SREBP Coordinates Iron and Ergosterol Homeostasis to Mediate Triazole Drug and Hypoxia Responses in the Human Fungal Pathogen
Sterol regulatory element binding proteins (SREBPs) are a class of basic helix-loop-helix transcription factors that regulate diverse cellular responses in eukaryotes. Adding to the recognized importance of SREBPs in human health, SREBPs in the human fungal pathogens Cryptococcus neoformans and Aspergillus fumigatus are required for fungal virulence and susceptibility to triazole antifungal drugs. To date, the exact mechanism(s) behind the role of SREBP in these observed phenotypes is not clear. Here, we report that A. fumigatus SREBP, SrbA, mediates regulation of iron acquisition in response to hypoxia and low iron conditions. To further define SrbA's role in iron acquisition in relation to previously studied fungal regulators of iron metabolism, SreA and HapX, a series of mutants were generated in the ΔsrbA background. These data suggest that SrbA is activated independently of SreA and HapX in response to iron limitation, but that HapX mRNA induction is partially dependent on SrbA. Intriguingly, exogenous addition of high iron or genetic deletion of sreA in the ΔsrbA background was able to partially rescue the hypoxia growth, triazole drug susceptibility, and decrease in ergosterol content phenotypes of ΔsrbA. Thus, we conclude that the fungal SREBP, SrbA, is critical for coordinating genes involved in iron acquisition and ergosterol biosynthesis under hypoxia and low iron conditions found at sites of human fungal infections. These results support a role for SREBP–mediated iron regulation in fungal virulence, and they lay a foundation for further exploration of SREBP's role in iron homeostasis in other eukaryotes.
Vyšlo v časopise:
SREBP Coordinates Iron and Ergosterol Homeostasis to Mediate Triazole Drug and Hypoxia Responses in the Human Fungal Pathogen. PLoS Genet 7(12): e32767. doi:10.1371/journal.pgen.1002374
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002374
Souhrn
Sterol regulatory element binding proteins (SREBPs) are a class of basic helix-loop-helix transcription factors that regulate diverse cellular responses in eukaryotes. Adding to the recognized importance of SREBPs in human health, SREBPs in the human fungal pathogens Cryptococcus neoformans and Aspergillus fumigatus are required for fungal virulence and susceptibility to triazole antifungal drugs. To date, the exact mechanism(s) behind the role of SREBP in these observed phenotypes is not clear. Here, we report that A. fumigatus SREBP, SrbA, mediates regulation of iron acquisition in response to hypoxia and low iron conditions. To further define SrbA's role in iron acquisition in relation to previously studied fungal regulators of iron metabolism, SreA and HapX, a series of mutants were generated in the ΔsrbA background. These data suggest that SrbA is activated independently of SreA and HapX in response to iron limitation, but that HapX mRNA induction is partially dependent on SrbA. Intriguingly, exogenous addition of high iron or genetic deletion of sreA in the ΔsrbA background was able to partially rescue the hypoxia growth, triazole drug susceptibility, and decrease in ergosterol content phenotypes of ΔsrbA. Thus, we conclude that the fungal SREBP, SrbA, is critical for coordinating genes involved in iron acquisition and ergosterol biosynthesis under hypoxia and low iron conditions found at sites of human fungal infections. These results support a role for SREBP–mediated iron regulation in fungal virulence, and they lay a foundation for further exploration of SREBP's role in iron homeostasis in other eukaryotes.
