EDITORIAL
Today, Hfq is recognized as a bacterial RNA chaperone dynamically interacting with different RNA species and playing a crucial role in RNA-based regulation. Hfq forms homohexameric ring-like complexes exposing different faces for interaction with RNAs. It is a member of the Sm and Sm-like (Lsm) protein family that is widespread in all domains of life. In recent years, Hfq has attracted much attention for its activity in promoting imperfect base pairing of regulatory small RNAs (sRNAs) with their mRNA targets, affecting either RNA stability or mRNA translation. With increasing recognition of the relevance of sRNA-based regulation in prokaryotes, Hfq has become the focus of extensive research. The current knowledge on its functional role and mechanistic insights into its mode of action have been comprehensively reviewed (1–3). Genome-wide RNA coimmunoprecipitation studies showed that Hfq targets a plethora of RNAs in vivo (4–6). Although diverse RNA species are bound by Hfq, it seems to interact preferentially with sRNAs and mRNAs.
Hfq entered the scene in the 1960s, originally identified as a mysterious Escherichia coli host factor promoting replication of the Qβ RNA phage (7, 8), which inspired the name of this protein (host factor Qβ phage). It took more than 20 years before the hfq gene was identified and sequenced (9). Strong pleiotropic effects of an hfq mutation, the high abundance of the protein, and its preference for binding to AU-rich RNA fueled early speculations about a phage infection-independent role in E. coli.
The first studies reporting Hfq-dependent regulation of a host mRNA were published by Muffler et al. (10) and in the Journal of Bacteriology (JB) by Brown and Elliott (11) at about the same time in 1996. Both studies identified Hfq as an important factor for translation of the rpoS mRNA encoding the stationary-phase sigma factor RpoS (σS) in E. coli. This alternative sigma factor serves as the master regulator of the general stress response and is one of the key factors in the regulatory network controlling biofilm formation (12). Only a year later, papers in JB provided hints about a role of Hfq as a global regulator involved in the expression of σS-dependent and -independent genes (13) and proposed the 5′ untranslated region as the regulatory target in the rpoS mRNA (14). Based on suppressor mutations upstream of rpoS alleviating the negative effect of an hfq mutation on rpoS expression, Brown and Elliott (14) suggested that the secondary structure of the rpoS mRNA plays an important role in Hfq-dependent regulation of rpoS.
These findings set the stage for subsequent discoveries of numerous Hfq-regulated mRNAs and associated regulatory mechanisms. sRNA-mediated and Hfq-dependent activation of rpoS mRNA translation has since been discovered (reviewed in reference 15), and the induced change in the rpoS mRNA secondary structure has become a paradigm of translational activation by sRNAs (16). Three sRNAs—ArcZ, reflecting the redox state of the respiratory chain, DrsA, induced by low temperature, and RprA, activated by cell envelope stress—provide distinct inputs for integration of multiple environmental signals leading to enhanced levels of RpoS (15).
The discoveries of regulatory RNAs and Hfq revealed a new layer of regulation that had been missed for decades of genetic and molecular research. Although not ubiquitous, Hfq is widespread in the bacterial world. Its function as a flexible RNA matchmaker explains its important and pleiotropic role in bacterial physiology. Yet there is still much to discover about the physiological role of Hfq and the molecular mechanisms making this protein a globally important RNA chaperone in bacteria.
The views expressed in this Editorial do not necessarily reflect the views of the journal or of ASM.
REFERENCES
- 1.Vogel J, Luisi BF. 2011. Hfq and its constellation of RNA. Nat Rev Microbiol 9:578–589. doi: 10.1038/nrmicro2615. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Sobrero P, Valverde C. 2012. The bacterial protein Hfq: much more than a mere RNA-binding factor. Crit Rev Microbiol 38:276–299. doi: 10.3109/1040841X.2012.664540. [DOI] [PubMed] [Google Scholar]
- 3.Updegrove TB, Zhang A, Storz G. 2016. Hfq: the flexible RNA matchmaker. Curr Opinion Microbiol 30:133–138. doi: 10.1016/j.mib.2016.02.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Wassarman KM, Repoila F, Rosenow C, Storz G, Gottesman S. 2001. Identification of novel small RNAs using comparative genomics and microarrays. Genes Dev 15:1637–1651. doi: 10.1101/gad.901001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Zhang A, Wassarman KM, Rosenow C, Tjaden BC, Storz G, Gottesman S. 2003. Global analysis of small RNA and mRNA targets of Hfq. Mol Microbiol 50:1111–1124. doi: 10.1046/j.1365-2958.2003.03734.x. [DOI] [PubMed] [Google Scholar]
- 6.Sittka A, Lucchini S, Papenfort K, Sharma CM, Rolle K, Binnewies TT, Hinton JCD, Vogel J. 2008. Deep sequencing analysis of small noncoding RNA and mRNA targets of the global post-transcriptional regulator, Hfq. PLoS Genet 4:e1000163. doi: 10.1371/journal.pgen.1000163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Franze de Fernandez MT, Eoyang L, August JT. 1968. Factor fraction required for the synthesis of bacteriophage Qβ-RNA. Nature 219:588–590. doi: 10.1038/219588a0. [DOI] [PubMed] [Google Scholar]
- 8.Franze de Fernandez MT, Hayward WS, August JT. 1972. 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. [PubMed] [Google Scholar]
- 9.Kajitani M, Ishihama A. 1991. Identification and sequence determination of the host factor gene for bacteriophage Qβ. Nucleic Acids Res 19:1063–1066. doi: 10.1093/nar/19.5.1063. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Muffler A, Fischer D, Hengge-Aronis R. 1996. The RNA-binding protein HF-I, known as a host factor for phage Qβ RNA replication, is essential for rpoS translation in Escherichia coli. Genes Dev 10:1143–1151. doi: 10.1101/gad.10.9.1143. [DOI] [PubMed] [Google Scholar]
- 11.Brown L, Elliott T. 1996. 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Hengge R. 2011. The general stress response in Gram-negative bacteria, p 251–289. In Storz G, Hengge R (ed), Bacterial stress responses. ASM Press, Washington, DC. [Google Scholar]
- 13.Muffler A, Traulsen DD, Fischer D, Lange R, Hengge-Aronis R. 1997. The RNA-binding protein HF-I plays a global regulatory role which is largely, but not exclusively, due to its role in expression of the σS subunit of RNA polymerase in Escherichia coli. J Bacteriol 179:297–300. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Brown L, Elliott T. 1997. Mutations that increase expression of the rpoS gene and decrease its dependence on hfq function in Salmonella typhimurium. J Bacteriol 179:656–662. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Mika F, Hengge R. 2014. Small RNAs in the control of RpoS, CsgD, and biofilm architecture of Escherichia coli. RNA Biol 11:494–507. doi: 10.4161/rna.28867. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Soper T, Mandin P, Majdalani N, Gottesman S, Woodson SA. 2010. Positive regulation by small RNAs and the role of Hfq. Proc Natl Acad Sci U S A 107:9602–9607. doi: 10.1073/pnas.1004435107. [DOI] [PMC free article] [PubMed] [Google Scholar]