi: 10.1186/gb-2009-10-3-r25 19261174; PubMed Central PMCID: PMC2690996.

60. Homann OR, Johnson AD. MochiView: versatile software for genome browsing and DNA motif analysis. BMC Biol. 2010;8:49. doi: 10.1186/1741-7007-8-49 20409324; PubMed Central PMCID: PMC2867778.

61. Ramirez F, Dundar F, Diehl S, Gruning BA, Manke T. deepTools: a flexible platform for exploring deep-sequencing data. Nucleic Acids Res. 2014;42(Web Server issue):W187–91. doi: 10.1093/nar/gku365 24799436; PubMed Central PMCID: PMC4086134.

62. Bailey TL, Johnson J, Grant CE, Noble WS. The MEME Suite. Nucleic Acids Res. 2015;43(W1):W39–49. doi: 10.1093/nar/gkv416 25953851; PubMed Central PMCID: PMC4489269.

63. Tatusov RL, Galperin MY, Natale DA, Koonin EV. The COG database: a tool for genome-scale analysis of protein functions and evolution. Nucleic Acids Res. 2000;28(1):33–6. doi: 10.1093/nar/28.1.33 10592175; PubMed Central PMCID: PMC102395.

64. Huerta-Cepas J, Szklarczyk D, Heller D, Hernandez-Plaza A, Forslund SK, Cook H, et al. eggNOG 5.0: a hierarchical, functionally and phylogenetically annotated orthology resource based on 5090 organisms and 2502 viruses. Nucleic Acids Res. 2019;47(D1):D309–D14. doi: 10.1093/nar/gky1085 30418610; PubMed Central PMCID: PMC6324079.

65. Huerta-Cepas J, Forslund K, Coelho LP, Szklarczyk D, Jensen LJ, von Mering C, et al. Fast Genome-Wide Functional Annotation through Orthology Assignment by eggNOG-Mapper. Mol Biol Evol. 2017;34(8):2115–22. doi: 10.1093/molbev/msx148 28460117; PubMed Central PMCID: PMC5850834.

66. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25(1):25–9. doi: 10.1038/75556 10802651; PubMed Central PMCID: PMC3037419.

67. Alexa A, Rahnenführer J. Gene set enrichment analysis with topGO. 2009.

68. Luo W, Pant G, Bhavnasi YK, Blanchard SG Jr., Brouwer C. Pathview Web: user friendly pathway visualization and data integration. Nucleic Acids Res. 2017;45(W1):W501–W8. doi: 10.1093/nar/gkx372 28482075; PubMed Central PMCID: PMC5570256.

69. Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017;45(D1):D353–D61. doi: 10.1093/nar/gkw1092 27899662; PubMed Central PMCID: PMC5210567.

70. Conrad KA, Rodriguez R, Salcedo EC, Rauceo JM. The Candida albicans stress response gene Stomatin-Like Protein 3 is implicated in ROS-induced apoptotic-like death of yeast phase cells. PLoS One. 2018;13(2):e0192250. doi: 10.1371/journal.pone.0192250 29389961; PubMed Central PMCID: PMC5794166.


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