Iron uptake and transport by the carboxymycobactin-mycobactin siderophore machinery of Mycobacterium tuberculosis is dependent on the iron-regulated protein HupB

Choudhury, Mitali; Koduru, Tejaswi Naidu; Kumar, Naveen; Salimi, Sasan; Desai, Kavya; Prabhu, N. Prakash; Sritharan, Manjula

doi:10.1007/s10534-021-00292-2

Cited by 13 publications

(14 citation statements)

References 31 publications

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“…Moreover, HbhA and HupB are both mycobacterial histone‐like proteins, whose moonlighting functions overlaps (Pethe et al ., 2001b; Mueller‐Ortiz et al ., 2002). Very recently, HupB was proposed to be an iron transporter in Mtb (Choudhury et al ., 2021) displaying both cytosolic and cell surface localization, similarly to HbhA.…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, HbhA and HupB are both mycobacterial histone-like proteins, whose moonlighting functions overlaps (Pethe et al, 2001b;Mueller-Ortiz et al, 2002). Very recently, HupB was proposed to be an iron transporter in Mtb (Choudhury et al, 2021) displaying both cytosolic and cell surface localization, similarly to HbhA. There may also be a connection between HbhA and detoxification processes, through the biosynthesis and the use of coenzyme F 420 , as three different proteins involved in that process were identified as HbhA interactants, MSMEG_0048, FbiD/MSMEG_2392 and FbiC/ MSMEG_5126.…”

Section: Discussionmentioning

confidence: 99%

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Interconnection of the mycobacterial heparin‐binding hemagglutinin with cholesterol degradation and heme/iron pathways identified by proximity‐dependent biotin identification inMycobacterium smegmatis

Veyron‐Churlet

Saliou

Locht

2021

Environmental Microbiology

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Deciphering protein-protein interactions is a critical step in the identification and the understanding of biological mechanisms deployed by pathogenic bacteria. The development of in vivo technologies to characterize these interactions is still in its infancy, especially for bacteria whose subcellular organization is particularly complex, such as mycobacteria. In this work, we used the proximity-dependent biotin identification (BioID) to define the mycobacterial heparin-binding hemagglutinin (HbhA) interactome in the saprophytic bacterium Mycobacterium smegmatis. M. smegmatis is a commonly used model to study and characterize the physiology of pathogenic mycobacteria, such as Mycobacterium tuberculosis. Here, we adapted the BioID technology to in vivo protein-protein interactions studies in M. smegmatis, which presents several advantages, such as maintaining the complex organization of the mycomembrane, offering the possibility to study membrane or cell wall-associated proteins, including HbhA, in the presence of cofactors and post-translational modifications, such as the complex methylation pattern of HbhA. Using this technology, we found that HbhA is interconnected with cholesterol degradation and heme/iron pathways. These results are in line with previous studies showing the dual localization of HbhA, associated with the cell wall and intracytoplasmic lipid inclusions, and its induction under high iron growth conditions. AbbreviationsAPEX ascorbic acid peroxidase BioID proximity-dependent biotin identification BirA E. coli biotin ligase CW cell wall HbhA heparin-binding hemagglutinin HRP horseradish peroxidase ILI intracytoplasmic lipid inclusions Mtb Mycobacterium tuberculosis PPI protein-protein interactions

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Interconnection of the mycobacterial heparin‐binding hemagglutinin with cholesterol degradation and heme/iron pathways identified by proximity‐dependent biotin identification inMycobacterium smegmatis

Veyron‐Churlet

Saliou

Locht

2021

Environmental Microbiology

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“…But surprisingly, HupB is also found on the cell surface, where it can bind carboxymycobactin. HupB has been postulated to serve as Fe 3+ -carboxymycobactin receptor and direct transfer of iron from carboxymycobactin to mycobactin ( Gobin and Horwitz, 1996 ; Choudhury et al., 2021 ). Iron bound to carboxymycobactin can also be imported into the cell independently of mycobactin, via the iron-regulated ABC transporter, IrtAB ( Rodriguez and Smith, 2006 ; Rodriguez et al., 2008 ; Ryndak et al., 2010 ; Arnold et al., 2020 ).…”

Section: Upregulation Of Iron Acquisition and Control Of Intracellula...mentioning

confidence: 99%

The Iron Response of Mycobacterium tuberculosis and Its Implications for Tuberculosis Pathogenesis and Novel Therapeutics

Rodríguez

Sharma

Biswas

et al. 2022

Front. Cell. Infect. Microbiol.

