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A Cascade of Iron-Containing Proteins Governs the Genetic Iron Starvation Response to Promote Iron Uptake and Inhibit Iron Storage in Fission Yeast


Iron is an essential biometal but it is also toxic, and therefore its intracellular availability from disposable iron pools is tightly regulated. From bacteria to higher eukaryotes, iron starvation triggers complex genetic responses to exacerbate the otherwise limited iron uptake and decrease intracellular iron storage and usage. These responses are triggered in very distinct ways in each organism. In fission yeast, two transcriptional repressors, Php4 and Fep1, mediate the iron usage/iron import cellular response to iron starvation, respectively, and a glutaredoxin Grx4-Fra2 heterodimer governs both repressors. We show here that iron is an essential component of the Grx4-Fra2 heterodimers and of the transcriptional repressor Fep1. Under normal iron conditions, iron-containing Grx4 maintains Php4 retained in the cytosol, and iron depletion forces their dissociation and Php4 nuclear accumulation. On the other hand, iron-bridged Grx4-Fra2 is bound to Fep1 at repressed promoters, and iron depletion forces reverse metal transfer from Fep1 to Grx4-Fra2, and transcriptional de-repression. These complex molecular events occur upon iron scarcity to induce iron import and decrease iron usage, and explains how a single protein complex, Grx4-Fra2, can both activate and inactivate transcription to mount a survival response.


Vyšlo v časopise: 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 11(3): e32767. doi:10.1371/journal.pgen.1005106
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005106

Souhrn

Iron is an essential biometal but it is also toxic, and therefore its intracellular availability from disposable iron pools is tightly regulated. From bacteria to higher eukaryotes, iron starvation triggers complex genetic responses to exacerbate the otherwise limited iron uptake and decrease intracellular iron storage and usage. These responses are triggered in very distinct ways in each organism. In fission yeast, two transcriptional repressors, Php4 and Fep1, mediate the iron usage/iron import cellular response to iron starvation, respectively, and a glutaredoxin Grx4-Fra2 heterodimer governs both repressors. We show here that iron is an essential component of the Grx4-Fra2 heterodimers and of the transcriptional repressor Fep1. Under normal iron conditions, iron-containing Grx4 maintains Php4 retained in the cytosol, and iron depletion forces their dissociation and Php4 nuclear accumulation. On the other hand, iron-bridged Grx4-Fra2 is bound to Fep1 at repressed promoters, and iron depletion forces reverse metal transfer from Fep1 to Grx4-Fra2, and transcriptional de-repression. These complex molecular events occur upon iron scarcity to induce iron import and decrease iron usage, and explains how a single protein complex, Grx4-Fra2, can both activate and inactivate transcription to mount a survival response.


Zdroje

1. Mercier A, Pelletier B, Labbe S (2006) 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 5: 1866–1881. 16963626

2. Pelletier B, Beaudoin J, Mukai Y, Labbe S (2002) Fep1, an iron sensor regulating iron transporter gene expression in Schizosaccharomyces pombe. J Biol Chem 277: 22950–22958. 11956219

3. Pelletier B, Beaudoin J, Philpott CC, Labbe S (2003) Fep1 represses expression of the fission yeast Schizosaccharomyces pombe siderophore-iron transport system. Nucleic Acids Res 31: 4332–4344. 12888492

4. Mercier A, Labbe S (2010) Iron-dependent remodeling of fungal metabolic pathways associated with ferrichrome biosynthesis. Appl Environ Microbiol 76: 3806–3817. doi: 10.1128/AEM.00659-10 20435771

5. Jbel M, Mercier A, Pelletier B, Beaudoin J, Labbe S (2009) Iron activates in vivo DNA binding of Schizosaccharomyces pombe transcription factor Fep1 through its amino-terminal region. Eukaryot Cell 8: 649–664. doi: 10.1128/EC.00001-09 19252122

6. Pelletier B, Trott A, Morano KA, Labbe S (2005) Functional characterization of the iron-regulatory transcription factor Fep1 from Schizosaccharomyces pombe. J Biol Chem 280: 25146–25161. 15866870

7. Mercier A, Labbe S (2009) 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 284: 20249–20262. doi: 10.1074/jbc.M109.009563 19502236

