Review Article | Published:

Hfq and its constellation of RNA

Nature Reviews Microbiology volume 9, pages 578589 (2011) | Download Citation

Abstract

Hfq is an RNA-binding protein that is common to diverse bacterial lineages and has key roles in the control of gene expression. By facilitating the pairing of small RNAs with their target mRNAs, Hfq affects the translation and turnover rates of specific transcripts and contributes to complex post-transcriptional networks. These functions of Hfq can be attributed to its ring-like oligomeric architecture, which presents two non-equivalent binding surfaces that are capable of multiple interactions with RNA molecules. Distant homologues of Hfq occur in archaea and eukaryotes, reflecting an ancient origin for the protein family and hinting at shared functions. In this Review, we describe the salient structural and functional features of Hfq and discuss possible mechanisms by which this protein can promote RNA interactions to catalyse specific and rapid regulatory responses in vivo.

Key points

  • Hfq is a conserved bacterial RNA-binding protein with complex roles in post-transcriptional gene regulation. Although studies of Hfq are rapidly advancing through the insights provided from crystal structures and from studies of mutant phenotypes and genetic responses, many aspects remain poorly understood.

  • At the level of protein structure, Hfq has a simple fold, with small protomers of 11 kDa forming a ring-like quaternary architecture that presents two distinct surfaces which can bind RNA. Homologues of Hfq that have a similar ring-like quaternary structure occur in the archaea and eukaryotes. Recent X-ray crystal structures and solution data provide insight into how Hfq binds RNA, with its two RNA-binding surfaces having distinct sequence preferences.

  • At the level of phenotype and gene expression, compelling data show a role for Hfq in mediating complex processes, such as quorum sensing and invasive virulence of pathogens.

  • One key function of bacterial Hfq is to mediate the activity of small non-coding RNAs (sRNAs) in the modulation of mRNA translation. Hfq seems to display in vivo specificity towards certain sRNAs and mRNAs.

  • Depending on its RNA partner and the context, Hfq can mediate either silencing or activation of gene expression at the post-transcriptional level. Although some aspects of these processes may be interpreted based on the available crystallographic and biochemical data, the current understanding is not sufficiently advanced to make robust predictions for the outcome of a given Hfq–RNA interaction.

  • Hfq cooperates with protein partners, such as ribonuclease E (RNase E) and the transcription termination factor Rho, for its biological activity. The association of Hfq with RNase E seems to trigger degradation of certain mRNAs that are recognized through sRNA partners.

  • Although Hfq is an abundant protein, it seems to be present at limiting concentrations for its binding partners. Thus, it is difficult to understand how an sRNA binds to Hfq to become an efficient mediator of gene regulation, and how Hfq contributes to fast-acting regulatory responses.

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References

  1. 1.

    & Eukaryotic Lsm proteins: lessons from bacteria. Nature Struct. Mol. Biol. 12, 1031–1036 (2005).

  2. 2.

    , & The bacterial Sm-like protein Hfq: a key player in RNA transactions. Mol. Microbiol. 51, 1525–1533 (2004).

  3. 3.

    & Bacterial small RNA regulators: versatile roles and rapidly evolving variations. Cold Spring Harb. Perspect. Biol. 27 Oct 2010 (doi:10.1101/cshperspect.a003798).

  4. 4.

    & The role of Hfq in bacterial pathogens. Curr. Opin. Microbiol. 13, 24–33 (2010).

  5. 5.

    & Regulatory RNA in bacterial pathogens. Cell Host Microbe 8, 116–127 (2010).

  6. 6.

    Mechanism of RNA silencing by Hfq-binding small RNAs. Curr. Opin. Microbiol. 10, 134–139 (2007).

  7. 7.

    & Activation of gene expression by small RNA. Curr. Opin. Microbiol. 12, 674–682 (2009).

  8. 8.

    , , , & Identification of novel small RNAs using comparative genomics and microarrays. Genes Dev. 15, 1637–1651 (2001).

  9. 9.

    et al. Global analysis of small RNA and mRNA targets of Hfq. Mol. Microbiol. 50, 1111–1124 (2003).

  10. 10.

    et al. Deep sequencing analysis of small noncoding RNA and mRNA targets of the global post-transcriptional regulator, Hfq. PLoS Genet. 4, e1000163 (2008). References 8–10 report the development and application of versatile approaches to identify Hfq-associated RNA species at the global level in vivo, and reveal that Hfq targets many more cellular transcripts than had previously been appreciated.

