A Novel CH Transcription Factor that Regulates Expression Interdependently with GliZ in

English version České info

Fungal infections cause severe problems for immune-compromised individuals. Current antifungal treatment is problematic, as some therapies are toxic to humans and others are not highly effective. These fungal infections also burden hospitals, as costs to treat and prevent such disease runs high. Aspergillus fumigatus is the most common cause of fungal infections worldwide. A. fumigatus produces a variety of toxins that aid the fungus in survival both in the environment and within host systems. Genes involved in producing such toxins are often found in clusters within the genome, being almost exclusively dependent on transcription factors located within the clusters. Gliotoxin, one such toxin, is known to negatively affect immune cell function. Although gliotoxin has been studied extensively, information is still lacking with regards to regulation of gliotoxin biosynthesis. Our lab has discovered a novel C2H2 transcription factor, GipA, which plays an important role in gliotoxin production. Not only does GipA enhance gliotoxin production when over-expressed, but loss of GipA causes a significant reduction in gliotoxin production. As this gene is not located within the gliotoxin cluster, understanding its mode of action and upstream partners could shed light on toxin production in general and lead to better, more effective antifungal therapies.

Vyšlo v časopise: A Novel CH Transcription Factor that Regulates Expression Interdependently with GliZ in. PLoS Genet 10(5): e32767. doi:10.1371/journal.pgen.1004336
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004336

Souhrn

Zdroje

1. KameiK, WatanabeA (2005) Aspergillus mycotoxins and their effect on the host. Med Mycol 43 Suppl 1: S95–99.

2. BayramO, BrausGH (2012) Coordination of secondary metabolism and development in fungi: the velvet family of regulatory proteins. FEMS Microbiol Rev 36: 1–24.

3. KellerNP, TurnerG, BennettJW (2005) Fungal secondary metabolism - from biochemistry to genomics. Nat Rev Microbiol 3: 937–947.

4. BrakhageAA (2013) Regulation of fungal secondary metabolism. Nat Rev Microbiol 11: 21–32.

5. YuJH, KellerN (2005) Regulation of secondary metabolism in filamentous fungi. Annu Rev Phytopathol 43: 437–458.

6. CalvoAM, WilsonRA, BokJW, KellerNP (2002) Relationship between secondary metabolism and fungal development. Microbiol Mol Biol Rev 66: 447–459 table of contents.

7. SiglC, HaasH, SpechtT, PfallerK, KurnsteinerH, et al. Among developmental regulators, StuA but not BrlA is essential for penicillin V production in Penicillium chrysogenum. Appl Environ Microbiol 77: 972–982.

8. BrakhageAA, BrowneP, TurnerG (1992) Regulation of Aspergillus nidulans penicillin biosynthesis and penicillin biosynthesis genes acvA and ipnA by glucose. J Bacteriol 174: 3789–3799.

9. LatgeJP (1999) Aspergillus fumigatus and aspergillosis. Clin Microbiol Rev 12: 310–350.

10. YuJ, BhatnagarD, EhrlichKC (2002) Aflatoxin biosynthesis. Rev Iberoam Micol 19: 191–200.

11. McDonaghA, FedorovaND, CrabtreeJ, YuY, KimS, et al. (2008) Sub-telomere directed gene expression during initiation of invasive aspergillosis. PLoS Pathog 4: e1000154.

12. BokJW, ChungD, BalajeeSA, MarrKA, AndesD, et al. (2006) GliZ, a transcriptional regulator of gliotoxin biosynthesis, contributes to Aspergillus fumigatus virulence. Infect Immun 74: 6761–6768.

13. GardinerDM, HowlettBJ (2005) Bioinformatic and expression analysis of the putative gliotoxin biosynthetic gene cluster of Aspergillus fumigatus. FEMS Microbiol Lett 248: 241–248.

14. FoxEM, GardinerDM, KellerNP, HowlettBJ (2008) A Zn(II)2Cys6 DNA binding protein regulates the sirodesmin PL biosynthetic gene cluster in Leptosphaeria maculans. Fungal Genet Biol 45: 671–682.