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Most pathogenic bacteria require iron for growth. However, this metal is not freely available in the mammalian host. Due to its poor solubility and propensity to catalyze the generation of reactive oxygen species, host iron is kept in solution bound to specialized iron binding proteins. Access to iron is an important factor in the outcome of bacterial infections; iron limitation frequently induces virulence and drives pathogenic interactions with host cells. Here, we review the response of Mycobacterium tuberculosis to changes in iron availability, the relevance of this response to TB pathogenesis, and its potential for the design of new therapeutic interventions.

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“…Binding of HupB to the mbtB is iron-dependent and is thought to induce expression in the absence of IdeR binding (Figure 1A) (28). HupB was identified in the cell wall fraction of Mtb, and recently a novel role in the transfer of iron between extracellular ferri-carboxymycobactin and membrane-bound mycobactin was proposed (30). A hupB knockout strain of Mtb showed a marked reduction in mycobactin and carboxymycobactin levels and was unable to survive in macrophages (28), likely due to impaired iron acquisition during intracellular growth.…”

Section: Iron Homeostasis and Mtb Pathogenesismentioning

confidence: 99%

Host and Bacterial Iron Homeostasis, an Underexplored Area in Tuberculosis Biomarker Research

2021

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Mycobacterium tuberculosis (Mtb) “a human adapted pathogen” has found multiple ways to manipulate the host immune response during infection. The human immune response to Mtb infection is a highly complex cascade of reactions, with macrophages as preferred intracellular location. Interaction with the host through infection gives rise to expression of specific gene products for survival and multiplication within the host. The signals that the pathogens encounter during infection cause them to selectively express genes in response to signals. One strategy to identify Mtb antigens with diagnostic potential is to identify genes that are specifically induced during infection or in specific disease stages. The shortcomings of current immunodiagnostics include the failure to detect progression from latent infection to active tuberculosis disease, and the inability to monitor treatment efficacy. This highlights the need for new tuberculosis biomarkers. These biomarkers should be highly sensitive and specific diagnosing TB infection, specifically distinguishing between latent infection and active disease. The regulation of iron levels by the host plays a crucial role in the susceptibility and outcome of Mtb infection. Of interest are the siderophore biosynthetic genes, encoded by the mbt-1 and mbt-2 loci and the SUF (mobilization of sulphur) operon (sufR-sufB-sufD-sufC-csd-nifU-sufT), which encodes the primary iron-sulphur cluster biogenesis system. These genes are induced during iron limitation and intracellular growth of Mtb, pointing to their importance during infection.

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Iron uptake and transport by the carboxymycobactin-mycobactin siderophore machinery of Mycobacterium tuberculosis is dependent on the iron-regulated protein HupB

Cited by 13 publications

References 31 publications

Interconnection of the mycobacterial heparin‐binding hemagglutinin with cholesterol degradation and heme/iron pathways identified by proximity‐dependent biotin identification inMycobacterium smegmatis

Interconnection of the mycobacterial heparin‐binding hemagglutinin with cholesterol degradation and heme/iron pathways identified by proximity‐dependent biotin identification inMycobacterium smegmatis

The Iron Response of Mycobacterium tuberculosis and Its Implications for Tuberculosis Pathogenesis and Novel Therapeutics

Host and Bacterial Iron Homeostasis, an Underexplored Area in Tuberculosis Biomarker Research

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