  11. 11.

    , , & Deep sequencing of Salmonella RNA associated with heterologous Hfq proteins in vivo reveals small RNAs as a major target class and identifies RNA processing phenotypes. RNA Biol. 6, 266–275 (2009).

  12. 12.

    et al. Detection of small RNAs in Pseudomonas aeruginosa by RNomics and structure-based bioinformatic tools. Microbiology 154, 3175–3187 (2008).

  13. 13.

    et al. Identification of small Hfq-binding RNAs in Listeria monocytogenes. RNA 12, 1383–1396 (2006).

  14. 14.

    & Base pairing small RNAs and their roles in global regulatory networks. FEMS Microbiol. Rev. 34, 866–882 (2010).

  15. 15.

    & Multiple target regulation by small noncoding RNAs rewires gene expression at the post-transcriptional level. Res. Microbiol. 160, 278–287 (2009).

  16. 16.

    et al. The small RNA chaperone Hfq and multiple small RNAs control quorum sensing in Vibrio harveyi and Vibrio cholerae. Cell 118, 69–82 (2004).

  17. 17.

    & Remodelling of the Escherichia coli outer membrane by two small regulatory RNAs. Mol. Microbiol. 59, 231–247 (2006).

  18. 18.

    et al. Two antisense RNAs target the transcriptional regulator CsgD to inhibit curli synthesis. EMBO J. 29, 1840–1850 (2010).

  19. 19.

    & Two seemingly homologous noncoding RNAs act hierarchically to activate glmS mRNA translation. PLoS Biol. 6, e64 (2008).

  20. 20.

    , , , & The small RNA GlmY acts upstream of the sRNA GlmZ in the activation of glmS expression and is subject to regulation by polyadenylation in Escherichia coli. Nucleic Acids Res. 36, 2570–2580 (2008).

  21. 21.

    , , & Switching off small RNA regulation with trap-mRNA. Mol. Microbiol. 73, 790–800 (2009).

  22. 22.

    , , & Caught at its own game: regulatory small RNA inactivated by an inducible transcript mimicking its target. Genes Dev. 23, 2004–2015 (2009).

  23. 23.

    & A dual function for a bacterial small RNA: SgrS performs base pairing-dependent regulation and encodes a functional polypeptide. Proc. Natl Acad. Sci. USA 104, 20454–20459 (2007).

  24. 24.

    et al. The small RNA PhrS stimulates synthesis of the Pseudomonas aeruginosa quinolone signal. Mol. Microbiol. 80, 868–885 (2011).

  25. 25.

    et al. The OxyS regulatory RNA represses rpoS translation and binds the Hfq (HF-I) protein. EMBO J. 17, 6061–6068 (1998).

  26. 26.

    et al. Specific and pleiotropic patterns of mRNA regulation by ArcZ, a conserved, Hfq-dependent small RNA. Mol. Microbiol. 74, 139–158 (2009).

  27. 27.

    & Disruption of small RNA signaling caused by competition for Hfq. Proc. Natl Acad. Sci. USA 108, 1110–1115 (2011). This paper demonstrates the effects of limiting intracellular Hfq concentrations on sRNA-mediated responses. Competition for Hfq binding is important for the organization of networks and for crosstalk between signalling pathways; these findings imply that Hfq–RNA effector complexes need to assemble or to act through channelling or compartmentalization.

  28. 28.

    et al. snRNP Sm proteins share two evolutionarily conserved sequence motifs which are involved in Sm protein–protein interactions. EMBO J. 14, 2076–2088 (1995).

  29. 29.

    et al. Crystal structures of two Sm protein complexes and their implications for the assembly of the spliceosomal snRNPs. Cell 96, 375–387 (1999).

  30. 30.

    , , & Oligomerization behavior of the archaeal Sm2-type protein from Archaeoglobus fulgidus. Protein Sci. 15, 2310–2317 (2006).

  31. 31.

    , , , & The second RNA chaperone, Hfq2, is also required for survival under stress and full virulence of Burkholderia cenocepacia J2315. J. Bacteriol. 193, 1515–1526.

  32. 32.

    , , & The Zymomonas mobilis regulator hfq contributes to tolerance against multiple lignocellulosic pretreatment inhibitors. BMC Microbiol. 10, 135 (2010).

  33. 33.

    , , , & Crystal structure of human spliceosomal U1 snRNP at 5.5 Å resolution. Nature 458, 475–480 (2009).

  34. 34.

