Mycobacterium bovis aconitase-IRE interactions: integrating iron, oxidative and nitrosative stress responses

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Mycobacterium bovis is the causative agent of bovine TB, a major problem for UK cattle farming. We have identified an iron-responsive element (IRE) in the 5' coding region of an M. bovis gene, which encodes an essential cell wall hydrolase. IREs in target messenger RNA molecules are recognized by the apo-form of aconitase proteins (Acn) to mediate post-transcriptional gene expression. The regulatory function of Acn is triggered by collapse of the [4Fe-4S] cluster, which is present at the active site when Acn acts as an enzyme in the Krebs cycle, in response to the oxidative/nitrosative stress conditions that prevail in M. bovis's preferred niche - a lung macrophage. This project is based on the hypothesis that M. bovis Acn is a trigger enzyme that participates in regulatory circuits linking central metabolic function to cell wall remodeling in response to the macrophage environment.Whilst the function of eukaryotic Acns in regulation of iron homeostasis has been well-characterized, the role of bacterial Acns is understudied. Cell-wall remodeling is a fundamental feature of TB pathogenesis in the transition between replicative and non-replicative states that characterize active and latent stages of infection. Understanding the mechanism of switching between catalytic and regulatory roles of M. bovis Acn and the role this plays in shutting down central metabolism (Acn is essential for mycobacterial growth) and remodeling the cell-wall will provide the scientific underpinning to establish the significance of post-transcriptional regulation in M. bovis persistence.