8. Mercier A, Watt S, Bahler J, Labbe S (2008) Key function for the CCAAT-binding factor Php4 to regulate gene expression in response to iron deficiency in fission yeast. Eukaryot Cell 7: 493–508. doi: 10.1128/EC.00446-07 18223116

9. Outten CE, Albetel AN (2013) Iron sensing and regulation in Saccharomyces cerevisiae: Ironing out the mechanistic details. Curr Opin Microbiol 16: 662–668. doi: 10.1016/j.mib.2013.07.020 23962819

10. Muhlenhoff U, Molik S, Godoy JR, Uzarska MA, Richter N, et al. (2010) Cytosolic monothiol glutaredoxins function in intracellular iron sensing and trafficking via their bound iron-sulfur cluster. Cell Metab 12: 373–385. doi: 10.1016/j.cmet.2010.08.001 20889129

11. Li H, Outten CE (2012) Monothiol CGFS Glutaredoxins and BolA-like Proteins: [2Fe-2S] Binding Partners in Iron Homeostasis. Biochemistry.

12. Ojeda L, Keller G, Muhlenhoff U, Rutherford JC, Lill R, et al. (2006) Role of glutaredoxin-3 and glutaredoxin-4 in the iron regulation of the Aft1 transcriptional activator in Saccharomyces cerevisiae. J Biol Chem 281: 17661–17669. 16648636

13. Pujol-Carrion N, Belli G, Herrero E, Nogues A, de la Torre-Ruiz MA (2006) Glutaredoxins Grx3 and Grx4 regulate nuclear localisation of Aft1 and the oxidative stress response in Saccharomyces cerevisiae. J Cell Sci 119: 4554–4564. 17074835

14. Li H, Mapolelo DT, Dingra NN, Naik SG, Lees NS, et al. (2009) The yeast iron regulatory proteins Grx3/4 and Fra2 form heterodimeric complexes containing a [2Fe-2S] cluster with cysteinyl and histidyl ligation. Biochemistry 48: 9569–9581. doi: 10.1021/bi901182w 19715344

15. Li H, Mapolelo DT, Dingra NN, Keller G, Riggs-Gelasco PJ, et al. (2011) Histidine 103 in Fra2 is an iron-sulfur cluster ligand in the [2Fe-2S] Fra2-Grx3 complex and is required for in vivo iron signaling in yeast. J Biol Chem 286: 867–876. doi: 10.1074/jbc.M110.184176 20978135

16. Chung WH, Kim KD, Roe JH (2005) Localization and function of three monothiol glutaredoxins in Schizosaccharomyces pombe. Biochem Biophys Res Commun 330: 604–610. 15796926

17. Jbel M, Mercier A, Labbe S (2011) Grx4 monothiol glutaredoxin is required for iron limitation-dependent inhibition of Fep1. Eukaryot Cell 10: 629–645. doi: 10.1128/EC.00015-11 21421748

18. Kim KD, Kim HJ, Lee KC, Roe JH (2011) Multi-domain CGFS-type glutaredoxin Grx4 regulates iron homeostasis via direct interaction with a repressor Fep1 in fission yeast. Biochem Biophys Res Commun 408: 609–614. doi: 10.1016/j.bbrc.2011.04.069 21531205

19. Lillig CH, Berndt C, Vergnolle O, Lonn ME, Hudemann C, et al. (2005) Characterization of human glutaredoxin 2 as iron-sulfur protein: a possible role as redox sensor. Proc Natl Acad Sci U S A 102: 8168–8173. 15917333

20. Berndt C, Hudemann C, Hanschmann EM, Axelsson R, Holmgren A, et al. (2007) How does iron-sulfur cluster coordination regulate the activity of human glutaredoxin 2? Antioxid Redox Signal 9: 151–157. 17115894

21. Coblenz A, Wolf K (1995) Gcs1, a gene encoding gamma-glutamylcysteine synthetase in the fission yeast Schizosaccharomyces pombe. Yeast 11: 1171–1177. 8619315

22. Kumanovics A, Chen OS, Li L, Bagley D, Adkins EM, et al. (2008) 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 283: 10276–10286. doi: 10.1074/jbc.M801160200 18281282

