Iron is an essential nutrient, but it can also be toxic. Therefore, iron homeostasis must be strictly regulated. Transcriptional control of iron-dependent gene expression in the rhizobia and other taxa of the is fundamentally different from the Fur paradigm in and other model systems. Rather than sense iron directly, the rhizobia employ the iron response regulator (Irr) to monitor and respond to the status of an iron-dependent process, namely, heme biosynthesis. This novel control mechanism allows iron homeostasis to be integrated with other cellular processes, and it permits differential control of iron regulon genes in a manner not readily achieved by Fur. Moreover, studies of Irr have defined a role for heme in conditional protein stability that has been subsequently described in eukaryotes. Finally, Irr-mediated control of iron metabolism may reflect a cellular strategy that accommodates a greater reliance on manganese.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Amarelle V, Koziol U, Rosconi F, Noya F, O'Brian MR, Fabiano E. 1.  2010. A new small regulatory protein, HmuP, modulates haemin acquisition in Sinorhizobium meliloti. Microbiology 156:1873–82 [Google Scholar]
  2. Anderson ES, Paulley JT, Gaines JM, Valderas MW, Martin DW. 2.  et al. 2009. The manganese transporter MntH is a critical virulence determinant for Brucella abortus 2308 in experimentally infected mice. Infect. Immun. 77:3466–74 [Google Scholar]
  3. Anderson ES, Paulley JT, Martinson DA, Gaines JM, Steele H, Roop RM II. 3.  2011. The iron-responsive regulator Irr is required for wild-type expression of the gene encoding the heme transporter BhuA in Brucella abortus 2308. J. Bacteriol. 193:5359–64 [Google Scholar]
  4. Anjem A, Imlay JA. 4.  2012. Mononuclear iron enzymes are primary targets of hydrogen peroxide stress. J. Biol. Chem. 287:15544–56 [Google Scholar]
  5. Anjem A, Varghese S, Imlay JA. 5.  2009. Manganese import is a key element of the OxyR response to hydrogen peroxide in Escherichia coli. Mol. Microbiol. 72:844–58 [Google Scholar]
  6. Battisti JM, Smitherman LS, Sappington KN, Parrow NL, Raghavan R, Minnick MF. 6.  2007. Transcriptional regulation of the heme binding protein gene family of Bartonella quintana is accomplished by a novel promoter element and iron response regulator. Infect. Immun. 75:4373–85 [Google Scholar]
  7. Bellini P, Hemmings AM. 7.  2006. In vitro characterization of a bacterial manganese uptake regulator of the Fur superfamily. Biochemistry 45:2686–98 [Google Scholar]
  8. Bhubhanil S, Chamsing J, Sittipo P, Chaoprasid P, Sukchawalit R, Mongkolsuk S. 8.  2014. Roles of Agrobacterium tumefaciens membrane-bound ferritin (MbfA) in iron transport and resistance to iron under acidic conditions. Microbiology 160:863–71 [Google Scholar]
  9. Chao TC, Becker A, Buhrmester J, Puhler A, Weidner S. 9.  2004. The Sinorhizobium meliloti fur gene regulates, with dependence on Mn(II), transcription of the sitABCD operon, encoding a metal-type transporter. J. Bacteriol. 186:3609–20 [Google Scholar]
  10. Chao TC, Buhrmester J, Hansmeier N, Puhler A, Weidner S. 10.  2005. Role of the regulatory gene rirA in the transcriptional response of Sinorhizobium meliloti to iron limitation. Appl. Environ. Microbiol. 71:5969–82 [Google Scholar]
