The mycobacterial iron‐dependent regulator <scp>IdeR</scp> induces ferritin (<scp><i>bfrB</i></scp>) by alleviating <scp>L</scp>sr2 repression

Kurthkoti, Krishna; Tare, Priyanka; Paitchowdhury, Rakhi; Gowthami, Vykuntham Naga; García, María Jesús García; Colangeli, Roberto; Chatterji, Dipankar; Nagaraja, Valakunja; Rodríguez, G. Marcela

doi:10.1111/mmi.13166

Cited by 31 publications

(41 citation statements)

References 35 publications

(56 reference statements)

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“…Earlier studies with MtLsr2 showed that it is a DNA-bridging protein (Chen et al, 2008) that preferentially binds to and regulates A/T-rich regions of the Mtb genome (Gordon et al, 2010). The bridging mode of MtLsr2 has been shown to be involved in repression of the Fe storage gene bfrB under low Fe conditions (Kurthkoti et al, 2015). On the other hand, MtHU is a sequence non-specific DNA-binding protein that condenses DNA into globular, ball-like structures (Ghosh et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Physical and functional interaction between nucleoid‐associated proteins HU and Lsr2 of Mycobacterium tuberculosis: altered DNA binding and gene regulation

Datta¹,

Jha²,

Ahmed³

et al. 2019

Molecular Microbiology

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Summary Nucleoid‐associated proteins (NAPs) in bacteria contribute to key activities such as DNA compaction, chromosome organization and regulation of gene expression. HU and Lsr2 are two principal NAPs in Mycobacterium tuberculosis (Mtb). HU is essential for Mtb survival and is one of the most abundant NAPs. It differs from other eubacterial HU proteins in having a long, flexible lysine‐ and arginine‐rich carboxy‐terminal domain. Lsr2 of Mtb is the functional analogue of the bacterial NAP commonly called H‐NS. Lsr2 binds to and regulates expression of A/T‐rich portions of the otherwise G/C‐rich mycobacterial chromosome. Here, we demonstrate that HU and Lsr2 interact to form a complex. The interaction occurs primarily through the flexible carboxy‐terminal domain of HU and the acidic amino‐terminal domain of Lsr2. The resulting complex, upon binding to DNA, forms thick nucleoprotein rods, in contrast to the DNA bridging seen with Lsr2 and the DNA compaction seen with HU. Furthermore, transcription assays indicate that the HU‐Lsr2 complex is a regulator of gene expression. This physical and functional interaction between two NAPs, which has not been reported previously, is likely to be important for DNA organization and gene expression in Mtb and perhaps other bacterial species.

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Section: Discussionmentioning

confidence: 99%

Physical and functional interaction between nucleoid‐associated proteins HU and Lsr2 of Mycobacterium tuberculosis: altered DNA binding and gene regulation

Datta¹,

Jha²,

Ahmed³

et al. 2019

Molecular Microbiology

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“…In vitro studies showed that IdeR in the presence of iron bound the promoter DNA of bfrA and bfrB (36). In-depth analysis of the transcriptional regulation of bfrB showed that IdeR exerted its effect by countering the repressor effect of Lsr2, another histone-like DNA-binding protein (67). It was proposed that Lsr2 functioned as a repressor of bfrB transcription under low-iron conditions, but in the presence of iron, Lsr2 was displaced by IdeR-Fe 2ϩ complexes that bound four tandemly placed IdeR boxes in the bfrB promoter, thereby promoting the transcription of bfrB.…”

Section: Toxicity Of Iron: Protective Role Of the Iron Storage Proteimentioning

confidence: 99%

Iron Homeostasis in Mycobacterium tuberculosis: Mechanistic Insights into Siderophore-Mediated Iron Uptake

2016

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Mycobacterium tuberculosis requires iron for normal growth but faces a limitation of the metal ion due to its low solubility at biological pH and the withholding of iron by the mammalian host. The pathogen expresses the Fe 3؉ -specific siderophores mycobactin and carboxymycobactin to chelate the metal ion from insoluble iron and the host proteins transferrin, lactoferrin, and ferritin. Siderophore-mediated iron uptake is essential for the survival of M. tuberculosis, as knockout mutants, which were defective in siderophore synthesis or uptake, failed to survive in low-iron medium and inside macrophages. But as excess iron is toxic due to its catalytic role in the generation of free radicals, regulation of iron uptake is necessary to maintain optimal levels of intracellular iron. The focus of this review is to present a comprehensive overview of iron homeostasis in M. tuberculosis that is discussed in the context of mycobactin biosynthesis, transport of iron across the mycobacterial cell envelope, and storage of excess iron. The clinical significance of the serum iron status and the expression of the iron-regulated protein HupB in tuberculosis (TB) patients is presented here, highlighting the potential of HupB as a marker, notably in extrapulmonary TB cases.

