Proteomic profiling of the monothiol glutaredoxin Grx3 reveals its global role in the regulation of iron dependent processes
Autoři:
Selma S. Alkafeef aff001; Shelley Lane aff001; Clinton Yu aff003; Tingting Zhou aff001; Norma V. Solis aff004; Scott G. Filler aff004; Lan Huang aff003; Haoping Liu aff001
Působiště autorů:
Department of Biological Chemistry, University of California, Irvine, California, United States of America
aff001; Department of Biochemistry, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
aff002; Department of Physiology & Biophysics, University of California, Irvine, California, United States of America
aff003; Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America
aff004; David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
aff005
Vyšlo v časopise:
Proteomic profiling of the monothiol glutaredoxin Grx3 reveals its global role in the regulation of iron dependent processes. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008881
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008881
Souhrn
Iron is an essential nutrient required as a cofactor for many biological processes. As a fungal commensal-pathogen of humans, Candida albicans encounters a range of bioavailable iron levels in the human host and maintains homeostasis with a conserved regulatory circuit. How C. albicans senses and responds to iron availability is unknown. In model yeasts, regulation of the iron homeostasis circuit requires monothiol glutaredoxins (Grxs), but their functions beyond the regulatory circuit are unclear. Here, we show Grx3 is required for virulence and growth on low iron for C. albicans. To explore the global roles of Grx3, we applied a proteomic approach and performed in vivo cross-linked tandem affinity purification coupled with mass spectrometry. We identified a large number of Grx3 interacting proteins that function in diverse biological processes. This included Fra1 and Bol2/Fra2, which function with Grxs in intracellular iron trafficking in other organisms. Grx3 interacts with and regulates the activity of Sfu1 and Hap43, components of the C. albicans iron regulatory circuit. Unlike the regulatory circuit, which determines expression or repression of target genes in response to iron availability, Grx3 amplifies levels of gene expression or repression. Consistent with the proteomic data, the grx3 mutant is sensitive to heat shock, oxidative, nitrosative, and genotoxic stresses, and shows growth dependence on histidine, leucine, and tryptophan. We suggest Grx3 is a conserved global regulator of iron-dependent processes occurring within the cell.
Klíčová slova:
Biosynthesis – Candida albicans – Gene expression – Homeostasis – Mouse models – Saccharomyces cerevisiae – Transcription factors – Transcriptional control
Zdroje
1. Almeida RS, Wilson D, Hube B. Candida albicans iron acquisition within the host. FEMS Yeast Res. 2009;9(7):1000–12. doi: 10.1111/j.1567-1364.2009.00570.x 19788558
2. Noble SM. Candida albicans specializations for iron homeostasis: from commensalism to virulence. Curr Opin Microbiol. 2013;16(6):708–15. doi: 10.1016/j.mib.2013.09.006 24121029
3. Lan CY, Rodarte G, Murillo LA, Jones T, Davis RW, Dungan J, et al. Regulatory networks affected by iron availability in Candida albicans. Mol Microbiol. 2004;53(5):1451–69. doi: 10.1111/j.1365-2958.2004.04214.x 15387822
4. Chen C, Pande K, French SD, Tuch BB, Noble SM. An iron homeostasis regulatory circuit with reciprocal roles in Candida albicans commensalism and pathogenesis. Cell Host Microbe. 2011;10(2):118–35. doi: 10.1016/j.chom.2011.07.005 21843869
5. Chen C, Noble SM. Post-transcriptional regulation of the Sef1 transcription factor controls the virulence of Candida albicans in its mammalian host. PLoS Pathog. 2012;8(11):e1002956. doi: 10.1371/journal.ppat.1002956 23133381
6. Baek YU, Li M, Davis DA. Candida albicans ferric reductases are differentially regulated in response to distinct forms of iron limitation by the Rim101 and CBF transcription factors. Eukaryot Cell. 2008;7(7):1168–79. doi: 10.1128/EC.00108-08 18503007
