The mycobacterial iron-dependent regulator IdeR induces ferritin (bfrB) by alleviating Lsr2 repression

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Abstract

Summary

Emerging evidence indicates that precise regulation of iron (Fe) metabolism and maintenance of Fe homeostasis inMycobacterium tuberculosis(Mtb) are essential for its survival and proliferation in the host. IdeR is a central transcriptional regulator ofMtbgenes involved in Fe metabolism. While it is well understood how IdeR functions as a repressor, how it induces transcription of a subset of its targets is still unclear. We investigated the molecular mechanism of IdeR-mediated positive regulation ofbfrB, the gene encoding the major Fe-storage protein ofMtb. We found thatbfrBinduction by Fe required direct interaction of IdeR with a DNA sequence containing four tandem IdeR-binding boxes located upstream of thebfrBpromoter. Results ofin vivoandin vitrotranscription assays identified a direct repressor ofbfrB, the histone-like protein Lsr2. IdeR counteracted Lsr2-mediated repressionin vitro, suggesting that IdeR inducesbfrBtranscription by antagonizing the repressor activity of Lsr2. Together, these results elucidate the main mechanism ofbfrBpositive regulation by IdeR and identify Lsr2 as a new factor contributing to Fe homeostasis in mycobacteria.

This study identifies the histone-like protein Lsr2 as a repressor of the ferritin (bfrB) gene in M. tuberculosis and the mechanism of IdeR-Fe mediated induction of bfrB. In complex with iron IdeR binds upstream the bfrB promoter displacing Lsr2 and relieving bfrB repression.

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