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.