Zdroje
1. KornitzerD 2009 Fungal mechanisms for host iron acquisition. Current opinion in microbiology 12 377 383
2. SchrettlMBeckmannNVargaJHeinekampTJacobsenID 2010 HapX-mediated adaption to iron starvation is crucial for virulence of Aspergillus fumigatus. PLoS Pathog 6 e1001124 doi:10.1371/journal.ppat.1001124
3. SchrettlMIbrahim-GranetODroinSHuerreMLatgeJP 2010 The crucial role of the Aspergillus fumigatus siderophore system in interaction with alveolar macrophages. Microbes and infection/Institut Pasteur 12 1035 1041
4. SchrettlMBignellEKraglCSabihaYLossO 2007 Distinct roles for intra- and extracellular siderophores during Aspergillus fumigatus infection. PLoS Pathog 3 e128 doi:10.1371/journal.ppat.0030128
5. SchrettlMBignellEKraglCJoechlCRogersT 2004 Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence. The Journal of experimental medicine 200 1213 1219
6. HissenAHChowJMPintoLJMooreMM 2004 Survival of Aspergillus fumigatus in serum involves removal of iron from transferrin: the role of siderophores. Infection and immunity 72 1402 1408
7. JungWHKronstadJW 2008 Iron and fungal pathogenesis: a case study with Cryptococcus neoformans. Cellular microbiology 10 277 284
8. JungWHShamAWhiteRKronstadJW 2006 Iron regulation of the major virulence factors in the AIDS-associated pathogen Cryptococcus neoformans. PLoS Biol 4 e410 doi:10.1371/journal.pbio.0040410
9. MendelGA 1961 Studies on iron absorption. I. The relationships between the rate of erythropoiesis, hypoxia and iron absorption. Blood 18 727 736
10. RolfsAKvietikovaIGassmannMWengerRH 1997 Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1. The Journal of biological chemistry 272 20055 20062
11. MukhopadhyayCKMazumderBFoxPL 2000 Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. The Journal of biological chemistry 275 21048 21054
12. LeePJJiangBHChinBYIyerNVAlamJ 1997 Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. The Journal of biological chemistry 272 5375 5381
13. YoonDPastoreYDDivokyVLiuEMlodnickaAE 2006 Hypoxia-inducible factor-1 deficiency results in dysregulated erythropoiesis signaling and iron homeostasis in mouse development. The Journal of biological chemistry 281 25703 25711
14. PeyssonnauxCNizetVJohnsonRS 2008 Role of the hypoxia inducible factors HIF in iron metabolism. Cell cycle 7 28 32
15. SchrettlMKimHSEisendleMKraglCNiermanWC 2008 SreA-mediated iron regulation in Aspergillus fumigatus. Molecular microbiology 70 27 43
16. LiuHGravelatFNChiangLYChenDVanierG 2010 Aspergillus fumigatus AcuM regulates both iron acquisition and gluconeogenesis. Molecular microbiology 78 1038 1054
17. ChangYCBienCMLeeHEspenshadePJKwon-ChungKJ 2007 Sre1p, a regulator of oxygen sensing and sterol homeostasis, is required for virulence in Cryptococcus neoformans. Mol Microbiol 64 614 629
18. ChunCDLiuOWMadhaniHD 2007 A Link between virulence and homeostatic responses to hypoxia during infection by the human fungal pathogen Cryptococcus neoformans. PLoS Pathog 3 e22 doi:10.1371/journal.ppat.0030022
19. WillgerSDPuttikamonkulSKimKHBurrittJBGrahlN 2008 A sterol-regulatory element binding protein is required for cell polarity, hypoxia adaptation, azole drug resistance, and virulence in Aspergillus fumigatus. PLoS Pathog 4 e1000200 doi:10.1371/journal.ppat.1000200
20. GrahlNCramerRAJr 2009 Regulation of hypoxia adaptation: an overlooked virulence attribute of pathogenic fungi? Med Mycol 1 16
21. WezenskySJCramerRA 2010 Implications of hypoxic microenvironments during invasive aspergillosis. Med Mycol
22. ErnstJFTielkerD 2009 Responses to hypoxia in fungal pathogens. Cellular microbiology 11 183 190