  11. da Silva Neto J, Lourenco R, Marques M. 11.  2013. Global transcriptional response of Caulobacter crescentus to iron availability. BMC Genomics 14:549 [Google Scholar]
  12. da Silva Neto JF, Braz VS, Italiani VCS, Marques MV. 12.  2009. Fur controls iron homeostasis and oxidative stress defense in the oligotrophic alpha-proteobacterium Caulobacter crescentus. Nucleic Acids Res. 37:4812–25 [Google Scholar]
  13. Davies BW, Walker GC. 13.  2007. Disruption of sitA compromises Sinorhizobium meliloti for manganese uptake required for protection against oxidative stress. J. Bacteriol. 189:2101–9 [Google Scholar]
  14. Diaz-Mireles E, Wexler M, Sawers G, Bellini D, Todd JD, Johnston AW. 14.  2004. The Fur-like protein Mur of Rhizobium leguminosarum is a Mn2+-responsive transcriptional regulator. Microbiology 150:1447–56 [Google Scholar]
  15. Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM. 15.  et al. 1998. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280:69–77 [Google Scholar]
  16. Escamilla-Hernandez R, O'Brian MR. 16.  2012. HmuP is a co-activator of Irr-dependent expression of heme utilization genes in Bradyrhizobium japonicum. J. Bacteriol. 194:3137–43 [Google Scholar]
  17. Escolar L, Perez-Martin J, de Lorenzo V. 17.  1999. Opening the iron box: transcriptional metalloregulation by the Fur protein. J. Bacteriol. 181:6223–29 [Google Scholar]
  18. Ettema TJG, Andersson SGE. 18.  2009. The α-proteobacteria: the Darwin finches of the bacterial world. Biol. Lett. 5:429–32 [Google Scholar]
  19. Frawley ER, Crouch MV, Bingham-Ramos LK, Robbins HF, Wang W. 19.  et al. 2013. Iron and citrate export by a major facilitator superfamily pump regulates metabolism and stress resistance in Salmonella Typhimurium. PNAS 110:12054–59 [Google Scholar]
  20. Friedman YE, O'Brian MR. 20.  2004. The ferric uptake regulator (Fur) protein from Bradyrhizobium japonicum is an iron-responsive transcriptional repressor in vitro. J. Biol. Chem. 279:32100–5 [Google Scholar]
  21. Grass G, Otto M, Fricke B, Haney CJ, Rensing C. 21.  et al. 2005. FieF (YiiP) from Escherichia coli mediates decreased cellular accumulation of iron and relieves iron stress. Arch. Microbiol. 183:9–18 [Google Scholar]
  22. Hamza I, Chauhan S, Hassett R, O'Brian MR. 22.  1998. The bacterial Irr protein is required for coordination of heme biosynthesis with iron availability. J. Biol. Chem. 273:21669–74 [Google Scholar]
  23. Hamza I, Hassett R, O'Brian MR. 23.  1999. Identification of a functional fur gene in Bradyrhizobium japonicum. J. Bacteriol. 181:5843–46 [Google Scholar]
  24. Hamza I, Qi Z, King ND, O'Brian MR. 24.  2000. Fur-independent regulation of iron metabolism by Irr in Bradyrhizobium japonicum. Microbiology 146:669–76 [Google Scholar]
  25. Hibbing ME, Fuqua C. 25.  2011. Antiparallel and interlinked control of cellular iron levels by the Irr and RirA regulators of Agrobacterium tumefaciens. J. Bacteriol. 193:3461–72 [Google Scholar]
  26. Hohle TH, Franck WL, Stacey G, O'Brian MR. 26.  2011. Bacterial outer membrane channel for divalent metal ion acquisition. PNAS 108:15390–95 [Google Scholar]
  27. Hohle TH, O'Brian MR. 27.  2009. The mntH gene encodes the major Mn2+ transporter in Bradyrhizobium japonicum and is regulated by manganese via the Fur protein. Mol. Microbiol. 72:399–409 [Google Scholar]
