Hfq RNA Chaperone and the Mechanism of RNA-Dependent Regulation

细菌中的小非编码RNA（sRNAs）调节细胞生长和应激反应， 与RNA伴侣蛋白Hfq连接。sRNA控制毒力的表达 致病菌中的因子和毒素，并允许细菌在恶劣的环境中生存 干燥、氧化或酸性等条件，使它们能够击败宿主的防御， 在医院环境中持续存在。相反，许多菌株的毒力降低或 当sRNA被禁用时会减弱。 尽管在不同的细菌物种中已经鉴定出数千种sRNA， Hfq物理识别mRNA靶点以改变基因表达的理解要少得多。 已经鉴定了基本的RNA-Hfq相互作用基序。这项研究的目的是 研究这些模块化相互作用基序如何联合收割机上调或下调 不同的基因靶点单分子光谱学将用于研究Hfq如何促进 sRNA-mRNA碱基配对，而生物化学，物理和遗传方法将用于 探测不同类别的Hfq-RNA复合物的三维结构。最后，新的 将研究通过固有无序肽自动调节Hfq的模型。 了解sRNA如何在细菌中打开和关闭基因对于理解和 治疗微生物疾病。这项研究的结果将揭示新的抗菌药物 靶向并帮助sRNA的工程化以控制细菌生长。由于Hfq是 与Sm蛋白同源，结果将与人类Sm和Lsm蛋白如何起作用有关 mRNA周转和前体mRNA剪接。

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.