23. Jacques JF, Mercier A, Brault A, Mourer T, Labbe S (2014) Fra2 is a co-regulator of Fep1 inhibition in response to iron starvation. PLoS One 9: e98959. doi: 10.1371/journal.pone.0098959 24897379

24. Labbe S, Pelletier B, Mercier A (2007) Iron homeostasis in the fission yeast Schizosaccharomyces pombe. Biometals 20: 523–537. 17211681

25. Hidalgo E, Demple B (1994) An iron-sulfur center essential for transcriptional activation by the redox-sensing SoxR protein. EMBO J 13: 138–146. 8306957

26. Netz DJ, Mascarenhas J, Stehling O, Pierik AJ, Lill R (2014) Maturation of cytosolic and nuclear iron-sulfur proteins. Trends Cell Biol 24: 303–312. doi: 10.1016/j.tcb.2013.11.005 24314740

27. Harrison KA, Marzluf GA (2002) Characterization of DNA binding and the cysteine rich region of SRE, a GATA factor in Neurospora crassa involved in siderophore synthesis. Biochemistry 41: 15288–15295. 12484767

28. Chao LY, Marletta MA, Rine J (2008) Sre1, an iron-modulated GATA DNA-binding protein of iron-uptake genes in the fungal pathogen Histoplasma capsulatum. Biochemistry 47: 7274–7283. doi: 10.1021/bi800066s 18549241

29. Mapolelo DT, Zhang B, Randeniya S, Albetel AN, Li H, et al. (2013) Monothiol glutaredoxins and A-type proteins: partners in Fe-S cluster trafficking. Dalton Trans 42: 3107–3115. doi: 10.1039/c2dt32263c 23292141

30. Puig S, Askeland E, Thiele DJ (2005) Coordinated remodeling of cellular metabolism during iron deficiency through targeted mRNA degradation. Cell 120: 99–110. 15652485

31. Marguerat S, Schmidt A, Codlin S, Chen W, Aebersold R, et al. (2012) Quantitative analysis of fission yeast transcriptomes and proteomes in proliferating and quiescent cells. Cell 151: 671–683. doi: 10.1016/j.cell.2012.09.019 23101633

32. Calvo IA, Gabrielli N, Iglesias-Baena I, Garcia-Santamarina S, Hoe KL, et al. (2009) Genome-wide screen of genes required for caffeine tolerance in fission yeast. PLoS One 4: e6619. doi: 10.1371/journal.pone.0006619 19672306

33. Castillo EA, Ayte J, Chiva C, Moldon A, Carrascal M, et al. (2002) Diethylmaleate activates the transcription factor Pap1 by covalent modification of critical cysteine residues. Mol Microbiol 45: 243–254. 12100563

34. Vivancos AP, Castillo EA, Jones N, Ayte J, Hidalgo E (2004) Activation of the redox sensor Pap1 by hydrogen peroxide requires modulation of the intracellular oxidant concentration. Mol Microbiol 52: 1427–1435. 15165244

35. Calvo IA, Garcia P, Ayte J, Hidalgo E (2012) The transcription factors Pap1 and Prr1 collaborate to activate antioxidant, but not drug tolerance, genes in response to H2O2. Nucleic Acids Res 40: 4816–4824. doi: 10.1093/nar/gks141 22344694

36. Benson FE, Stasiak A, West SC (1994) Purification and characterization of the human Rad51 protein, an analogue of E. coli RecA. EMBO J 13: 5764–5771. 7988572

37. Tamarit J, Irazusta V, Moreno-Cermeno A, Ros J (2006) Colorimetric assay for the quantitation of iron in yeast. Anal Biochem 351: 149–151. 16403430

38. Chen JS, Mortenson LE (1977) Inhibition of methylene blue formation during determination of the acid-labile sulfide of iron-sulfur protein samples containing dithionite. Anal Biochem 79: 157–165. 869173

39. Sanso M, Gogol M, Ayte J, Seidel C, Hidalgo E (2008) Transcription factors Pcr1 and Atf1 have distinct roles in stress- and Sty1-dependent gene regulation. Eukaryot Cell 7: 826–835. doi: 10.1128/EC.00465-07 18375616

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