Differential Roles of Iron Storage Proteins in Maintaining the Iron Homeostasis in Mycobacterium tuberculosis

Khare, Garima; Nangpal, Prachi; Tyagi, Anil K.

doi:10.1371/journal.pone.0169545

Cited by 45 publications

(62 citation statements)

References 36 publications

(54 reference statements)

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“…The host uses the oxidative stress to combat infection by pathogenic micro‐organisms, and it has already been reported that bacterioferritins provide a key mechanism of protection against this host defence (Khare et al ). To determine if the presence of recombinant bacterioferritin reduced the harmful effects of oxidative stress, Mycma_BfrA and Mycma strains growth were analysed in MM supplemented with 50 µmol l −1 of FeCl 3 containing various concentration of H 2 O 2 .…”

Section: Resultsmentioning

confidence: 99%

“…The importance of bacterioferritins in the virulence and pathogenicity of Mycobacterium remains unclear, although some studies have proposed a role of this protein in the iron homeostasis of the bacillus (Pandey and Rodriguez ; Reddy et al ; Khare et al ). The influence of bacterioferritin during host infection was suggested to be dispensable, as mutants for this protein presented similar behaviour to the parental strains in different models of infection (Pandey and Rodriguez ; Reddy et al ).…”

Section: Discussionmentioning

confidence: 99%

“…The dispensable role of BfrA suggested by Pandey and Rodriguez raised the question as to why M. tuberculosis maintain both ferritins‐like proteins. Recently, Khare et al () made a contribution to the understanding of the specific roles of both BfrB and BfrA in iron homeostasis of Mtb, using single and double mutants for these proteins. It was demonstrated that both ferritin and bacterioferritin have a nonredundant and crucial role in the iron homeostasis, but this function is related to the surrounding microenvironment of the cell.…”

Section: Introductionmentioning

confidence: 99%

“…It was proposed that under low iron conditions, BfrA is the main source of iron while during high iron availability, BfrB is essential to reduce the oxidative stress produced by the iron. Furthermore, it was demonstrated that both proteins are essential for the bacillus survival under oxidative stress and hypoxia, but in the last condition, the BfrB seems to have a more important role (Khare et al ). Another study showed that bacterioferritin present catalase and Dps‐like activities suggesting these functions could be involved in the bacillus survival under oxidative stress (Mohanty et al ).…”

Section: Introductionmentioning

confidence: 99%

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Mycobacterium abscessus subsp. massiliense expressing bacterioferritin have improved resistance to stressful conditions

et al. 2020

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Aims The importance of bacterioferritin in the virulence and pathogenicity of the genus Mycobacterium is still unclear. The aim of this study was to analyse if the expression of a recombinant bacterioferritin from M. tuberculosis (Mtb) by Mycma could improve the capacity of this bacillus to resist the host defence mechanisms. Methods and Results Recombinant Mycma, expressing bacterioferritin (Rv1876) from Mtb, was developed by transformation with pMIP12_Rv1876. To determine bacterioferritin influence on Mycma physiology and virulence, the mycobacteria growth was analysed in vitro and in vivo. It was observed that the expression of bacterioferritin improved the growth rate of recombinant Mycma_BfrA under iron excess and oxidative stress, as compared to the wild type. Furthermore, in the murine model of infection, it was observed that Mycma_BfrA‐infected mice had higher bacillary load and a more pronounced lesion in the lungs when compared with the wild type. Conclusion This study showed that bacterioferritin confers additional resistance to stress conditions, resulting in increased pathogenicity of Mycma during mice infection. Significance and Impact of the Study This study provides new insights about the importance of bacterioferritin in the virulence and pathogenicity of the Mycobacterium genus.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mycobacterium abscessus subsp. massiliense expressing bacterioferritin have improved resistance to stressful conditions

et al. 2020

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“…Under stationary phase stress, Msm encapsulin appears to primarily enclose DyP, a potent protein antioxidant (14). The main role of BrfB, another potential encapsulated protein, is to relieve iron toxicity (26). EM models provide a good indication of the relative abundance of binding partners in a protein complex; more abundant members will dominate the density (7,27).…”

Section: Discussionmentioning

confidence: 99%

Structural investigation of Mycobacterial protein complexes involved in the stationary phase stress response