    , , , & Structures of the pleiotropic translational regulator Hfq and an Hfq–RNA complex: a bacterial Sm-like protein. EMBO J. 21, 3546–3556 (2002).

  35. 35.

    , & Structure of Escherichia coli Hfq bound to polyriboadenylate RNA. Proc. Natl Acad. Sci. USA 106, 19292–19297 (2009). A report and insightful interpretation of the crystal structure of Hfq in complex with RNA bound through the distal face of Hfq. This structure provides a rationalization of many other studies, including the findings that the proximal and distal faces of Hfq have different binding preferences.

  36. 36.

    et al. Genomic SELEX for Hfq-binding RNAs identifies genomic aptamers predominantly in antisense transcripts. Nucleic Acids Res. 38, 3794–3808 (2010).

  37. 37.

    et al. Escherichia coli Hfq has distinct interaction surfaces for DsrA, rpoS and poly(A) RNAs. Nature Struct. Mol. Biol. 11, 1206–1214 (2004). A pioneering study probing the effects of individually mutating a large number of Hfq residues, showing that the two faces of Hfq have different propensities for different RNA species.

  38. 38.

    , , , & RNAs actively cycle on the Sm-like protein Hfq. Genes Dev. 24, 2621–2626 (2010). An elegant work proposing active cycling of RNA on the Hfq molecules, and probing this model with a variety of methods.

  39. 39.

    & What is cooperativity? Angew. Chem. Int. Ed. Engl. 48, 7488–7499 (2009).

  40. 40.

    & Involvement of a novel transcriptional activator and small RNA in post-transcriptional regulation of the glucose phosphoenolpyruvate phosphotransferase system. Mol. Microbiol. 54, 1076–1089 (2004).

  41. 41.

    , , & Base-pairing requirement for RNA silencing by a bacterial small RNA and acceleration of duplex formation by Hfq. Mol. Microbiol. 61, 1013–1022 (2006).

  42. 42.

    et al. Hfq-dependent regulation of OmpA synthesis is mediated by an antisense RNA. Genes Dev. 19, 2355–2366 (2005).

  43. 43.

    , , & A small RNA regulates multiple ABC transporter mRNAs by targeting C/A-rich elements inside and upstream of ribosome-binding sites. Genes Dev. 21, 2804–2817 (2007).

  44. 44.

    & The 5′ end of two redundant sRNAs is involved in the regulation of multiple targets, including their own regulator. Nucleic Acids Res. 36, 6781–6794 (2008).

  45. 45.

    et al. Systematic deletion of Salmonella small RNA genes identifies CyaR, a conserved CRP-dependent riboregulator of OmpX synthesis. Mol. Microbiol. 68, 890–906 (2008).

  46. 46.

    , , , & Evidence for an autonomous 5′ target recognition domain in an Hfq-associated small RNA. Proc. Natl Acad. Sci. USA 107, 20435–20440 (2010).

  47. 47.

    , , , & Recognition of heptameric seed sequence underlies multi-target regulation by RybB small RNA in Salmonella enterica. Mol. Microbiol. 78, 380–394 (2010). References 46 and 47 investigate the modular structure of a prototypical Hfq-associated sRNA.

  48. 48.

    & Hfq, a new chaperoning role: binding to messenger RNA determines access for small RNA regulator. EMBO J. 23, 396–405 (2004).

  49. 49.

    , , & Identification of the Hfq-binding site on DsrA RNA: Hfq binds without altering DsrA secondary structure. RNA 9, 33–43 (2003).

  50. 50.

    et al. Hfq: a bacterial Sm-like protein that mediates RNA-RNA interaction. Mol. Cell 9, 23–30 (2002).

  51. 51.

    , , , & Positive regulation by small RNAs and the role of Hfq. Proc. Natl Acad. Sci. USA 107, 9602–9607 (2010). This investigation combines in vitro and in vivo experiments which suggest that Hfq increases RNA duplex strength in cognate sRNA–mRNA pairs.

  52. 52.

    & An upstream Hfq binding site in the fhlA mRNA leader region facilitates the OxyS-fhlA interaction. PLoS ONE 5, e13028 (2010).

  53. 53.

    & The RNA binding protein Hfq interacts specifically with tRNAs. RNA 14, 514–523 (2008).

  54. 54.

    , , , & Hfq stimulates the activity of the CCA-adding enzyme. BMC Mol. Biol. 8, 92 (2007).

  55. 55.

