Telomeric (s) in spp. Encode Mediator Subunits That Regulate Distinct Virulence Traits

English version České info

Candida albicans and C. dubliniensis are fungal pathogens of humans. Both species possess TLO genes encoding proteins with homology to the Med2 subunit of Mediator. The more virulent pathogen C. albicans has 15 copies of the TLO gene whereas the less pathogenic species C. dubliniensis has only two (TLO1 and TLO2). In this study we show that a C. dubliniensis mutant missing both TLO1 and TLO2 is defective in virulence functions, including hyphal growth and stress responses but forms increased levels of biofilm. Analysis of gene expression in the tlo1Δ/tlo2Δ mutant revealed extensive differences relative to wild-type cells, including aberrant expression of starvation responses in nutrient-rich medium and retarded expression of hypha-induced transcripts in serum. Tlo1 protein was found to interact with genes and this was associated with both gene activation and repression. TLO1 was found to be better at restoring hyphal growth compared to TLO2 and but was less effective than TLO2 in supressing biofilm formation in the tlo1Δ/tlo2Δ strain. Thus, Tlo proteins regulate many virulence properties in Candida spp. and the expansion of the TLO family in C. albicans may account for the increased adaptability of this species relative to other Candida species.

Vyšlo v časopise: Telomeric (s) in spp. Encode Mediator Subunits That Regulate Distinct Virulence Traits. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004658
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004658

Souhrn

Zdroje

1. LorenzMC, BenderJA, FinkGR (2004) Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryotic Cell 3: 1076–1087.

2. PérezJC, JohnsonAD (2013) Regulatory Circuits That Enable Proliferation of the FungusCandida albicans in a Mammalian Host. PLoS Pathog 9: e1003780.

3. KadoshD, JohnsonAD (2005) Induction of the Candida albicans filamentous growth program by relief of transcriptional repression: a genome-wide analysis. Mol Biol Cell 16: 2903–2912.

4. ConawayRC, ConawayJW (2011) Origins and activity of the Mediator complex. Seminars in Cell and Developmental Biology 22: 729–734.

5. MalikS, RoederRG (2010) The metazoan Mediator co-activator complex as an integrative hub for transcriptional regulation. Nature Reviews Genetics 11: 761–772.

6. BjörklundS, GustafssonCM (2005) The yeast Mediator complex and its regulation. Trends in Biochemical Sciences 30: 240–244.

7. ThompsonCM, YoungRA (1995) General requirement for RNA polymerase II holoenzymes in vivo. Proc Natl Acad Sci USA 92: 4587–4590.

8. AnsariSA, MorseRH (2013) Mechanisms of Mediator complex action in transcriptional activation. Cell Mol Life Sci 70: 2743–2756.

9. ZhangA, PetrovKO, HyunER, LiuZ, GerberSA, et al. (2012) The Tlo Proteins Are Stoichiometric Components of Candida albicans Mediator Anchored via the Med3 Subunit. Eukaryotic Cell 11: 874–884.

10. BraunBR, van Het HoogM, d'EnfertC, MartchenkoM, DunganJ, et al. (2005) A human-curated annotation of the Candida albicans genome. PLoS Genet 1: 36–57.

11. van Het HoogM, RastTJ, MartchenkoM, GrindleS, DignardD, et al. (2007) Assembly of the Candida albicans genome into sixteen supercontigs aligned on the eight chromosomes. Genome Biol 8: R52.

12. AndersonMZ, BallerJA, DulmageK, WigenL, BermanJ (2012) The Three Clades of the Telomere-Associated TLO Gene Family of Candida albicans Have Different Splicing, Localization, and Expression Features. Eukaryotic Cell 11: 1268–1275.

13. BourbonH-M (2008) Comparative genomics supports a deep evolutionary origin for the large, four-module transcriptional mediator complex. Nucleic Acids Res 36: 3993–4008.

14. JacksonAP, GambleJA, YeomansT, MoranGP, SaundersD, et al. (2009) Comparative genomics of the fungal pathogens Candida dubliniensis and Candida albicans. Genome Res 19: 2231–2244.

15. UwamahoroN, QuY, JelicicB, LoTL, BeaurepaireC, et al. (2012) The Functions of Mediator in Candida albicans Support a Role in Shaping Species-Specific Gene Expression. PLoS Genet 8: e1002613.

16. ZhangA, LiuZ, MyersLC (2013) Differential Regulation of White-Opaque Switching by Individual Subunits of Candida albicans Mediator. Eukaryotic Cell 12: 1293–1304.

17. MoranGP, ColemanDC, SullivanDJ (2012) Candida albicans versus Candida dubliniensis: Why Is C. albicans More Pathogenic? Int J Microbiol 2012: 205921.

18. StokesC, MoranGP, SpieringMJ, ColeGT, ColemanDC, et al. (2007) Lower filamentation rates of Candida dubliniensis contribute to its lower virulence in comparison with Candida albicans. Fungal Genet Biol 44: 920–931.

19. MoranGP, MacCallumDM, SpieringMJ, ColemanDC, SullivanDJ (2007) Differential regulation of the transcriptional repressor NRG1 accounts for altered host-cell interactions in Candida albicans and Candida dubliniensis. Mol Microbiol 66: 915–929.

20. O'ConnorL, CapliceN, ColemanDC, SullivanDJ, MoranGP (2010) Differential filamentation of Candida albicans and C. dubliniensis is governed by nutrient regulation of UME6 expression. Eukaryotic Cell doi:10.1128/EC.00042-10

21. EnjalbertB, MoranGP, VaughanC, YeomansT, MacCallumDM, et al. (2009) 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 72: 216–228.

