Host glyceraldehyde-3-phosphate dehydrogenase-mediated iron acquisition is hijacked by intraphagosomal Mycobacterium tuberculosis

Patidar, Anil; Malhotra, Himanshu; Chaudhary, Surbhi; Kumar, Manoj; Dilawari, Rahul; Chaubey, Gaurav Kumar; Dhiman, Asmita; Modanwal, Radheshyam; Talukdar, Sharmila; Raje, Chaaya Iyengar; Raje, Manoj

doi:10.1007/s00018-021-04110-3

Cited by 7 publications

(5 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, it is plausible that the iron acquisition mechanisms or molecules exploited by Mtb inside the host can also be targeted. Based upon our previous fndings, Mtb hijacks mammalian secreted Glyceraldehyde-3-phosphate dehydrogenase (sGAPDH) for the targeted delivery of host iron carrier proteins Lactoferrin (Lf) and Transferrin (Tf) to intracellular bacilli [32].…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosisexploits SIRT2 for iron acquisition to facilitate its intracellular survival

Talukdar,

Modanwal,

Chaubey

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Iron availability is a critical factor for both bacteria and humans, and its availability significantly influences host-pathogen dynamics. As Mtb has coevolved with the human race, Mtb relentlessly tries to exploit iron from the tightly regulated iron machinery of host. Sirtuins are evolutionary conserved NAD+-dependent deacetylases involved in various cellular processes including infection. Notably, the cytosolic protein, Sirtuin 2 regulates cellular iron homeostasis in hepatocytes and after Mtb infection, SIRT2 translocates to the nucleus leading to decreased protective immune response. However, the underlying mechanism as to how Mtb exploits SIRT2 for iron acquisition remains unknown. In the current study, we observe that the decreased bacillary load in SIRT2 inhibited or knock down cells is due to low availability of iron to the bacilli. Inhibition or knockdown of SIRT2 in Mtb infected cells displays differential modulation of iron import and export proteins suggesting ongoing tussle by host to limit the bioavailability of iron to pathogen. More specifically, by flow cytometry analysis, we show significant upregulation of cell surface Apo Tf and GAPDH in infected SIRT2 inhibited macrophages. Thus, in SIRT2 depleted state, we delineate a different mechanism of iron export occurring through Apo Tf and GAPDH during infection in contrast to the classical iron exporter Fpn1. Collectively, our findings showed the importance of SIRT2-mediated iron regulation in Mtb pathogenesis and can encourage designing of novel host-targeted therapeutics.

show abstract

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosisexploits SIRT2 for iron acquisition to facilitate its intracellular survival

Talukdar,

Modanwal,

Chaubey

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…GAPDH is an abundantly expressed multifunctional protein that is secreted by cells and along with lactoferrin has been known to play a key role in the innate immune defenses [ 28 , 41 , 53 ]. These protective effects are manifested through close interaction between host molecules and host/microbial components that are vital for pathogen entry and survival.…”

Section: Discussionmentioning

confidence: 99%

“…Inves-tigations have revealed that GAPDH is also involved in a wide range of diverse activities such as membrane transport, cytoskeleton assembly, nuclear material export, protein phosphotransferase activity, membrane fusion, DNA replication and repair [21][22][23]. Apart from its normal physiological functions, several groups have identified the role of GAPDH in various pathological conditions such as infection biology, apoptosis, autophagy, efferocytosis, and neuronal degenerative disorders [16,21,[24][25][26][27][28]. It is also identified to play a role in the mammalian innate immune defense machinery [29].…”

Section: Introductionmentioning

confidence: 99%

Glyceraldehyde-3-Phosphate Dehydrogenase Binds with Spike Protein and Inhibits the Entry of SARS-CoV-2 into Host Cells