    , , & A small bacterial RNA regulates a putative ABC transporter. J. Biol. Chem. 280, 7901–7908 (2005).

  56. 56.

    & Hfq is a regulator of F-plasmid TraJ and TraM synthesis in Escherichia coli. J. Bacteriol. 188, 124–131 (2006).

  57. 57.

    et al. Novel small RNA-encoding genes in the intergenic regions of Escherichia coli. Curr. Biol. 11, 941–950 (2001).

  58. 58.

    & RNase E-dependent processing stabilizes MicX, a Vibrio cholerae sRNA. Mol. Microbiol. 65, 373–385 (2007).

  59. 59.

    & Integrating anaerobic/aerobic sensing and the general stress response through the ArcZ small RNA. EMBO J. 29, 3094–3107 (2010).

  60. 60.

    et al. RNomics in Escherichia coli detects new sRNA species and indicates parallel transcriptional output in bacteria. Nucleic Acids Res. 31, 6435–6443 (2003).

  61. 61.

    , , , & Feedback control of glucosamine-6-phosphate synthase GlmS expression depends on the small RNA GlmZ and involves the novel protein YhbJ in Escherichia coli. Mol. Microbiol. 65, 1518–1533 (2007).

  62. 62.

    & Host factor Hfq of Escherichia coli stimulates elongation of poly(A) tails by poly(A) polymerase I. Proc. Natl Acad. Sci. USA 97, 1501–1505 (2000).

  63. 63.

    et al. Hfq affects the length and the frequency of short oligo(A) tails at the 3′ end of Escherichia coli rpsO mRNAs. Nucleic Acids Res. 31, 4017–4023 (2003).

  64. 64.

    , & The Sm-like protein Hfq regulates polyadenylation dependent mRNA decay in Escherichia coli. Mol. Microbiol. 54, 905–920 (2004).

  65. 65.

    & Structural basis for RNA 3′ end recognition by Hfq. Proc. Natl Acad. Sci. USA (in the press).

  66. 66.

    , , & PolyU tail of rho-independent terminator of bacterial small RNAs is essential for Hfq action. Proc. Natl Acad. Sci. USA (in the press).

  67. 67.

    , , , & The Sm-like Hfq protein increases OxyS RNA interaction with target mRNAs. Mol. Cell 9, 11–22 (2002). Together with reference 50, this article reports evidence that Hfq is a member of the Sm–LSm family, which specializes in facilitating the annealing of sRNAs with cognate targets.

  68. 68.

    et al. σE-dependent small RNAs of Salmonella respond to membrane stress by accelerating global omp mRNA decay. Mol. Microbiol. 62, 1674–1688 (2006).

  69. 69.

    , & Translational repression is sufficient for gene silencing by bacterial small noncoding RNAs in the absence of mRNA destruction. Proc. Natl Acad. Sci. USA 103, 4858–4863 (2006).

  70. 70.

    , & Control of Fur synthesis by the non-coding RNA RyhB and iron-responsive decoding. EMBO J. 26, 965–975 (2007).

  71. 71.

    , , , & The Escherichia coli OxyS regulatory RNA represses fhlA translation by blocking ribosome binding. EMBO J. 17, 6069–6075 (1998).

  72. 72.

    , , , & Spot 42 RNA mediates discoordinate expression of the E. coli galactose operon. Genes Dev. 16, 1696–1706 (2002).

  73. 73.

    , , & RNA, but not protein partners, is directly responsible for translational silencing by a bacterial Hfq-binding small RNA. Proc. Natl Acad. Sci. USA 105, 10332–10337 (2008).

  74. 74.

    , , , & Small RNA binding to 5′ mRNA coding region inhibits translational initiation. Mol. Cell 32, 827–837 (2008).

  75. 75.

    , , & RNA chaperone activity of the Sm-like Hfq protein. EMBO Rep. 4, 284–289 (2003).

  76. 76.

    , , , & Hfq (HF1) stimulates ompA mRNA decay by interfering with ribosome binding. Genes Dev. 14, 1109–1118 (2000). A study providing evidence that Hfq can also regulate some mRNAs without the requirement of a cognate sRNA.

  77. 77.

    , , , & Interaction of the RNA chaperone Hfq with mRNAs: direct and indirect roles of Hfq in iron metabolism of Escherichia coli. Mol. Microbiol. 50, 897–909 (2003).

  78. 78.