7. Singh RP, Prasad HK, Sinha I, Agarwal N, Natarajan K. Cap2-HAP complex is a critical transcriptional regulator that has dual but contrasting roles in regulation of iron homeostasis in Candida albicans. J Biol Chem. 2011;286(28):25154–70. doi: 10.1074/jbc.M111.233569 21592964
8. Hsu PC, Yang CY, Lan CY. Candida albicans Hap43 is a repressor induced under low-iron conditions and is essential for iron-responsive transcriptional regulation and virulence. Eukaryot Cell. 2011;10(2):207–25. doi: 10.1128/EC.00158-10 21131439
9. Pelletier B, Beaudoin J, Mukai Y, Labbe S. Fep1, an Iron Sensor Regulating Iron Transporter Gene Expression in Schizosaccharomyces pombe. J Biol Chem. 2002;277(25):22950–8. doi: 10.1074/jbc.M202682200 11956219
10. Mercier A, Pelletier B, Labbe S. A transcription factor cascade involving Fep1 and the CCAAT-binding factor Php4 regulates gene expression in response to iron deficiency in the fission yeast Schizosaccharomyces pombe. Eukaryot Cell. 2006;5(11):1866–81. doi: 10.1128/EC.00199-06 16963626
11. Chao LY, Marletta MA, Rine J. Sre1, an Iron-Modulated GATA DNA-Binding Protein of Iron-Uptake Genes in the Fungal Pathogen Histoplasma capsulatum. Biochemistry. 2008;47(27):7274–83. doi: 10.1021/bi800066s 18549241
12. Hwang LH, Seth E, Gilmore SA, Sil A. SRE1 regulates iron-dependent and -independent pathways in the fungal pathogen Histoplasma capsulatum. Eukaryot Cell. 2012;11(1):16–25. doi: 10.1128/EC.05274-11 22117028
13. Jung WH, Sham A, White R, Kronstad JW. Iron regulation of the major virulence factors in the AIDS-associated pathogen Cryptococcus neoformans. PLoS Biol. 2006;4(12):e410. doi: 10.1371/journal.pbio.0040410 17121456
14. Jung WH, Saikia S, Hu G, Wang J, Fung CK, D'Souza C, et al. HapX positively and negatively regulates the transcriptional response to iron deprivation in Cryptococcus neoformans. PLoS Pathog. 2010;6(11):e1001209. doi: 10.1371/journal.ppat.1001209 21124817
15. Li H, Outten CE. Monothiol CGFS glutaredoxins and BolA-like proteins: [2Fe-2S] binding partners in iron homeostasis. Biochemistry. 2012;51(22):4377–89. doi: 10.1021/bi300393z 22583368
16. Zaffagnini M, Michelet L, Massot V, Trost P, Lemaire SD. Biochemical characterization of glutaredoxins from Chlamydomonas reinhardtii reveals the unique properties of a chloroplastic CGFS-type glutaredoxin. J Biol Chem. 2008;283(14):8868–76. doi: 10.1074/jbc.M709567200 18216016
17. Muhlenhoff U, Molik S, Godoy JR, Uzarska MA, Richter N, Seubert A, et al. Cytosolic monothiol glutaredoxins function in intracellular iron sensing and trafficking via their bound iron-sulfur cluster. Cell Metab. 2010;12(4):373–85. doi: 10.1016/j.cmet.2010.08.001 20889129
18. Braymer JJ, Lill R. Iron-sulfur cluster biogenesis and trafficking in mitochondria. J Biol Chem. 2017;292(31):12754–63. doi: 10.1074/jbc.R117.787101 28615445
19. Kumanovics A, Chen OS, Li L, Bagley D, Adkins EM, Lin H, et al. Identification of FRA1 and FRA2 as genes involved in regulating the yeast iron regulon in response to decreased mitochondrial iron-sulfur cluster synthesis. J Biol Chem. 2008;283(16):10276–86. doi: 10.1074/jbc.M801160200 18281282
20. Ojeda L, Keller G, Muhlenhoff U, Rutherford JC, Lill R, Winge DR. Role of glutaredoxin-3 and glutaredoxin-4 in the iron regulation of the Aft1 transcriptional activator in Saccharomyces cerevisiae. J Biol Chem. 2006;281(26):17661–9. doi: 10.1074/jbc.M602165200 16648636
21. Pujol-Carrion N, Belli G, Herrero E, Nogues A, de la Torre-Ruiz MA. Glutaredoxins Grx3 and Grx4 regulate nuclear localisation of Aft1 and the oxidative stress response in Saccharomyces cerevisiae. J Cell Sci. 2006;119(Pt 21):4554–64. doi: 10.1242/jcs.03229 17074835
22. Li H, Mapolelo DT, Dingra NN, Naik SG, Lees NS, Hoffman BM, et al. The yeast iron regulatory proteins Grx3/4 and Fra2 form heterodimeric complexes containing a [2Fe-2S] cluster with cysteinyl and histidyl ligation. Biochemistry. 2009;48(40):9569–81. doi: 10.1021/bi901182w 19715344