  28. Hohle TH, O'Brian MR. 28.  2010. Transcriptional control of the Bradyrhizobium japonicum irr gene requires repression by Fur and antirepression by Irr. J. Biol. Chem. 285:26074–80 [Google Scholar]
  29. Hohle TH, O'Brian MR. 29.  2012. Manganese is required for oxidative metabolism in unstressed Bradyrhizobium japonicum cells. Mol. Microbiol. 84:766–77 [Google Scholar]
  30. Hohle TH, O'Brian MR. 30.  2014. Magnesium-dependent processes are targets of bacterial manganese toxicity. Mol. Microbiol. 93:736–47 [Google Scholar]
  31. Hu RG, Wang H, Xia Z, Varshavsky A. 31.  2008. The N-end rule pathway is a sensor of heme. PNAS 105:76–81 [Google Scholar]
  32. Ishikawa H, Kato M, Hori H, Ishimori K, Kirisako T. 32.  et al. 2005. Involvement of heme regulatory motif in heme-mediated ubiquitination and degradation of IRP2. Mol. Cell 19:171–81 [Google Scholar]
  33. Jaggavarapu S, O'Brian MR. 33.  2014. Differential control of Bradyrhizobium japonicum iron stimulon genes through variable affinity of the iron response regulator (Irr) for target gene promoters and selective loss of activator function. Mol. Microbiol. 92:609–24 [Google Scholar]
  34. Jeong J, Rouault TA, Levine RL. 34.  2004. Identification of a heme-sensing domain in iron regulatory protein 2. J. Biol. Chem. 279:45450–54 [Google Scholar]
  35. Kitphati W, Ngok-Ngam P, Suwanmaneerat S, Sukchawalit R, Mongkolsuk S. 35.  2007. Agrobacterium tumefaciens fur has important physiological roles in iron and manganese homeostasis, the oxidative stress response, and full virulence. Appl. Environ. Microbiol. 73:4760–68 [Google Scholar]
  36. Lu M, Fu D. 36.  2007. Structure of the zinc transporter YiiP. Science 317:1746–48 [Google Scholar]
  37. Martinez M, Ugalde RA, Almiron M. 37.  2005. Dimeric Brucella abortus Irr protein controls its own expression and binds haem. Microbiology 151:3427–33 [Google Scholar]
  38. Martinez M, Ugalde RA, Almiron M. 38.  2006. Irr regulates brucebactin and 2,3-dihydroxybenzoic acid biosynthesis, and is implicated in the oxidative stress resistance and intracellular survival of Brucella abortus. Microbiology 152:2591–98 [Google Scholar]
  39. Menscher EA, Caswell CC, Anderson ES, Roop RM. 39.  2012. Mur regulates the gene encoding the manganese transporter MntH in Brucella abortus 2308. J. Bacteriol. 194:561–66 [Google Scholar]
  40. Ngok-Ngam P, Ruangkiattikul N, Mahavihakanont A, Virgem SS, Sukchawalit R, Mongkolsuk S. 40.  2009. Roles of Agrobacterium tumefaciens RirA in iron regulation, oxidative stress response, and virulence. J. Bacteriol. 191:2083–90 [Google Scholar]
  41. Nicolaou SA, Fast AG, Nakamaru-Ogiso E, Papoutsakis ET. 41.  2013. Overexpression of fetA (ybbL) and fetB (ybbM), encoding an iron exporter, enhances resistance to oxidative stress in Escherichia coli. Appl. Environ. Microbiol. 79:7210–19 [Google Scholar]
  42. Nienaber A, Hennecke H, Fischer HM. 42.  2001. Discovery of a haem uptake system in the soil bacterium Bradyrhizobium japonicum. Mol. Microbiol. 41:787–800 [Google Scholar]
  43. O'Brian MR, Fabiano E. 43.  2010. Mechanisms and regulation of iron homeostasis in the rhizobia. Iron Uptake and Homeostasis in Microorganisms P Cornelis, SC Andrews 37–63 Norfolk, UK: Caister Academic [Google Scholar]