    , , , & Both RNase E and RNase III control the stability of sodB mRNA upon translational inhibition by the small regulatory RNA RyhB. Nucleic Acids Res. 33, 1678–1689 (2005).

  79. 79.

    & The rpoS mRNA leader recruits Hfq to facilitate annealing with DsrA sRNA. RNA 14, 1907–1917 (2008).

  80. 80.

    Despite similar binding to the Hfq protein regulatory RNAs widely differ in their competition performance. Biochemistry 50, 4427–4440 (2011).

  81. 81.

    , & Antisense RNAs in bacteria and their genetic elements. Adv. Genet. 46, 361–398 (2002).

  82. 82.

    , & Effect of RyhB small RNA on global iron use in Escherichia coli. J. Bacteriol. 187, 6962–6971 (2005).

  83. 83.

    , , & A minimal base-pairing region of a bacterial small RNA SgrS required for translational repression of ptsG mRNA. Mol. Microbiol. 76, 782–792 (2010).

  84. 84.

    , & Coupled degradation of a small regulatory RNA and its mRNA targets in Escherichia coli. Genes Dev. 17, 2374–2383 (2003). The clear demonstration of a functional link between Hfq and RNase E in sRNA-mediated regulation.

  85. 85.

    & Cycling of the Sm-like protein Hfq on the DsrA small regulatory RNA. J. Mol. Biol. 344, 1211–1223 (2004).

  86. 86.

    , , & The host factor required for RNA phage Qβ RNA replication in vitro. Intracellular location, quantitation, and purification by polyadenylate-cellulose chromatography. J. Biol. Chem. 250, 3607–3612 (1975).

  87. 87.

    , , , & Regulation of the Escherichia coli hfq gene encoding the host factor for phage Qβ. J. Bacteriol. 176, 531–534 (1994).

  88. 88.

    , , , & Growth phase-dependent variation in protein composition of the Escherichia coli nucleoid. J. Bacteriol. 181, 6361–6370 (1999).

  89. 89.

    , & Translational autocontrol of the Escherichia coli hfq RNA chaperone gene. RNA 11, 976–984 (2005).

  90. 90.

    et al. A small non-coding RNA of the invasion gene island (SPI-1) represses outer membrane protein synthesis from the Salmonella core genome. Mol. Microbiol. 66, 1174–1191 (2007).

  91. 91.

    , , , & A small, stable RNA induced by oxidative stress: role as a pleiotropic regulator and antimutator. Cell 90, 43–53 (1997).

  92. 92.

    et al. Quantifying E. coli proteome and transcriptome with single-molecule sensitivity in single cells. Science 329, 533–538 (2010).

  93. 93.

    , & What are the molecular ties that maintain genomic loops? Trends Genet. 23, 126–133 (2007).

  94. 94.

    et al. The archaeal Lsm protein binds to small RNAs. J. Biol. Chem. 285, 34429–34438 (2010).

  95. 95.

    & Role of polynucleotide phosphorylase in sRNA function in Escherichia coli. RNA 17, 1172–1189 (2011).

  96. 96.

    et al. Interaction network containing conserved and essential protein complexes in Escherichia coli. Nature 433, 531–537 (2005).

  97. 97.

    et al. Global functional atlas of Escherichia coli encompassing previously uncharacterized proteins. PLoS Biol. 7, e96 (2009).

  98. 98.

    , , & CspC regulates rpoS transcript levels and complements hfq deletions. Res. Microbiol. 161, 694–700 (2010).

  99. 99.

    et al. The Sm-like RNA chaperone Hfq mediates transcription antitermination at Rho-dependent terminators. EMBO J. 14 Jun 2011 (doi:10.1038/emboj.2011.192). A report of the modulating effect of Hfq on Rho and the possibility that this is influenced by RNA. Perhaps this interaction helps to direct Hfq or Hfq–RNA complexes to active transcription sites.

  100. 100.

    All things must pass: contrasts and commonalities in eukaryotic and bacterial mRNA decay. Nature Rev. Mol. Cell Biol. 11, 467–478 (2010).

  101. 101.

    , & Small RNA-mediated regulation at the level of transcript stability. RNA Biol. 7, 140–144 (2010).

  102. 102.

    , & RNase E-based ribonucleoprotein complexes: mechanical basis of mRNA destabilization mediated by bacterial noncoding RNAs. Genes Dev. 19, 2176–2186 (2005). This article proposes a direct protein interaction between Hfq and RNase E, resulting in specialized complexes that are mutually exclusive with the larger RNase E-based degradosome.

