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Molecular characterization of the hemin uptake locus (hmu) from Yersinia pestis and analysis of hmu mutants for hemin and hemoprotein utilization.

ABSTRACT: Sequence analysis of the hemin uptake locus (hmu) of Yersinia pestis revealed five genes, hmuRSTUV, required for use of hemin and hemoproteins as iron sources. The translated gene products have homologies with proteins of the hemin transport genes of several gram-negative bacteria. Promoters were identified upstream of hmuP'R (p1) and upstream of hmuS (p2); p1, which contains a Fur box, is regulated by iron and Fur, while p2 exhibits weak, but constitutive, activity. HmuR, which has homology with TonB-dependent outer membrane (OM) receptors, is localized to the OM of Y. pestis and is required for utilizing hemin and all hemoproteins under iron-depleted conditions. The proposed ABC transporter, HmuTUV, is necessary for use of hemin, hemin-albumin, and myoglobin, but not hemoglobin, hemoglobin-haptoglobin, or heme-hemopexin, as iron sources. In the absence of HmuTUV, HmuS, a cytoplasmic protein, is involved in use of hemoglobin and heme-hemopexin. In mice, the 50% lethal doses of Y. pestis DeltahmuP'RSTUV mutants injected subcutaneously or retro-orbitally did not differ from that of the Hmu(+) parent strain. Thus, the hmu system is not essential for infection in mice via these routes. Growth studies showed that a DeltahmuP'RSTUV mutant could grow in iron-depleted medium containing high concentrations of hemoglobin, suggesting that an Hmu-independent, lower-affinity hemoglobin uptake system may exist.

SUBMITTER: Thompson JM

PROVIDER: S-EPMC96668 | biostudies-literature | 1999 Aug

REPOSITORIES: biostudies-literature

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Molecular characterization of the hemin uptake locus (hmu) from Yersinia pestis and analysis of hmu mutants for hemin and hemoprotein utilization.

Thompson J M JM Jones H A HA Perry R D RD

Infection and immunity 19990801 8

Sequence analysis of the hemin uptake locus (hmu) of Yersinia pestis revealed five genes, hmuRSTUV, required for use of hemin and hemoproteins as iron sources. The translated gene products have homologies with proteins of the hemin transport genes of several gram-negative bacteria. Promoters were identified upstream of hmuP'R (p1) and upstream of hmuS (p2); p1, which contains a Fur box, is regulated by iron and Fur, while p2 exhibits weak, but constitutive, activity. HmuR, which has homology wit ...[more]

PMID: 10417152

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Project description:Despite the mammalian host actively sequestering iron to limit pathogenicity, heme (or hemin when oxidized) and hemoproteins serve as important sources of iron for many bloodborne pathogens. The HmuRSTUV hemin uptake system allows Yersinia species to uptake and utilize hemin and hemoproteins as iron sources. HmuR is a TonB-dependent outer membrane receptor for hemin and hemoproteins. HmuTUV comprise a inner membrane ABC transporter that transports hemin and hemoproteins from the periplasmic space into the bacterial cytoplasm, where it is degraded by HmuS. Here we show that hmuSTUV but not hmuR are expressed under iron replete conditions, whereas hmuR as well as hmuSTUV are expressed under iron limiting conditions, suggesting complex transcriptional control. Indeed, expression of hmuSTUV in the presence of inorganic iron, but not in the presence of hemin, requires the global regulator IscR acting from a promoter in the intergenic region between hmuR and hmuS. This effect of IscR appears to be direct by binding a site mapped by DNaseI footprinting. In contrast, expression of hmuR under iron limiting conditions requires derepression of the ferric uptake regulator Fur acting from the hmuR promoter, as Fur binding upstream of hmuR was demonstrated biochemically. Differential expression by both Fur and IscR would facilitate maximal hemin uptake and utilization when iron and heme availability is low while maintaining the capacity for periplasmic removal and cytosolic detoxification of heme under a wider variety of conditions. We also demonstrate that a Y. pseudotuberculosis ΔiscR mutant has a survival defect when incubated in whole blood, in which iron is sequestered by heme-containing proteins. Surprisingly, this phenotype was independent of the Hmu system, the type III secretion system, complement, and the ability of Yersinia to replicate intracellularly. These results suggest that IscR regulates multiple virulence factors important for Yersinia survival and growth in mammalian tissues and reveal a surprising complexity of heme uptake expression and function under differing conditions of iron.

Dataset Information

Molecular characterization of the hemin uptake locus (hmu) from Yersinia pestis and analysis of hmu mutants for hemin and hemoprotein utilization.

Publications

Molecular characterization of the hemin uptake locus (hmu) from Yersinia pestis and analysis of hmu mutants for hemin and hemoprotein utilization.

Similar Datasets

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