23. Ueta R, Fujiwara N, Iwai K, Yamaguchi-Iwai Y. Iron-induced dissociation of the Aft1p transcriptional regulator from target gene promoters is an initial event in iron-dependent gene suppression. Mol Cell Biol. 2012;32(24):4998–5008. doi: 10.1128/MCB.00726-12 23045394
24. Encinar del Dedo J, Gabrielli N, Carmona M, Ayte J, Hidalgo E. A cascade of iron-containing proteins governs the genetic iron starvation response to promote iron uptake and inhibit iron storage in fission yeast. PLoS Genet. 2015;11(3):e1005106. doi: 10.1371/journal.pgen.1005106 25806539
25. Mercier A, Labbe S. Both Php4 function and subcellular localization are regulated by iron via a multistep mechanism involving the glutaredoxin Grx4 and the exportin Crm1. J Biol Chem. 2009;284(30):20249–62. doi: 10.1074/jbc.M109.009563 19502236
26. Vachon P, Mercier A, Jbel M, Labbe S. The monothiol glutaredoxin Grx4 exerts an iron-dependent inhibitory effect on Php4 function. Eukaryot Cell. 2012;11(6):806–19. doi: 10.1128/EC.00060-12 22523368
27. Jbel M, Mercier A, Labbe S. Grx4 monothiol glutaredoxin is required for iron limitation-dependent inhibition of Fep1. Eukaryot Cell. 2011;10(5):629–45. doi: 10.1128/EC.00015-11 21421748
28. Kim KD, Kim HJ, Lee KC, Roe JH. Multi-domain CGFS-type glutaredoxin Grx4 regulates iron homeostasis via direct interaction with a repressor Fep1 in fission yeast. Biochem Biophys Res Commun. 2011;408(4):609–14. doi: 10.1016/j.bbrc.2011.04.069 21531205
29. Chaves GM, Bates S, MacCallum DM, Odds FC. Candida albicans GRX2, encoding a putative glutaredoxin, is required for virulence in a murine model. Genet Mol Res. 2007;6(4):1051–63. 18273798
30. Enjalbert B, MacCallum DM, Odds FC, Brown AJ. Niche-specific activation of the oxidative stress response by the pathogenic fungus Candida albicans. Infect Immun. 2007;75(5):2143–51. doi: 10.1128/IAI.01680-06 17339352
31. Zhang D, Dong Y, Yu Q, Kai Z, Zheng M, Jia C, et al. Function of glutaredoxin 3 (Grx3) in oxidative stress response caused by iron homeostasis disorder in Candida albicans. Future Microbiol. 2017;12(15):1397–412.
32. Lo HJ, Köhler JR, DiDomenico B, Loebenberg D, Cacciapuoti A, Fink GR. Nonfilamentous C. albicans mutants are avirulent. Cell. 1997;90(5):939–49. doi: 10.1016/s0092-8674(00)80358-x 9298905
33. Alkafeef SS, Yu C, Huang L, Liu H. Wor1 establishes opaque cell fate through inhibition of the general co-repressor Tup1 in Candida albicans. PLoS Genet. 2018;14(1):e1007176. doi: 10.1371/journal.pgen.1007176 29337983
34. Tagwerker C, Flick K, Cui M, Guerrero C, Dou Y, Auer B, et al. A tandem affinity tag for two-step purification under fully denaturing conditions. Molecular and Cellular Proteomics. 2006;5(4):737–48. doi: 10.1074/mcp.M500368-MCP200 16432255
35. Fang L, Kaake RM, Patel VR, Yang Y, Baldi P, Huang L. Mapping the protein interaction network of the human COP9 signalosome complex using a label-free QTAX strategy. Mol Cell Proteomics. 2012;11(5):138–47. doi: 10.1074/mcp.M111.016352 22474085
36. Guerrero C, Tagwerker C, Kaiser P, Huang L. An integrated mass spectrometry-based proteomic approach: quantitative analysis of tandem affinity-purified in vivo cross-linked protein complexes (QTAX) to decipher the 26 S proteasome-interacting network. Mol Cell Proteomics. 2006;5(2):366–78. doi: 10.1074/mcp.M500303-MCP200 16284124
37. Mellacheruvu D, Wright Z, Couzens AL, Lambert JP, St-Denis NA, Li T, et al. The CRAPome: a contaminant repository for affinity purification-mass spectrometry data. Nat Methods. 2013;10(8):730–6. doi: 10.1038/nmeth.2557 23921808
38. Cherry JM, Hong EL, Amundsen C, Balakrishnan R, Binkley G, Chan ET, et al. Saccharomyces Genome Database: the genomics resource of budding yeast. Nucleic Acids Res. 2012;40(Database issue):D700–5. doi: 10.1093/nar/gkr1029 22110037
39. Lock A, Rutherford K, Harris MA, Hayles J, Oliver SG, Bahler J, et al. PomBase 2018: user-driven reimplementation of the fission yeast database provides rapid and intuitive access to diverse, interconnected information. Nucleic Acids Res. 2019;47(D1):D821–D7. doi: 10.1093/nar/gky961 30321395