23. EspenshadePJ 2006 SREBPs: sterol-regulated transcription factors. Journal of cell science 119 973 976
24. RawsonRB 2003 Control of lipid metabolism by regulated intramembrane proteolysis of sterol regulatory element binding proteins (SREBPs). Biochem Soc Symp 221 231
25. RawsonRB 2003 The SREBP pathway–insights from Insigs and insects. Nat Rev Mol Cell Biol 4 631 640
26. NomuraTHorikawaMShimamuraSHashimotoTSakamotoK 2010 Fat accumulation in Caenorhabditis elegans is mediated by SREBP homolog SBP-1. Genes & nutrition 5 17 27
27. TontonozPKimJBGravesRASpiegelmanBM 1993 ADD1: a novel helix-loop-helix transcription factor associated with adipocyte determination and differentiation. Molecular and cellular biology 13 4753 4759
28. YokoyamaCWangXBriggsMRAdmonAWuJ 1993 SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 75 187 197
29. ToddBLStewartEVBurgJSHughesALEspenshadePJ 2006 Sterol regulatory element binding protein is a principal regulator of anaerobic gene expression in fission yeast. Mol Cell Biol 26 2817 2831
30. HughesALToddBLEspenshadePJ 2005 SREBP pathway responds to sterols and functions as an oxygen sensor in fission yeast. Cell 120 831 842
31. LianTSimmerMID'SouzaCASteenBRZuyderduynSD 2005 Iron-regulated transcription and capsule formation in the fungal pathogen Cryptococcus neoformans. Molecular microbiology 55 1452 1472
32. JungWHShamALianTSinghAKosmanDJ 2008 Iron source preference and regulation of iron uptake in Cryptococcus neoformans. PLoS Pathog 4 e45 doi:10.1371/journal.ppat.0040045
33. JungWHSaikiaSHuGWangJFungCK 2010 HapX positively and negatively regulates the transcriptional response to iron deprivation in Cryptococcus neoformans. PLoS Pathog 6 e1001209 doi:10.1371/journal.ppat.1001209
34. AlmeidaRSWilsonDHubeB 2009 Candida albicans iron acquisition within the host. FEMS yeast research 9 1000 1012
35. HeymannPGeradsMSchallerMDromerFWinkelmannG 2002 The siderophore iron transporter of Candida albicans (Sit1p/Arn1p) mediates uptake of ferrichrome-type siderophores and is required for epithelial invasion. Infection and immunity 70 5246 5255
36. RamananNWangY 2000 A high-affinity iron permease essential for Candida albicans virulence. Science 288 1062 1064
37. SweetSPDouglasLJ 1991 Effect of iron deprivation on surface composition and virulence determinants of Candida albicans. Journal of general microbiology 137 859 865
38. TattersallP 1990 Iron deficiency and candida infection. The Practitioner 234 326
39. KirkpatrickCHGreenIRichRRSchadeAL 1971 Inhibition of growth of Candida albicans by iron-unsaturated lactoferrin: relation to host-defense mechanisms in chronic mucocutaneous candidiasis. The Journal of infectious diseases 124 539 544
40. EsterlyNBBrammerSRCrounseRG 1967 The relationship of transferrin and iron to serum inhibition of Candida albicans. The Journal of investigative dermatology 49 437 442
41. BienCMChangYCNesWDKwon-ChungKJEspenshadePJ 2009 Cryptococcus neoformans Site-2 protease is required for virulence and survival in the presence of azole drugs. Molecular microbiology 74 672 690
42. ChunCDLiuOWMadhaniHD 2007 A link between virulence and homeostatic responses to hypoxia during infection by the human fungal pathogen Cryptococcus neoformans. PLoS Pathog 3 e22 doi:10.1371/journal.ppat.0030022
43. HaasHZadraIStofflerGAngermayrK 1999 The Aspergillus nidulans GATA factor SREA is involved in regulation of siderophore biosynthesis and control of iron uptake. The Journal of biological chemistry 274 4613 4619
44. HortschanskyPEisendleMAl-AbdallahQSchmidtADBergmannS 2007 Interaction of HapX with the CCAAT-binding complex–a novel mechanism of gene regulation by iron. The EMBO journal 26 3157 3168