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“…425 H-NS-mediated repression can be alleviated through competition for binding to similar 426 sequences by other transcription factors. Equivalent 'counter-silencing' mechanisms 427 have been reported for Lsr2 in the mycobacteria(Kurthkoti et al, 2015). Given that at least a subset of 428 the Lsr2-controlled specialized metabolic clusters are expressed under particular growth conditions in S.429 venezuelae (e.g.…”

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confidence: 99%

Silencing cryptic specialized metabolism inStreptomycesby the nucleoid-associated protein Lsr2

Gehrke

Zhang

Pimentel‐Elardo

et al. 2019

Preprint

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1Lsr2 is a nucleoid-associated protein conserved throughout the actinobacteria, including the antibiotic-2 producing Streptomyces. Streptomyces species encode paralogous Lsr2 proteins or 3 LsrL), and we show here that of the two, Lsr2 has greater functional significance. We found that Lsr2 4 binds AT-rich sequences throughout the chromosome, and broadly represses gene expression. 5 Strikingly, specialized metabolic clusters were over-represented amongst its targets, and the cryptic 6 nature of many of these clusters appears to stem from Lsr2-mediated repression. Manipulating Lsr2 7 activity in model species and uncharacterized isolates resulted in the production of new metabolites not 8 seen in wild type strains. Our results suggest that the transcriptional silencing of biosynthetic clusters by 9Lsr2 may protect Streptomyces from the inappropriate expression of specialized metabolites, and 10 provide global control over Streptomyces' arsenal of signalling and antagonistic compounds. 11 12 Interestingly, however, most clusters are poorly expressed under normal laboratory conditions, and in 54 many cases their associated metabolites remain uncharacterized. This is also the case for the 55 filamentous fungi, many of whom have a broad, untapped specialized metabolic repertoire, courtesy of 56 transcriptional silencing by histones (Pfannenstiel and Keller, 2019). Significant efforts are being made to 57 stimulate the production of these 'cryptic' metabolites in both bacteria and fungi, as they are widely 58 regarded as productive sources of new natural products (Craney et al., 2013;Ochi and Hosaka, 2013; 59 Scharf and Brakhage, 2013;Yoon and Nodwell, 2014; Daniel-Ivad et al., 2017;Onaka, 2017). 60We sought to investigate the role of the nucleoid-associated proteins Lsr2 and LsrL in gene 61 regulation in Streptomyces. We found that deleting lsr2 from the chromosome of Streptomyces 62 venezuelae had minor effects on S. venezuelae growth and development and major effects on 63 metabolism. In contrast, deleting lsrL had no detectable impact on development, and only a minor effect 64 on metabolism. Focussing on Lsr2, we determined that it bound AT-rich regions, generally repressed the 65 expression of prophage genes and other genes unique to S. venezuelae (presumably acquired by lateral 66 gene transfer), and suppressed antisense gene expression. The most profound effect of lsr2 deletion, 67 however, was the large-scale activation of specialized metabolic cluster gene expression. Lsr2 directly 68 repressed the transcription of many cryptic clusters in a way that is analogous to Lsr2-and H-NS-69 mediated repression of pathogenicity islands in other bacteria, and histone-mediated cluster silencing in 70 fungi. Unexpectedly, Lsr2 also controlled the expression of well-characterized and highly-conserved 71 clusters, suggesting that Lsr2 control has been broadly integrated into the regulatory cascades governing 72 specialized metabolism. Our results suggest that Lsr2 functions as a metabolic gatekeeper in the 73 strepto...

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

Cited by 31 publications

References 35 publications

Physical and functional interaction between nucleoid‐associated proteins HU and Lsr2 of Mycobacterium tuberculosis: altered DNA binding and gene regulation

Physical and functional interaction between nucleoid‐associated proteins HU and Lsr2 of Mycobacterium tuberculosis: altered DNA binding and gene regulation

Iron Homeostasis in Mycobacterium tuberculosis: Mechanistic Insights into Siderophore-Mediated Iron Uptake

Silencing cryptic specialized metabolism inStreptomycesby the nucleoid-associated protein Lsr2

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