40. Stark C, Breitkreutz BJ, Reguly T, Boucher L, Breitkreutz A, Tyers M. BioGRID: a general repository for interaction datasets. Nucleic Acids Res. 2006;34(Database issue):D535–9. doi: 10.1093/nar/gkj109 16381927
41. 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
42. Frey AG, Palenchar DJ, Wildemann JD, Philpott CC. A Glutaredoxin·BolA Complex Serves as an Iron-Sulfur Cluster Chaperone for the Cytosolic Cluster Assembly Machinery. J Biol Chem. 2016;291(43):22344–56. doi: 10.1074/jbc.M116.744946 27519415
43. Jacques JF, Mercier A, Brault A, Mourer T, Labbe S. Fra2 is a co-regulator of Fep1 inhibition in response to iron starvation. PLoS One. 2014;9(6):e98959. doi: 10.1371/journal.pone.0098959 24897379
44. Mi H, Huang X, Muruganujan A, Tang H, Mills C, Kang D, et al. PANTHER version 11: expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements. Nucleic Acids Res. 2017;45(D1):D183–D9. doi: 10.1093/nar/gkw1138 27899595
45. Mi H, Muruganujan A, Casagrande JT, Thomas PD. Large-scale gene function analysis with the PANTHER classification system. Nat Protoc. 2013;8(8):1551–66. doi: 10.1038/nprot.2013.092 23868073
46. Mi H, Thomas P. PANTHER pathway: an ontology-based pathway database coupled with data analysis tools. Methods Mol Biol. 2009;563:123–40. doi: 10.1007/978-1-60761-175-2_7 19597783
47. Dlouhy AC, Beaudoin J, Labbe S, Outten CE. Schizosaccharomyces pombe Grx4 regulates the transcriptional repressor Php4 via [2Fe-2S] cluster binding. Metallomics. 2017;9(8):1096–105. doi: 10.1039/c7mt00144d 28725905
48. Weissman Z, Kornitzer D. A family of Candida cell surface haem-binding proteins involved in haemin and haemoglobin-iron utilization. Mol Microbiol. 2004;53(4):1209–20. doi: 10.1111/j.1365-2958.2004.04199.x 15306022
49. Ihrig J, Hausmann A, Hain A, Richter N, Hamza I, Lill R, et al. Iron regulation through the back door: iron-dependent metabolite levels contribute to transcriptional adaptation to iron deprivation in Saccharomyces cerevisiae. Eukaryot Cell. 2010;9(3):460–71. doi: 10.1128/EC.00213-09 20008079
50. Paul VD, Lill R. Biogenesis of cytosolic and nuclear iron-sulfur proteins and their role in genome stability. Biochim Biophys Acta. 2015;1853(6):1528–39. doi: 10.1016/j.bbamcr.2014.12.018 25583461
51. Veatch JR, McMurray MA, Nelson ZW, Gottschling DE. Mitochondrial dysfunction leads to nuclear genome instability via an iron-sulfur cluster defect. Cell. 2009;137(7):1247–58. doi: 10.1016/j.cell.2009.04.014 19563757
52. Stehling O, Vashisht AA, Mascarenhas J, Jonsson ZO, Sharma T, Netz DJA, et al. MMS19 Assembles Iron-Sulfur Proteins Required for DNA Metabolism and Genomic Integrity. Science. 2012;337(6091):195–9. doi: 10.1126/science.1219723 22678362
53. Zhang Y, Lyver ER, Nakamaru-Ogiso E, Yoon H, Amutha B, Lee DW, et al. Dre2, a conserved eukaryotic Fe/S cluster protein, functions in cytosolic Fe/S protein biogenesis. Mol Cell Biol. 2008;28(18):5569–82. doi: 10.1128/MCB.00642-08 18625724
54. Gari K, Ortiz AML, Borel V, Flynn H, Skehel JM, Boulton SJ. MMS19 Links Cytoplasmic Iron-Sulfur Cluster Assembly to DNA Metabolism. Science. 2012;337(6091):243–5. doi: 10.1126/science.1219664 22678361
55. Leng P, Sudbery PE, Brown AJP. Rad6p represses yeast‐hypha morphogenesis in the human fungal pathogen Candida albicans. Mol Microbiol. 200;35(5):1264–75. doi: 10.1046/j.1365-2958.2000.01801.x 10712706
56. Garcia-Prieto F, Gomez-Raja J, Andaluz E, Calderone R, Larriba G. Role of the homologous recombination genes RAD51 and RAD59 in the resistance of Candida albicans to UV light, radiomimetic and anti-tumor compounds and oxidizing agents. Fungal Genet Biol. 2010;47(5):433–45. doi: 10.1016/j.fgb.2010.02.007 20206282
57. Poor CB, Wegner SV, Li H, Dlouhy AC, Schuermann JP, Sanishvili R, et al. Molecular mechanism and structure of the Saccharomyces cerevisiae iron regulator Aft2. Proc Natl Acad Sci U S A. 2014;111(11):4043–8. doi: 10.1073/pnas.1318869111 24591629
58. Gerwien F, Safyan A, Wisgott S, Hille F, Kaemmer P, Linde J, et al. A Novel Hybrid Iron Regulation Network Combines Features from Pathogenic and Nonpathogenic Yeasts. MBio. 2016;7(5).