22. MoranGP, ColemanDC, SullivanDJ (2011) Comparative genomics and the evolution of pathogenicity in human pathogenic fungi. Eukaryotic Cell 10: 34–42.

23. MillerC, MaticI, MaierKC, SchwalbB, RoetherS, et al. (2012) Mediator Phosphorylation Prevents Stress Response Transcription During Non-stress Conditions. Journal of Biological Chemistry 287: 44017–44026.

24. AnsariSA, GanapathiM, BenschopJJ, HolstegeFCP, WadeJT, et al. (2011) Distinct role of Mediator tail module in regulation of SAGA-dependent, TATA-containing genes in yeast. EMBO J 31: 44–57.

25. ZakikhanyK, NaglikJR, Schmidt WesthausenA, HollandG, SchallerM, et al. (2007) In vivo transcript profiling of Candida albicans identifies a gene essential for interepithelial dissemination. Cell Microbiol 9: 2938–2954.

26. MarcilA, GadouryC, AshJ, ZhangJ, NantelA, et al. (2008) Analysis of PRA1 and its relationship to Candida albicans- macrophage interactions. Infect Immun 76: 4345–4358.

27. van de PeppelJ, KettelarijN, van BakelH, KockelkornTTJP, van LeenenD, et al. (2005) Mediator Expression Profiling Epistasis Reveals a Signal Transduction Pathway with Antagonistic Submodules and Highly Specific Downstream Targets. Molecular Cell 19: 511–522.

28. ParkD, LeeY, BhupindersinghG, IyerVR (2013) Widespread misinterpretable ChIP-seq bias in yeast. PLoS ONE 8: e83506 doi:10.1371/journal.pone.0083506

29. TeytelmanL, ThurtleDM, RineJ, van OudenaardenA (2013) Highly expressed loci are vulnerable to misleading ChIP localization of multiple unrelated proteins. Proceedings of the National Academy of Sciences 110: 18602–18607.

30. FanX, StruhlK (2009) Where Does Mediator Bind In Vivo? PLoS ONE 4: e5029 doi:10.1371/journal.pone.0005029.t002

31. UwamahoroN, Verma-GaurJ, ShenHH, QuY, LewisR, et al. (2014) The Pathogen Candida albicans Hijacks Pyroptosis for Escape from Macrophages. mBio 5: e00003–14–e00003–14 doi:10.1128/mBio.00003-14

32. MehtaS, MiklosI, SipiczkiM, SenguptaS, SharmaN (2009) The Med8 mediator subunit interacts with the Rpb4 subunit of RNA polymerase II and Ace2 transcriptional activator in Schizosaccharomyces pombe. FEBS Lett 583: 3115–3120.

33. LiuZ, MyersLC (2012) Med5(Nut1) and Med17(Srb4) are direct targets of mediator histone H4 tail interactions. PLoS ONE 7: e38416.

34. PengJ, ZhouJQ (2012) The tail-module of yeast Mediator complex is required for telomere heterochromatin maintenance. Nucleic Acids Res 40: 581–593.

35. ZhuX, WirénM, SinhaI, RasmussenNN, LinderT, et al. (2006) Genome-Wide Occupancy Profile of Mediator and the Srb8-11 Module Reveals Interactions with Coding Regions. Molecular Cell 22: 169–178.

36. AndrauJ-C, van de PaschL, LijnzaadP, BijmaT, KoerkampMG, et al. (2006) Genome-Wide Location of the Coactivator Mediator: Binding without Activation and Transient Cdk8 Interaction on DNA. Molecular Cell 22: 179–192.

37. LiuH, KöhlerJ, FinkGR (1994) Suppression of hyphal formation in Candida albicans by mutation of a STE12 homolog. Science 266: 1723–1726.

38. LeeKL, BuckleyHR, CampbellCC (1975) An amino acid liquid synthetic medium for the development of mycellal and yeast forms of Candida albicans. Med Mycol 13: 148–153.

39. Al-MosaidA, SullivanDJ, ColemanDC (2003) Differentiation of Candida dubliniensis from Candida albicans on Pal's agar. J Clin Microbiol 41: 4787–4789.

40. ReussO, VikA, KolterR, MorschhäuserJ (2004) The SAT1 flipper, an optimized tool for gene disruption in Candida albicans. Gene 341: 119–127.

41. SpieringMJ, MoranGP, ChauvelM, MacCallumDM, HigginsJ, et al. (2010) Comparative transcript profiling of Candida albicans and Candida dubliniensis identifies SFL2, a C. albicans gene required for virulence in a reconstituted epithelial infection model. Eukaryotic Cell 9: 251–265.

42. SubramanianA, TamayoP, MoothaVK, MukherjeeS, EbertBL, et al. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102: 15545–15550.

43. SellamA, van het HoogM, TebbjiF, BeaurepaireC, WhitewayM, et al. (2014) Modeling the Transcriptional Regulatory Network That Controls the Early Hypoxic Response in Candida albicans. Eukaryotic Cell 13: 675–690.

44. KetelC, WangHSW, McClellanM, BouchonvilleK, SelmeckiA, et al. (2009) Neocentromeres form efficiently at multiple possible loci in Candida albicans. PLoS Genet 5: e1000400.

45. GentlemanRC, CareyVJ, BatesDM, BolstadB, DettlingM, et al. (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5: R80.

46. ToedlingJ, SkylarO, SklyarO, KruegerT, FischerJJ, et al. (2007) Ringo–an R/Bioconductor package for analyzing ChIP-chip readouts. BMC Bioinformatics 8: 221.

47. WestessonO, SkinnerM, HolmesI (2013) Visualizing next-generation sequencing data with JBrowse. Brief Bioinformatics 14: 172–177.