15. ToddRB, AndrianopoulosA (1997) Evolution of a fungal regulatory gene family: the Zn(II)2Cys6 binuclear cluster DNA binding motif. Fungal Genet Biol 21: 388–405.

16. EhrlichKC, MontalbanoBG, CaryJW (1999) Binding of the C6-zinc cluster protein, AFLR, to the promoters of aflatoxin pathway biosynthesis genes in Aspergillus parasiticus. Gene 230: 249–257.

17. LiangSD, MarmorsteinR, HarrisonSC, PtashneM (1996) DNA sequence preferences of GAL4 and PPR1: how a subset of Zn2 Cys6 binuclear cluster proteins recognizes DNA. Mol Cell Biol 16: 3773–3780.

18. VasheeS, XuH, JohnstonSA, KodadekT (1993) How do “Zn2 cys6” proteins distinguish between similar upstream activation sites? Comparison of the DNA-binding specificity of the GAL4 protein in vitro and in vivo. J Biol Chem 268: 24699–24706.

19. SchrettlM, CarberryS, KavanaghK, HaasH, JonesGW, et al. (2010) Self-protection against gliotoxin–a component of the gliotoxin biosynthetic cluster, GliT, completely protects Aspergillus fumigatus against exogenous gliotoxin. PLoS Pathog 6: e1000952.

20. MogensenJ, NielsenHB, HofmannG, NielsenJ (2006) Transcription analysis using high-density micro-arrays of Aspergillus nidulans wild-type and creA mutant during growth on glucose or ethanol. Fungal Genet Biol 43: 593–603.

21. FengGH, LeonardTJ (1998) Culture conditions control expression of the genes for aflatoxin and sterigmatocystin biosynthesis in Aspergillus parasiticus and A. nidulans. Appl Environ Microbiol 64: 2275–2277.

22. BrandA (2012) Hyphal growth in human fungal pathogens and its role in virulence. Int J Microbiol 2012: 517529.

23. ComeraC, AndreK, LaffitteJ, ColletX, GaltierP, et al. (2007) Gliotoxin from Aspergillus fumigatus affects phagocytosis and the organization of the actin cytoskeleton by distinct signalling pathways in human neutrophils. Microbes Infect 9: 47–54.

24. KupfahlC, HeinekampT, GeginatG, RuppertT, HartlA, et al. (2006) Deletion of the gliP gene of Aspergillus fumigatus results in loss of gliotoxin production but has no effect on virulence of the fungus in a low-dose mouse infection model. Mol Microbiol 62: 292–302.

25. PahlHL, KraussB, Schulze-OsthoffK, DeckerT, TraencknerEB, et al. (1996) The immunosuppressive fungal metabolite gliotoxin specifically inhibits transcription factor NF-kappaB. J Exp Med 183: 1829–1840.

26. Kwon-ChungKJ, SuguiJA (2009) What do we know about the role of gliotoxin in the pathobiology of Aspergillus fumigatus? Med Mycol 47 Suppl 1: S97–103.

27. GardinerDM, JarvisRS, HowlettBJ (2005) The ABC transporter gene in the sirodesmin biosynthetic gene cluster of Leptosphaeria maculans is not essential for sirodesmin production but facilitates self-protection. Fungal Genet Biol 42: 257–263.

28. ScharfDH, HeinekampT, RemmeN, HortschanskyP, BrakhageAA, et al. (2012) Biosynthesis and function of gliotoxin in Aspergillus fumigatus. Appl Microbiol Biotechnol 93: 467–472.

29. BernardoPH, BraschN, ChaiCL, WaringP (2003) A novel redox mechanism for the glutathione-dependent reversible uptake of a fungal toxin in cells. J Biol Chem 278: 46549–46555.

30. CramerRAJr, GamcsikMP, BrookingRM, NajvarLK, KirkpatrickWR, et al. (2006) Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production. Eukaryot Cell 5: 972–980.

