The IrvA-Dependent Pathway: A Link Between Stress Adaptation and Virulence

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 DESCRIPTION (provided by applicant): The proposed research aims to investigate the molecular mechanisms used by the irvR/A regulatory system of Streptococcus mutans to control numerous accessory gene pathways in response to environmental stress. Our previous studies demonstrated that the central regulator of this system irvA is a riboregulatory mRNA. Its principal regulatory function is mediated through seed pairing with irvA mRNA, rather than through the function of its encoded protein. Such regulatory control is a new paradigm for the function of mRNAs. In this project, we are interested to determine the mechanisms used by S. mutans to modulate irvA expression, the role of irvA as a pleiotropic riboregulatory mRNA, and the ability of irvA to exploit the regulatory ribonuclease RNase J2 for the posttranscriptional control of gene expression. The goals of the project will be completed in three Aims. 1) To determine the mechanism controlling irvA expression, we will characterize the protein-protein interactions that modulate the stability and function of the proximal regulator of irvA gene expression, IrvR. This mechanism will be tested for its role in modulating biofilm integrity during environmental stress. 2) To understand the role of irvA as a pleiotropic riboregulatory mRNA, we will identify the overlapping geneset between the irvA regulon and a newly identified RNA chaperone required for irvA riboregulation. These genes will be tested for irvA- and chaperone-dependent regulation of target mRNA stability and seed pairing. 3) To investigate the ability of irvA to exploit RNase J2 for the control of gene expression, we will test irvA and RNA chaperone for their ability to modulate RNase J2 degradation of irvA target mRNAs via seed pairing. We will also determine the recognition elements in RNA that specify cleavage by RNase J2. The proposed studies will provide some of the first mechanistic insights into the posttranscriptional regulatory mechanisms used by oral bacteria and will demonstrate how key pathways are regulated in response to environmental stress. This will hopefully add an important layer to our understanding of S. mutans ability to influence oral ecology.