Kirykowicz

Woodward

2020

Preprint

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36Large protein complexes play key roles in mediating biological processes in the cell. Little 37 structural information is known on the protein complex mediators governing persistence in the 38 host for Mycobacterium tuberculosis (Mtb). We applied the 'shotgun EM' method for the 39 structural characterisation of protein complexes produced after exposure to stationary phase 40 stress for the model Mycobacterium, M smegmatis (Msm). We identified glutamine synthetase 41 I, essential for Mtb virulence, in addition to bacterioferritin, critical for Mtb iron regulation, 42 and encapsulin, which produces a cage-like structure to enclose target proteins. Further 43 investigation found that encapsulin carries dye-decolourising peroxidase (DyP), a potent 44 protein antioxidant, as the primary cargo during stationary phase stress. Our 'proof-of-concept' 45 application of this method offers insight into identifying potential key-mediators in Mtb 46 persistence. 47 immune response (1). Although some studies have shown potential key mediators in Mtb 53 survival in the host (2-4) there is a lack of structural information to guide drug discovery or 54 elucidate biological function. 55 56Structural data provides compelling evidence for the existence of protein complexes which are 57 physiologically relevant to the cell. In addition, this data offers valuable information on subunit 58 composition and mechanism of interaction, which yields biological insight governing its 59 potential actions (5). Single-particle transmission electron microscopy (TEM) is a powerful 60 3 method to reconstruct large protein complexes. The method has been successfully used to solve 61 the structures of protein complexes in a range of organisms from homogenous (6) as well as 62 heterogenous (7-10) samples. Combining 3D reconstruction of protein complexes from 63negative stain EM images with information obtained from mass spectrometry data ('shotgun 64 EM') (10) allows for a potentially high-throughput approach to finding complexes which could 65 play a key role in Mtb pathogenesis. 66 67 Although the 'shotgun EM' approach offers a faster method for solving the structures of a range 68 of protein complexes without the need for extensive purification (11), the approach still needs 69 to be tested and adapted for the organism of application (9,10,12). Here, we present our 70 'shotgun EM' methodology for the purification and TEM 3D reconstruction of Mycobacterial 71protein complexes from the model organism, M smegmatis (Msm), after exposure to stationary 72 phase stress which is known to induce a protective effect against subsequent exposure to 73 oxidative stress (13). We identified three protein complexes (glutamine synthetase I (GSI) (E.C 74 6.3.1.2), bacterioferritin (BrfA) (E.C 1.16.3.1), and encapsulin); the initial identity assigned by 75 mass spectrometry, as well as the 3D model and subunit composition, was validated by fitting 76 of homologous crystallographic structures into the low-resolution density. We demonstrate that 77 encapsulin encloses...

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Ferritin, cellular iron storage and regulation

2017

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Ferritin is considered the major iron storage protein which maintains a large iron core in its cavity and has ferroxidase activity. There are many types of ferritin particularly in prokaryotes that include the canonical 24-mer FTN molecules, the heme-containing BFR, the smaller 12-mer DPS and the newly recognized EncFtn of encapsulin that forms a very large iron storage compartment. Recent studies show that ferritin function is more dynamic than previous depicted and new mechanisms of ferritin iron recycling are emerging. They participate to the regulation of cellular iron homeostasis as those of ferritin biosynthesis, cooperating also with the iron-dependent mechanism of cellular iron secretion. Some of these basic processes are in common between unicellular and animal cells, and this review aims at discussing the findings on the connections between iron storage, cellular iron regulation and ferritin iron recycling that have been explored in unicellular organisms and in animals. © 2017 IUBMB Life, 69(6):414-422, 2017.

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Differential Roles of Iron Storage Proteins in Maintaining the Iron Homeostasis in Mycobacterium tuberculosis

Cited by 45 publications

References 36 publications

Mycobacterium abscessus subsp. massiliense expressing bacterioferritin have improved resistance to stressful conditions

Mycobacterium abscessus subsp. massiliense expressing bacterioferritin have improved resistance to stressful conditions

Structural investigation of Mycobacterial protein complexes involved in the stationary phase stress response

Ferritin, cellular iron storage and regulation

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