  44. Ojeda JF, Martinson DA, Menscher EA, Roop RM 2nd. 44.  2012. The bhuQ gene encodes a heme oxygenase that contributes to the ability of Brucella abortus 2308 to use heme as an iron source and is regulated by Irr. J. Bacteriol. 194:4052–58 [Google Scholar]
  45. Platero R, de Lorenzo V, Garat B, Fabiano E. 45.  2007. Sinorhizobium meliloti Fur-like (Mur) protein binds a Fur box-like sequence present in the mntA promoter in a manganese-responsive manner. Appl. Environ. Microbiol. 73:4832–38 [Google Scholar]
  46. Platero R, Peixoto L, O'Brian MR, Fabiano E. 46.  2004. Fur is involved in manganese-dependent regulation of mntA (sitA) expression in Sinorhizobium meliloti. Appl. Environ. Microbiol. 70:4349–55 [Google Scholar]
  47. Platero RA, Jaureguy M, Battistoni FJ, Fabiano ER. 47.  2003. Mutations in sitB and sitD genes affect manganese-growth requirements in Sinorhizobium meliloti. FEMS Microbiol. Lett. 218:65–70 [Google Scholar]
  48. Puri S, Hohle TH, O'Brian MR. 48.  2010. Control of bacterial iron homeostasis by manganese. PNAS 107:10691–95 [Google Scholar]
  49. Puri S, O'Brian MR. 49.  2006. The hmuQ and hmuD genes from Bradyrhizobium japonicum encode heme-degrading enzymes. J. Bacteriol. 188:6476–82 [Google Scholar]
  50. Qi Z, O'Brian MR. 50.  2002. Interaction between the bacterial iron response regulator and ferrochelatase mediates genetic control of heme biosynthesis. Mol. Cell 9:155–62 [Google Scholar]
  51. Rodionov DA, Gelfand MS. 51.  2006. Computational identification of BioR, a transcriptional regulator of biotin metabolism in Alphaproteobacteria, and of its binding signal. FEMS Microbiol. Lett. 255:102–7 [Google Scholar]
  52. Rodionov DA, Gelfand MS, Todd JD, Curson AR, Johnston AW. 52.  2006. Computational reconstruction of iron- and manganese-responsive transcriptional networks in alpha-proteobacteria. PLOS Comput. Biol. 2:e163 [Google Scholar]
  53. Rudolph G, Semini G, Hauser F, Lindemann A, Friberg M. 53.  et al. 2006. The iron control element, acting in positive and negative control of iron-regulated Bradyrhizobium japonicum genes, is a target for the Irr protein. J. Bacteriol. 188:733–44 [Google Scholar]
  54. Salahudeen AA, Thompson JW, Ruiz JC, Ma HW, Kinch LN. 54.  et al. 2009. An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis. Science 326:722–26 [Google Scholar]
  55. Sankari S, O'Brian MR. 55.  2014. A bacterial iron exporter for maintenance of iron homeostasis. J. Biol. Chem. 289:16498–507 [Google Scholar]
  56. Shin J-H, Jung HJ, An YJ, Cho Y-B, Cha S-S, Roe J-H. 56.  2011. Graded expression of zinc-responsive genes through two regulatory zinc-binding sites in Zur. PNAS 108:5045–50 [Google Scholar]
  57. Singleton C, White GF, Todd JD, Marritt SJ, Cheesman MR. 57.  et al. 2010. Heme-responsive DNA binding by the global iron regulator Irr from Rhizobium leguminosarum. J. Biol. Chem. 285:16023–31 [Google Scholar]
  58. Small SK, O'Brian MR. 58.  2011. The Bradyrhizobium japonicum frcB gene encodes a diheme ferric reductase. J. Bacteriol. 193:4088–94 [Google Scholar]
  59. Small SK, Puri S, Sangwan I, O'Brian MR. 59.  2009. Positive control of ferric siderophore receptor gene expression by the Irr protein in Bradyrhizobium japonicum. J. Bacteriol. 191:1361–68 [Google Scholar]
  60. Sobota JM, Gu M, Imlay JA. 60.  2014. Intracellular hydrogen peroxide and superoxide poison 3-deoxy-d-arabinoheptulosonate 7-phosphate synthase, the first committed enzyme in the aromatic biosynthetic pathway of Escherichia coli. J. Bacteriol. 196:1980–91 [Google Scholar]
