Small non-coding RNAs (sRNAs) in bacteria regulate cell growth and stress response in conjunction with an RNA chaperone protein Hfq. sRNAs control the expression of virulence factors and toxins in pathogenic bacteria, and allow bacteria to survive harsh environmental conditions such as dessication, oxidation or acidity that allow them to defeat host defenses or persist in hospital environments. Conversely, the virulence of many strains is reduced or attenuated when sRNAs are disabled. Although thousands of sRNAs have been identified in diverse bacterial species, how sRNAs and Hfq physically recognize mRNA targets to change gene expression is much less understood. The basic RNA-Hfq interaction motifs have been identified. The goal of this research is to investigate how these modular interaction motifs combine to upregulate or downregulate different gene targets. Single-molecule spectroscopy will used to study how Hfq facilitates sRNA-mRNA base pairing, while biochemical, physical and genetic methods will be used to probe the three-dimensional structure of different classes of Hfq-RNA complexes. Finally, a new model for auto-regulation of Hfq by an intrinsically disordered peptide will be investigated. Understanding how sRNAs turn genes on and off in bacteria is critical for understanding and treating microbial disease. The results of this research will uncover new antibacterial drug targets and aid the engineering of sRNAs for the control of bacterial growth. As Hfq is homologous to Sm proteins, the results will be relevant to how human Sm and Lsm proteins act in mRNA turnover and pre-mRNA splicing.

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PROJECT DESCRIPTION Bacterial pathogens use small RNA molecules to control genes that help them survive in the human body and produce toxins after infection. The goal of this research project is to determine how a key cellular protein chaperones these small RNAs to turn genes on and off in bacterial cells. The results of this research will lead to new ways of controlling bacterial infections.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics A Study Section (MGA)
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Preusch, Peter
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Johns Hopkins University
Schools of Arts and Sciences
United States
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Santiago-Frangos, Andrew; Woodson, Sarah A (2018) Hfq chaperone brings speed dating to bacterial sRNA. Wiley Interdiscip Rev RNA 9:e1475
Woodson, Sarah A; Panja, Subrata; Santiago-Frangos, Andrew (2018) Proteins That Chaperone RNA Regulation. Microbiol Spectr 6:
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Santiago-Frangos, Andrew; Jeliazkov, Jeliazko R; Gray, Jeffrey J et al. (2017) Acidic C-terminal domains autoregulate the RNA chaperone Hfq. Elife 6:
Santiago-Frangos, Andrew; Kavita, Kumari; Schu, Daniel J et al. (2016) C-terminal domain of the RNA chaperone Hfq drives sRNA competition and release of target RNA. Proc Natl Acad Sci U S A 113:E6089-E6096
Zheng, Amy; Panja, Subrata; Woodson, Sarah A (2016) Arginine Patch Predicts the RNA Annealing Activity of Hfq from Gram-Negative and Gram-Positive Bacteria. J Mol Biol 428:2259-2264
Panja, Subrata; Santiago-Frangos, Andrew; Schu, Daniel J et al. (2015) Acidic Residues in the Hfq Chaperone Increase the Selectivity of sRNA Binding and Annealing. J Mol Biol 427:3491-3500