Dilawari,

Chaubey,

Modanwal

et al. 2024

J Innate Immun

View full text Add to dashboard Cite

Introduction: Coronavirus disease 2019 caused by coronavirus-2 (SARS-CoV-2) has emerged as an aggressive viral pandemic. Health care providers confront a challenging task for rapid development of effective strategies to combat this and its long-term after effects. Virus entry into host cells involves interaction between receptor-binding domain (RBD) of spike (S) protein S1 subunit with angiotensin converting enzyme present on host cells. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a moonlighting enzyme involved in cellular glycolytic energy metabolism and micronutrient homeostasis. It is deployed in various cellular compartments and the extra cellular milieu. Though it is known to moonlight as a component of mammalian innate immune defense machinery, till date its role in viral restriction remains unknown. Method: Recombinant S protein, the RBD, and human GAPDH protein were used for solid phase binding assays and biolayer interferometry. Pseudovirus particles expressing four different strain variants of S protein all harboring ZsGreen gene as marker of infection were used for flow cytometry-based infectivity assays. Results: Pseudovirus entry into target cells in culture was significantly inhibited by addition of human GAPDH into the extracellular medium. Binding assays demonstrated that human GAPDH binds to S protein and RBD of SARS-CoV-2 with nanomolar affinity. Conclusions: Our investigations suggest that this interaction of GAPDH interferes in the viral docking with hACE2 receptors, thereby affecting viral ingress into mammalian cells.

show abstract

“…In mycobacterial infections, the survival of the bacilli in the host relies on the efficient uptake of this metal, which acts as a co-factor in several biological processes. Therefore, there is a growing interest in targeting the pathways involved in its acquisition [ 34 , 35 , 36 ]. In detail, the production of siderophores (mycobactins and carboxymycobactins) has been shown to be of crucial importance; hence, proteins involved in their assembly, transport, and functionality have been proposed as potential targets [ 37 , 38 , 39 , 40 , 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting Siderophore-Mediated Iron Uptake in M. abscessus: A New Strategy to Limit the Virulence of Non-Tuberculous Mycobacteria

et al. 2023

View full text Add to dashboard Cite

Targeting pathogenic mechanisms, rather than essential processes, represents a very attractive approach for the development of new antimycobacterial drugs. In this context, iron acquisition routes have recently emerged as potentially druggable pathways. However, the importance of siderophore biosynthesis in the virulence and pathogenicity of M. abscessus (Mab) is still poorly understood. In this study, we investigated the Salicylate Synthase (SaS) of Mab as an innovative molecular target for the development of inhibitors of siderophore production. Notably, Mab-SaS does not have any counterpart in human cells, making it an interesting candidate for drug discovery. Starting from the analysis of the binding of a series of furan-based derivatives, previously identified by our group as inhibitors of MbtI from M. tuberculosis (Mtb), we successfully selected the lead compound 1, exhibiting a strong activity against Mab-SaS (IC50 ≈ 5 µM). Computational studies characterized the key interactions between 1 and the enzyme, highlighting the important roles of Y387, G421, and K207, the latter being one of the residues involved in the first step of the catalytic reaction. These results support the hypothesis that 5-phenylfuran-2-carboxylic acids are also a promising class of Mab-SaS inhibitors, paving the way for the optimization and rational design of more potent derivatives.

show abstract

Host glyceraldehyde-3-phosphate dehydrogenase-mediated iron acquisition is hijacked by intraphagosomal Mycobacterium tuberculosis

Cited by 7 publications

References 62 publications

Mycobacterium tuberculosisexploits SIRT2 for iron acquisition to facilitate its intracellular survival

Mycobacterium tuberculosisexploits SIRT2 for iron acquisition to facilitate its intracellular survival

Glyceraldehyde-3-Phosphate Dehydrogenase Binds with Spike Protein and Inhibits the Entry of SARS-CoV-2 into Host Cells

Targeting Siderophore-Mediated Iron Uptake in M. abscessus: A New Strategy to Limit the Virulence of Non-Tuberculous Mycobacteria

Contact Info

Product

Resources

About