  61. Sobota JM, Imlay JA. 61.  2011. Iron enzyme ribulose-5-phosphate 3-epimerase in Escherichia coli is rapidly damaged by hydrogen peroxide but can be protected by manganese. PNAS 108:5402–7 [Google Scholar]
  62. Symmons MF, Bokma E, Koronakis E, Hughes C, Koronakis V. 62.  2009. The assembled structure of a complete tripartite bacterial multidrug efflux pump. PNAS 106:7173–78 [Google Scholar]
  63. Todd JD, Sawers G, Rodionov DA, Johnston AW. 63.  2006. The Rhizobium leguminosarum regulator IrrA affects the transcription of a wide range of genes in response to Fe availability. Mol. Genet. Genomics 275:564–77 [Google Scholar]
  64. Todd JD, Wexler M, Sawers G, Yeoman KH, Poole PS, Johnston AW. 64.  2002. RirA, an iron-responsive regulator in the symbiotic bacterium Rhizobium leguminosarum. Microbiology 148:4059–71 [Google Scholar]
  65. Vashisht AA, Zumbrennen KB, Huang X, Powers DN, Durazo A. 65.  et al. 2009. Control of iron homeostasis by an iron-regulated ubiquitin ligase. Science 326:718–21 [Google Scholar]
  66. Viguier C, Cuiv PO, Clarke P, O'Connell M. 66.  2005. RirA is the iron response regulator of the rhizobactin 1021 biosynthesis and transport genes in Sinorhizobium meliloti 2011. FEMS Microbiol. Lett. 246:235–42 [Google Scholar]
  67. Wexler M, Yeoman KH, Stevens JB, de Luca NG, Sawers G, Johnston AW. 67.  2001. The Rhizobium leguminosarum tonB gene is required for the uptake of siderophore and haem as sources of iron. Mol. Microbiol. 41:801–16 [Google Scholar]
  68. White GF, Singleton C, Todd JD, Cheesman MR, Johnston AW, Le Brun NE. 68.  2011. Heme binding to the second, lower-affinity site of the global iron regulator Irr from Rhizobium leguminosarum promotes oligomerization. FEBS J. 278:2011–21 [Google Scholar]
  69. Xuan YH, Hu YB, Chen L-Q, Sosso D, Ducat DC. 69.  et al. 2013. Functional role of oligomerization for bacterial and plant SWEET sugar transporter family. PNAS 110:E3685–94 [Google Scholar]
  70. Yang J, Ishimori K, O'Brian MR. 70.  2005. Two heme binding sites are involved in the regulated degradation of the bacterial iron response regulator (Irr) protein. J. Biol. Chem. 280:7671–76 [Google Scholar]
  71. Yang J, Kim KD, Lucas A, Drahos KE, Santos CS. 71.  et al. 2008. A novel heme-regulatory motif mediates heme-dependent degradation of the circadian factor period 2. Mol. Cell. Biol. 28:4697–711 [Google Scholar]
  72. Yang J, Panek HR, O'Brian MR. 72.  2006. Oxidative stress promotes degradation of the Irr protein to regulate haem biosynthesis in Bradyrhizobium japonicum. Mol. Microbiol. 60:209–18 [Google Scholar]
  73. Yang J, Sangwan I, Lindemann A, Hauser F, Hennecke H. 73.  et al. 2006. Bradyrhizobium japonicum senses iron through the status of haem to regulate iron homeostasis and metabolism. Mol. Microbiol. 60:427–37 [Google Scholar]
  74. Yu C, Genco CA. 74.  2012. Fur-mediated activation of gene transcription in the human pathogen Neisseria gonorrhoeae. J. Bacteriol. 194:1730–42 [Google Scholar]
  75. Zappa S, Bauer CE. 75.  2013. The LysR-type transcription factor HbrL is a global regulator of iron homeostasis and porphyrin synthesis in Rhodobacter capsulatus. Mol. Microbiol. 90:1277–92 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error