31. SpikesS, XuR, NguyenCK, ChamilosG, KontoyiannisDP, et al. (2008) Gliotoxin production in Aspergillus fumigatus contributes to host-specific differences in virulence. J Infect Dis 197: 479–486.

32. WaringP, NewcombeN, EdelM, LinQH, JiangH, et al. (1994) Cellular uptake and release of the immunomodulating fungal toxin gliotoxin. Toxicon 32: 491–504.

33. YoshidaLS, AbeS, TsunawakiS (2000) Fungal gliotoxin targets the onset of superoxide-generating NADPH oxidase of human neutrophils. Biochem Biophys Res Commun 268: 716–723.

34. FoxEM, HowlettBJ (2008) Biosynthetic gene clusters for epipolythiodioxopiperazines in filamentous fungi. Mycol Res 112: 162–169.

35. GardinerDM, CozijnsenAJ, WilsonLM, PedrasMS, HowlettBJ (2004) The sirodesmin biosynthetic gene cluster of the plant pathogenic fungus Leptosphaeria maculans. Mol Microbiol 53: 1307–1318.

36. BokJW, BalajeeSA, MarrKA, AndesD, NielsenKF, et al. (2005) LaeA, a regulator of morphogenetic fungal virulence factors. Eukaryot Cell 4: 1574–1582.

37. BokJW, KellerNP (2004) LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot Cell 3: 527–535.

38. ParkHS, BayramO, BrausGH, KimSC, YuJH (2012) Characterization of the velvet regulators in Aspergillus fumigatus. Mol Microbiol 86: 937–953.

39. MukherjeePK, KenerleyCM (2010) Regulation of morphogenesis and biocontrol properties in Trichoderma virens by a VELVET protein, Vel1. Appl Environ Microbiol 76: 2345–2352.

40. KrijgsheldP, BleichrodtR, van VeluwGJ, WangF, MullerWH, et al. (2013) Development in Aspergillus. Stud Mycol 74: 1–29.

41. SekonyelaR, PalmerJM, BokJW, JainS, BerthierE, et al. (2013) RsmA Regulates Aspergillus fumigatus Gliotoxin Cluster Metabolites Including Cyclo(L-Phe-L-Ser), a Potential New Diagnostic Marker for Invasive Aspergillosis. PLoS One 8: e62591.

42. JainR, ValianteV, RemmeN, DocimoT, HeinekampT, et al. (2011) The MAP kinase MpkA controls cell wall integrity, oxidative stress response, gliotoxin production and iron adaptation in Aspergillus fumigatus. Mol Microbiol 82: 39–53.

43. XueT, NguyenCK, RomansA, KontoyiannisDP, MayGS (2004) Isogenic auxotrophic mutant strains in the Aspergillus fumigatus genome reference strain AF293. Arch Microbiol 182: 346–353.

44. AleksenkoA, ClutterbuckAJ (1997) Autonomous plasmid replication in Aspergillus nidulans: AMA1 and MATE elements. Fungal Genet Biol 21: 373–387.

45. GemsD, JohnstoneIL, ClutterbuckAJ (1991) An autonomously replicating plasmid transforms Aspergillus nidulans at high frequency. Gene 98: 61–67.

46. UkilL, VaradarajA, GovindaraghavanM, LiuHL, OsmaniSA (2008) Copy number suppressors of the Aspergillus nidulans nimA1 mitotic kinase display distinctive and highly dynamic cell cycle-regulated locations. Eukaryot Cell 7: 2087–2099.

47. OsherovN, KontoyiannisDP, RomansA, MayGS (2001) Resistance to itraconazole in Aspergillus nidulans and Aspergillus fumigatus is conferred by extra copies of the A. nidulans P-450 14alpha-demethylase gene, pdmA. J Antimicrob Chemother 48: 75–81.

