The mycobacterial iron-dependent regulator IdeR induces ferritin (bfrB) by alleviating Lsr2 repression.
Emerging evidence indicates that precise regulation of iron (Fe) metabolism and maintenance of Fe homeostasis in Mycobacterium tuberculosis (Mtb) are essential for its survival and proliferation in the host. IdeR is a central transcriptional regulator of Mtb genes 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 of bfrB, the gene encoding the major Fe-storage protein of Mtb. We found that bfrB induction by Fe required direct interaction of IdeR with a DNA sequence containing four tandem IdeR-binding boxes located upstream of the bfrB promoter. Results of in vivo and in vitro transcription assays identified a direct repressor of bfrB, the histone-like protein Lsr2. IdeR counteracted Lsr2-mediated repression in vitro, suggesting that IdeR induces bfrB transcription by antagonizing the repressor activity of Lsr2. Together, these results elucidate the main mechanism of bfrB positive regulation by IdeR and identify Lsr2 as a new factor contributing to Fe homeostasis in mycobacteria.
Public Health Research Institute at New Jersey Medical School, Rutgers State University of New Jersey, 225 Warren Street, Newark, NJ, 07103, USA.
Krishna
K
Kurthkoti
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560 012, India.
Priyanka
P
Tare
Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560 012, India.
Rakhi
R
Paitchowdhury
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560 012, India.
Vykuntham Naga
VN
Gowthami
Departamento de Medicina Preventiva, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
Maria J
MJ
Garcia
Division of Infectious Disease and the Center for Emerging Pathogens, Department of Medicine, New Jersey Medical School, Rutgers State University of New Jersey, 225 Warren Street, Newark, NJ, 07103, USA.
Roberto
R
Colangeli
Molecular Biophysics Unit, Indian Institute of Science, Bangalore, 560 012, India.
Dipankar
D
Chatterji
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560 012, India.
Valakunja
V
Nagaraja
Public Health Research Institute at New Jersey Medical School, Rutgers State University of New Jersey, 225 Warren Street, Newark, NJ, 07103, USA.
G Marcela
GM
Rodriguez
D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005293:Ferritins / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D006657:Histones / Q000378:metabolism; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D006657:Histones; C096348:IdeR protein, Mycobacterium tuberculosis; C539619:Lsr2 protein, Mycobacterium tuberculosis; D012097:Repressor Proteins; D005293:Ferritins; D007501:Iron