45. WallnerABlatzerMSchrettlMSargBLindnerH 2009 Ferricrocin, a siderophore involved in intra- and transcellular iron distribution in Aspergillus fumigatus. Applied and environmental microbiology 75 4194 4196
46. KaplanJMcVey WardDCrispRJPhilpottCC 2006 Iron-dependent metabolic remodeling in S. cerevisiae. Biochimica et biophysica acta 1763 646 651
47. HughesALLeeCYBienCMEspenshadePJ 2007 4-Methyl sterols regulate fission yeast SREBP-Scap under low oxygen and cell stress. J Biol Chem 282 24388 24396
48. ToddBLStewartEVBurgJSHughesALEspenshadePJ 2006 Sterol regulatory element binding protein is a principal regulator of anaerobic gene expression in fission yeast. Molecular and cellular biology 26 2817 2831
49. VodischMScherlachKWinklerRHertweckCBraunHP 2011 Analysis of the Aspergillus fumigatus Proteome Reveals Metabolic Changes and the Activation of the Pseurotin A Biosynthesis Gene Cluster in Response to Hypoxia. Journal of proteome research
50. MelladoEDiaz-GuerraTMCuenca-EstrellaMRodriguez-TudelaJL 2001 Identification of two different 14-alpha sterol demethylase-related genes (cyp51A and cyp51B) in Aspergillus fumigatus and other Aspergillus species. Journal of clinical microbiology 39 2431 2438
51. MelladoEGarcia-EffronGBuitragoMJAlcazar-FuoliLCuenca-EstrellaM 2005 Targeted gene disruption of the 14-alpha sterol demethylase (cyp51A) in Aspergillus fumigatus and its role in azole drug susceptibility. Antimicrobial agents and chemotherapy 49 2536 2538
52. WarrilowAGMeloNMartelCMParkerJENesWD 2010 Expression, purification, and characterization of Aspergillus fumigatus sterol 14-alpha demethylase (CYP51) isoenzymes A and B. Antimicrobial agents and chemotherapy 54 4225 4234
53. PrasadTChandraAMukhopadhyayCKPrasadR 2006 Unexpected link between iron and drug resistance of Candida spp.: iron depletion enhances membrane fluidity and drug diffusion, leading to drug-susceptible cells. Antimicrobial agents and chemotherapy 50 3597 3606
54. PontecorvoGRoperJAHemmonsLMMacdonaldKDBuftonAW 1953 The genetics of Aspergillus nidulans. Adv Genet 5 141 238
55. KimSHuJOhYParkJChoiJ 2010 Combining ChIP-chip and expression profiling to model the MoCRZ1 mediated circuit for Ca/calcineurin signaling in the rice blast fungus. PLoS Pathog 6 e1000909 doi:10.1371/journal.ppat.1000909
56. GrahlNPuttikamonkulSMacdonaldJMGamcsikMPNgoLY 2011 In vivo hypoxia and a fungal alcohol dehydrogenase influence the pathogenesis of invasive pulmonary aspergillosis. PLoS Pathog 7 e1002145 doi:10.1371/journal.ppat.1002145
57. PuttikamonkulSWillgerSDGrahlNPerfectJRMovahedN 2010 Trehalose 6-phosphate phosphatase is required for cell wall integrity and fungal virulence but not trehalose biosynthesis in the human fungal pathogen Aspergillus fumigatus. Mol Microbiol 77 891 911
58. ObereggerHSchoeserMZadraIAbtBHaasH 2001 SREA is involved in regulation of siderophore biosynthesis, utilization and uptake in Aspergillus nidulans. Molecular microbiology 41 1077 1089
59. Konetschny-RappSHuschkaHGWinkelmannGJungG 1988 High-performance liquid chromatography of siderophores from fungi. Biology of metals 1 9 17
60. BergerHBasheerABockSReyes-DominguezYDalikT 2008 Dissecting individual steps of nitrogen transcription factor cooperation in the Aspergillus nidulans nitrate cluster. Molecular microbiology 69 1385 1398
61. Alcazar-FuoliLMelladoEGarcia-EffronGLopezJFGrimaltJO 2008 Ergosterol biosynthesis pathway in Aspergillus fumigatus. Steroids 73 339 347
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 12
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