  103. 103.

    , , , & Coding sequence targeting by MicC RNA reveals bacterial mRNA silencing downstream of translational initiation. Nature Struct. Mol. Biol. 16, 840–846 (2009).

  104. 104.

    & Translational control and target recognition by Escherichia coli small RNAs in vivo. Nucleic Acids Res. 35, 1018–1037 (2007).

  105. 105.

    , & Turn-over of the small non-coding RNA RprA in E. coli is influenced by osmolarity. Mol. Genet. Genomics 284, 307–318 (2011).

  106. 106.

    , , , & Regulation of the small regulatory RNA MicA by ribonuclease III: a target-dependent pathway. Nucleic Acids Res. 39, 2918–2930 (2011).

  107. 107.

    , , , & Coincident Hfq binding and RNase E cleavage sites on mRNA and small regulatory RNAs. RNA 9, 1308–1314 (2003).

  108. 108.

    , & The response regulator SprE (RssB) is required for maintaining poly(A) polymerase I-degradosome association during stationary phase. J. Bacteriol. 192, 3713–3721 (2010).

  109. 109.

    , , & Hfq binding at RhlB-recognition region of RNase E is crucial for the rapid degradation of target mRNAs mediated by sRNAs in Escherichia coli. Mol. Microbiol. 79, 419–432 (2011).

  110. 110.

    , , , & Small RNA-induced mRNA degradation achieved through both translation block and activated cleavage. Genes Dev. 25, 385–396 (2011).

  111. 111.

    et al. Reconstitution and analysis of the multienzyme Escherichia coli RNA degradosome. J. Mol. Biol. 382, 870–883 (2008).

  112. 112.

    , & RNase E autoregulates its synthesis in Escherichia coli by binding directly to a stem-loop in the rne 5′ untranslated region. Mol. Microbiol. 72, 470–478 (2009).

  113. 113.

    , , , & Rapid cleavage of RNA by RNase E in the absence of 5′ monophosphate stimulation. Mol. Microbiol. 76, 590–604 (2010).

  114. 114.

    , , , & Decapping activators in Saccharomyces cerevisiae act by multiple mechanisms. Mol. Cell 39, 773–783 (2010).

  115. 115.

    , & Two types of localization of the DNA-binding proteins within the Escherichia coli nucleoid. Genes Cells 5, 613–626 (2000).

  116. 116.

    , , & Cellular electron microscopy imaging reveals the localization of the Hfq protein close to the bacterial membrane. PLoS ONE 4, e8301 (2009).

  117. 117.

    , , , & Implication of membrane localization of target mRNA in the action of a small RNA: mechanism of post-transcriptional regulation of glucose transporter in Escherichia coli. Genes Dev. 19, 328–338 (2005).

  118. 118.

    , , , & E. coli DNA associated with isolated Hfq interacts with Hfq's distal surface and C-terminal domain. Biochim. Biophys. Acta 1799, 588–596 (2010).

  119. 119.

    , , & Hfq affects mRNA levels independently of degradation. BMC Mol. Biol. 11, 17 (2010).

  120. 120.

    , , & Host factor for coliphage Qβ RNA replication: presence in procaryotes and association with the 30S ribosomal subunit in Escherichia coli. Mol. Gen. Genet. 153, 39–43 (1977).

  121. 121.

    & Interaction of Escherichia coli RNA polymerase with the ribosomal protein S1 and the Sm-like ATPase Hfq. Biochemistry 42, 8022–8034 (2003).

  122. 122.

    , , & Interactions of the non-coding RNA DsrA and RpoS mRNA with the 30S ribosomal subunit. J. Biol. Chem. 278, 15815–15824 (2003).

  123. 123.

    et al. Interactions of ribosomal protein S1 with DsrA and rpoS mRNA. Biochem. Biophys. Res. Commun. 348, 662–668 (2006).

  124. 124.

    , , & Translational activation of rpoS mRNA by the non-coding RNA DsrA and Hfq does not require ribosome binding. Nucleic Acids Res. 38, 1284–1293 (2010).

  125. 125.

    & Evolutionary diversification of the Sm family of RNA-associated proteins. Mol. Biol. Evol. 25, 2255–2267 (2008).

  126. 126.

    , , & Identification and function of the RNA chaperone Hfq in the Lyme disease spirochete Borrelia burgdorferi. Mol. Microbiol. 78, 622–635 (2010). A fascinating example of the conservation of Hfq and its function in conjunction with sRNA in a bacterium that is evolutionarily distant from E. coli.