48. BrayerKJ, SegalDJ (2008) Keep your fingers off my DNA: protein-protein interactions mediated by C2H2 zinc finger domains. Cell Biochem Biophys 50: 111–131.

49. BrownRS (2005) Zinc finger proteins: getting a grip on RNA. Curr Opin Struct Biol 15: 94–98.

50. Berg JM TJ, Stryer L (2002) Examination of Three-Dimensional Structure Enhances Our Understanding of Evolutionary Relationships. Biochemistry. 5th ed. New York: W H Freeman.

51. WankeC, EckertS, AlbrechtG, van HartingsveldtW, PuntPJ, et al. (1997) The Aspergillus niger GCN4 homologue, cpcA, is transcriptionally regulated and encodes an unusual leucine zipper. Mol Microbiol 23: 23–33.

52. PerrinRM, FedorovaND, BokJW, CramerRA, WortmanJR, et al. (2007) Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLoS Pathog 3: e50.

53. SanchezJF, SomozaAD, KellerNP, WangCC (2012) Advances in Aspergillus secondary metabolite research in the post-genomic era. Nat Prod Rep 29: 351–371.

54. WolfeSA, NekludovaL, PaboCO (2000) DNA recognition by Cys2His2 zinc finger proteins. Annu Rev Biophys Biomol Struct 29: 183–212.

55. KellerNP, NesbittC, SarrB, PhillipsTD, BurowGB (1997) pH Regulation of Sterigmatocystin and Aflatoxin Biosynthesis in Aspergillus spp. Phytopathology 87: 643–648.

56. BrakhageAA, SproteP, Al-AbdallahQ, GehrkeA, PlattnerH, et al. (2004) Regulation of penicillin biosynthesis in filamentous fungi. Adv Biochem Eng Biotechnol 88: 45–90.

57. CaryJW, Harris-CowardPY, EhrlichKC, MackBM, KaleSP, et al. (2012) NsdC and NsdD affect Aspergillus flavus morphogenesis and aflatoxin production. Eukaryot Cell 11: 1104–1111.

58. RuijterGJ, VisserJ (1997) Carbon repression in Aspergilli. FEMS Microbiol Lett 151: 103–114.

59. Arratia-QuijadaJ, SanchezO, ScazzocchioC, AguirreJ (2012) FlbD, a Myb transcription factor of Aspergillus nidulans, is uniquely involved in both asexual and sexual differentiation. Eukaryot Cell 11: 1132–1142.

60. GarziaA, EtxebesteO, Herrero-GarciaE, UgaldeU, EspesoEA (2010) The concerted action of bZip and cMyb transcription factors FlbB and FlbD induces brlA expression and asexual development in Aspergillus nidulans. Mol Microbiol 75: 1314–1324.

61. BergmannS, FunkAN, ScherlachK, SchroeckhV, ShelestE, et al. (2010) Activation of a silent fungal polyketide biosynthesis pathway through regulatory cross talk with a cryptic nonribosomal peptide synthetase gene cluster. Appl Environ Microbiol 76: 8143–8149.

62. ReyesG, RomansA, NguyenCK, MayGS (2006) Novel mitogen-activated protein kinase MpkC of Aspergillus fumigatus is required for utilization of polyalcohol sugars. Eukaryot Cell 5: 1934–1940.

63. SchoberleTJ, Nguyen-ColemanCK, MayGS (2013) Plasmids for increased efficiency of vector construction and genetic engineering in filamentous fungi. Fungal Genet Biol 58–59: 1–9.

64. MayGS (1989) The highly divergent beta-tubulins of Aspergillus nidulans are functionally interchangeable. J Cell Biol 109: 2267–2274.

65. Maniatis T, Fritsch EF, Sambrook J (1982) Molecular Cloning: A Laboratory Manual. New York: Cold Spring Harbor Laboratory. 521 p.

66. JinJ, LeeYK, WickesBL (2004) Simple chemical extraction method for DNA isolation from Aspergillus fumigatus and other Aspergillus species. J Clin Microbiol 42: 4293–4296.