59. Attarian R, Hu G, Sánchez-León E, Caza M, Croll D, Do E, et al. The Monothiol Glutaredoxin Grx4 Regulates Iron Homeostasis and Virulence in Cryptococcus neoformans. MBio. 2018;9(6):e02377–18. doi: 10.1128/mBio.02377-18 30514787
60. Uzarska MA, Nasta V, Weiler BD, Spantgar F, Ciofi-Baffoni S, Saviello MR, et al. Mitochondrial Bol1 and Bol3 function as assembly factors for specific iron-sulfur proteins. Elife. 2016;5.
61. Roemer T, Jiang B, Davison J, Ketela T, Veillette K, Breton A, et al. Large-scale essential gene identification in Candida albicans and applications to antifungal drug discovery. Molecular Microbiology. 2003;50(1):167–81. doi: 10.1046/j.1365-2958.2003.03697.x 14507372
62. Feng Q, Summers E, Guo B, Fink GR. Ras Signaling Is Required for Serum-Induced Hyphal Differentiation in Candida albicans. J Bacteriol. 1999;181(20):6339–46. 10515923
63. Lane S, Di Lena P, Tormanen K, Baldi P, Liu H. Function and Regulation of Cph2 in Candida albicans. Eukaryot Cell. 2015;14(11):1114–26. doi: 10.1128/EC.00102-15 26342020
64. Homann OR, Dea J, Noble SM, Johnson AD. A phenotypic profile of the Candida albicans regulatory network. PLoS genetics. 2009;5:e1000783. doi: 10.1371/journal.pgen.1000783 20041210
65. Lu Y, Su C, Wang A, Liu H. Hyphal development in Candida albicans requires two temporally linked changes in promoter chromatin for initiation and maintenance. PLoS biology. 2011;9(7):e1001105. doi: 10.1371/journal.pbio.1001105 21811397
66. Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M. Accurate Proteome wide Label-free Quantification by Delayed Normalization and Maximal Peptide Ratio Extraction, Termed MaxLFQ. Mol Cell Proteomics. 2014;13(9):2513–26. doi: 10.1074/mcp.M113.031591 24942700
67. Schaab C, Geiger T, Stoehr G, Cox J, Mann M. Analysis of high accuracy, quantitative proteomics data in the MaxQB database. Mol Cell Proteomics. 2012;11(3):M111 014068. doi: 10.1074/mcp.M111.014068 22301388
68. Mi H, Muruganujan A, Ebert D, Huang X, Thomas PD. PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools. Nucleic Acids Res. 2019;47(D1):D419–D26. doi: 10.1093/nar/gky1038 30407594
69. Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nature biotechnology. 2008;26(12):1367–72. doi: 10.1038/nbt.1511 19029910
Článek vyšel v časopise
PLOS Genetics
2020 Číslo 6
- Může hubnutí souviset s vyšším rizikem nádorových onemocnění?
- Raději si zajděte na oční! Jak souvisí citlivost zraku s rozvojem demence?
- Co způsobuje pooperační infekce? Na vině může být i naše vlastní mikrobiota
- Čeká nás průlom v diagnostice karcinomu pankreatu?
- Polibek, který mi „vzal nohy“ aneb vzácný výskyt EBV u 70leté ženy – kazuistika
Nejčtenější v tomto čísle
- AXR1 affects DNA methylation independently of its role in regulating meiotic crossover localization
- Osteocalcin promotes bone mineralization but is not a hormone
- Super-resolution imaging of RAD51 and DMC1 in DNA repair foci reveals dynamic distribution patterns in meiotic prophase
- Steroid hormones regulate genome-wide epigenetic programming and gene transcription in human endometrial cells with marked aberrancies in endometriosis