  127. 127.

    et al. Defining a role for Hfq in Gram-positive bacteria: evidence for Hfq-dependent antisense regulation in Listeria monocytogenes. Nucleic Acids Res. 38, 907–919 (2009).

  128. 128.

    HITS-CLIP: panoramic views of protein–RNA regulation in living cells. Wiley Interdiscip. Rev. RNA 1, 266–286 (2010).

  129. 129.

    & The many pathways of RNA degradation. Cell 136, 763–776 (2009).

  130. 130.

    et al. Spatial organization of the flow of genetic information in bacteria. Nature 466, 77–81 (2010).

  131. 131.

    , , & Translation-independent localization of mRNA in E. coli. Science 331, 1081–1084 (2011).

  132. 132.

    , & Mobility of cytoplasmic, membrane, and DNA-binding proteins in Escherichia coli. Biophys. J. 98, 552–559 (2010).

  133. 133.

    , & Multifactorial determinants of protein expression in prokaryotic open reading frames. J. Mol. Biol. 402, 905–918 (2010).

  134. 134.

    , & Factor fraction required for the synthesis of bacteriophage Qβ-RNA. Nature 219, 588–590 (1968).

  135. 135.

    , & Synergism of mutations in bacteriophage Qbeta RNA affecting host factor dependence of qβ replicase. J. Mol. Biol. 295, 149–154 (2000).

  136. 136.

    , & Bacterial proteins required for replication of phage Q ribonucleic acid. Purification and properties of host factor I, a ribonucleic acid-binding protein. J. Biol. Chem. 247, 824–831 (1972).

  137. 137.

    & Nucleotide sequence specific interaction of host factor I with bacteriophage Qβ RNA. FEBS Lett. 43, 20–22 (1974).

  138. 138.

    & Site-specific interaction of Qβ host factor and ribosomal protein S1 with Qβ and R17 bacteriophage RNAs. J. Biol. Chem. 251, 1902–1912 (1976).

  139. 139.

    & Interaction of Escherichia coli host factor protein with Q beta ribonucleic acid. Biochemistry 19, 6146–6151 (1980).

  140. 140.

    & Interaction of Escherichia coli host factor protein with oligoriboadenylates. Biochemistry 19, 6138–6146 (1980).

  141. 141.

    , & Characterization of broadly pleiotropic phenotypes caused by an hfq insertion mutation in Escherichia coli K-12. Mol. Microbiol. 13, 35–49 (1994). A seminal paper identifying a broad set of physiological functions for Hfq in E. coli.

  142. 142.

    & Jr. The Brucella abortus host factor I (HF-I) protein contributes to stress resistance during stationary phase and is a major determinant of virulence in mice. Mol. Microbiol. 34, 690–700 (1999).

  143. 143.

    , & The RNA-binding protein HF-I, known as a host factor for phage Qbeta RNA replication, is essential for rpoS translation in Escherichia coli. Genes Dev. 10, 1143–1151 (1996).

  144. 144.

    & Efficient translation of the RpoS sigma factor in Salmonella typhimurium requires host factor I, an RNA-binding protein encoded by the hfq gene. J. Bacteriol. 178, 3763–3770 (1996). References 143 and 144 describe the first studies to identify an endogenous mRNA as a target of Hfq.

  145. 145.

    , & Hfq is necessary for regulation by the untranslated RNA DsrA. J. Bacteriol. 183, 1997–2005 (2001).

  146. 146.

    , , & Cyanobacteria contain a structural homologue of the Hfq protein with altered RNA-binding properties. FEBS J. 276, 3904–3915 (2009).

  147. 147.

    et al. Crystal structure of a novel Sm-like protein of putative cyanophage origin at 2.60 Å resolution. Proteins 75, 296–307 (2009).

  148. 148.

    & The Acinetobacter baylyi Hfq gene encodes a large protein with an unusual C terminus. J. Bacteriol. 191, 5553–5562 (2009).

  149. 149.

    et al. Moraxella catarrhalis expresses an unusual Hfq protein. Infect. Immun. 76, 2520–2530 (2008).

  150. 150.

    et al. Structural insights into the dynamics and function of the C-terminus of the E. coli RNA chaperone Hfq. Nucleic Acids Res. 39, 4900–4915 (2011).

  151. 151.

    , , , & Structural analysis of full-length Hfq from Escherichia coli. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 67, 536–540 (2011).

  152. 152.