67. NiermanWC, PainA, AndersonMJ, WortmanJR, KimHS, et al. (2005) Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature 438: 1151–1156.

68. MagnaniE, BartlingL, HakeS (2006) From Gateway to MultiSite Gateway in one recombination event. BMC Mol Biol 7: 46.

69. LamKN, van BakelH, CoteAG, van der VenA, HughesTR (2011) Sequence specificity is obtained from the majority of modular C2H2 zinc-finger arrays. Nucleic Acids Res 39: 4680–4690.

70. CoyleCM, PanaccioneDG (2005) An ergot alkaloid biosynthesis gene and clustered hypothetical genes from Aspergillus fumigatus. Appl Environ Microbiol 71: 3112–3118.

71. SchrettlM, BignellE, KraglC, SabihaY, LossO, et al. (2007) Distinct roles for intra- and extracellular siderophores during Aspergillus fumigatus infection. PLoS Pathog 3: 1195–1207.

72. AmesBD, HaynesSW, GaoX, EvansBS, KelleherNL, et al. (2011) Complexity generation in fungal peptidyl alkaloid biosynthesis: oxidation of fumiquinazoline A to the heptacyclic hemiaminal fumiquinazoline C by the flavoenzyme Af12070 from Aspergillus fumigatus. Biochemistry 50: 8756–8769.

73. AmesBD, LiuX, WalshCT (2010) Enzymatic processing of fumiquinazoline F: a tandem oxidative-acylation strategy for the generation of multicyclic scaffolds in fungal indole alkaloid biosynthesis. Biochemistry 49: 8564–8576.

74. O'HanlonKA, GallagherL, SchrettlM, JochlC, KavanaghK, et al. (2012) Nonribosomal peptide synthetase genes pesL and pes1 are essential for Fumigaclavine C production in Aspergillus fumigatus. Appl Environ Microbiol 78: 3166–3176.

75. ChooiYH, FangJ, LiuH, FillerSG, WangP, et al. (2013) Genome mining of a prenylated and immunosuppressive polyketide from pathogenic fungi. Org Lett 15: 780–783.

76. TsaiHF, WheelerMH, ChangYC, Kwon-ChungKJ (1999) A developmentally regulated gene cluster involved in conidial pigment biosynthesis in Aspergillus fumigatus. J Bacteriol 181: 6469–6477.

77. YinWB, BaccileJA, BokJW, ChenY, KellerNP, et al. (2013) A nonribosomal peptide synthetase-derived iron(III) complex from the pathogenic fungus Aspergillus fumigatus. J Am Chem Soc 135: 2064–2067.

78. LimFY, HouY, ChenY, OhJH, LeeI, et al. (2012) Genome-based cluster deletion reveals an endocrocin biosynthetic pathway in Aspergillus fumigatus. Appl Environ Microbiol 78: 4117–4125.

79. BerthierE, LimFY, DengQ, GuoCJ, KontoyiannisDP, et al. (2013) Low-volume toolbox for the discovery of immunosuppressive fungal secondary metabolites. PLoS Pathog 9: e1003289.

80. LinHC, ChooiYH, DhingraS, XuW, CalvoAM, et al. (2013) The fumagillin biosynthetic gene cluster in Aspergillus fumigatus encodes a cryptic terpene cyclase involved in the formation of beta-trans-bergamotene. J Am Chem Soc 135: 4616–4619.

81. MaiyaS, GrundmannA, LiX, LiSM, TurnerG (2007) Identification of a hybrid PKS/NRPS required for pseurotin A biosynthesis in the human pathogen Aspergillus fumigatus. Chembiochem 8: 1736–1743.

82. VodischM, ScherlachK, WinklerR, HertweckC, BraunHP, et al. (2011) Analysis of the Aspergillus fumigatus proteome reveals metabolic changes and the activation of the pseurotin A biosynthesis gene cluster in response to hypoxia. J Proteome Res 10: 2508–2524.