    , , , & The C-terminal domain of Escherichia coli Hfq is required for regulation. Nucleic Acids Res. 36, 133–143 (2008).

  153. 153.

    & Linking folding and binding. Curr. Opin. Struct. Biol. 19, 31–38 (2009).

  154. 154.

    , , & C-terminally truncated derivatives of Escherichia coli Hfq are proficient in riboregulation. J. Mol. Biol. 404, 173–182 (2010).

  155. 155.

    et al. Functional effects of variants of the RNA chaperone Hfq. Biochem. Biophys. Res. Commun. 323, 1017–1023 (2004).

  156. 156.

    Regulation of translation via mRNA structure in prokaryotes and eukaryotes. Gene 361, 13–37 (2005).

  157. 157.

    , & Interactions of the RNA-binding protein Hfq with cspA mRNA, encoding the major cold shock protein. J. Bacteriol. 192, 2482–2490 (2010).

  158. 158.

    , , & Structure of the DNA binding domain of E. coli SSB bound to ssDNA. Nature Struct. Biol. 7, 648–652 (2000).

  159. 159.

    , , & Structure of the single-stranded-DNA-binding domain of replication protein A bound to DNA. Nature 385, 176–181 (1997).

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Acknowledgements

We thank J. Steitz, K. Weber, A. Callaghan, H. Vincent, K. Bandyra and many other colleagues for stimulating discussions about Hfq–RNA interactions and about their work. We are indebted to O. Weichenrieder for help with figure 3b. We thank K. Lipkow and S. Andrews for discussion about intracellular diffusion rates in bacteria. Work in the Vogel laboratory is supported by the National Genome Reseach Network Plus (NGFN+) grant RNomics of Infectious diseases (funded by the German Federal Ministry of Education and Research (BMBF)), and by German Research Foundation (DFG) Priority Programme SPP1258 Sensory and Regulatory RNAs in Prokaryotes (Grants VO8751/2-4). The Luisi laboratory is supported by the Wellcome Trust.

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Affiliations

  1. Institute for Molecular Infection Biology, University of Würzburg, Joseph-Schneider-Strasse 2, Würzburg, D-97080 Germany.  joerg.vogel@uni-wuerzburg.de

    • Jörg Vogel
  2. Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK.  bfl20@mole.bio.cam.ac.uk

    • Ben F. Luisi

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Competing interests

The authors declare no competing financial interests.

Supplementary information

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  1. 1.

    Supplementary information S1 (table)

    Structural data for Hfq and Sm-like proteins.

Glossary

Chaperones

Protective carriers for a meta-stable state of a macromolecule; for proteins, chaperones assist protein folding, and in the context used here, a chaperone confers protection to RNA species that are vulnerable to chemical or enzymatic attack.

RNA decoys

Cellular RNAs that inactivate regulatory RNAs by mimicry of their actual targets.

Protomers

Subunits of an oligomeric assembly.

Hetero-oligomers

Protein assemblies in which the subunits are not chemically identical.

Spliceosome

The series of multicomponent assemblies that dynamically remodel and cleave introns from eukaryotic mRNAs.

Trans-actions

Regulatory base-pairing of a small RNA with a trans-encoded target mRNA.

Rho-independent transcription terminator

A stable secondary RNA structure followed by a short poly(U) stretch that destabilizes the RNA–DNA duplex during transcription so that the RNA polymerase falls off.

Aptamer

An oligonucleotide that is selected in vitro from a large population of combinatorial variants for a targeted property, such as binding to a defined protein.

Pseudoknot

A structure that is formed when duplex-forming regions are interwoven, so that half of one duplex is intercalated between the two halves of another duplex.

Poly(A) polymerase

An important enzyme that catalyses the addition of adenosine to the 3′ end of mRNA and thereby accelerates RNA turnover in vivo.

On rate

In classical reaction kinetics, the rate of complex formation, with dimensions of concentration per unit time for simple binary associations.

Polynucleotide phosphorylase

(PNPase). An exoribonuclease that uses phosphate as an attacking group to sequentially liberate nucleoside 5′-diphosphates from the 3′ end of an RNA.

Degradosome

A multi-enzyme assembly that was first identified in Escherichia coli and is found in many other bacterial lineages. In E. coli, the canonical components are ribonuclease E and polynucleotide phosphorylase, as well as a DEAD-box RNA helicase and the glycolytic enzyme enolase.

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DOI

https://doi.org/10.1038/nrmicro2615

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