Divalent-metal transport by NRAMP proteins at the interface of host–pathogen interactions
Abstract
The NRAMP family of divalent-metal transporters plays a key role in the homeostasis of iron and other metals. NRAMP2 (DMT1) acts as an iron-uptake protein in both the duodenum and in peripheral tissues. NRAMP1 functions as a divalent-metal efflux pump at the phagosomal membrane of macrophages and neutrophils, and mutations in NRAMP1 cause susceptibility to several intracellular pathogens. NRAMP homologues have been identified in bacteria and are involved in acquiring divalent metals from the extracellular environment. Interestingly, bacterial and mammalian NRAMP proteins would compete for the same essential substrates within the microenvironment of the phagosome, at the interface of host-pathogen interactions.
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Iron homeostasis and Lcn2 formation are linked to the activity of NRAMP1, which confers resistance to infections with intracellular pathogens such as Leishmania, Salmonella, or Mycobacteria.
“Iron homeostasis and Lnc2 formation are also linked to the activity of natural resistance associated macrophage protein 1 (NRAMP1 or SLC11A1), conferring resistance to infections with intracellular pathogens, such as Leishmania, Salmonella, or Mycobacteria (219, 220).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [219]
Macrophages express a phagolysosomal protein known as NRAMP1 (SLC11A1) which confers resistance to intracellular microbes such as Salmonella, Mycobacteria, or Leishmania.
“Macrophages also express a phagolysosomal protein, known as NRAMP1 (natural resistance associated macrophage protein 1, SLC11A1) which confers resistance to intracellular microbes such as Salmonella, Mycobacteria, or Leishmania (Forbes and Gros, 2001).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Forbes and Gros, 2001
Most studies have shown that Nramp1 shifts iron and other divalent cations from the phagolysosome to the cytosol.
“Most studies have shown that Nramp1 shifts iron and other divalent cations from the phagolysosome to the cytosol.”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [71]
Nramp1 is a phagolysosomal transporter with homology to Dmt1 (Nramp2).
“A phagolysosomal transporter with homology to Dmt1 (Nramp2) is Nramp1 [8, 20, 71, 75].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [71]
Early studies found differences among mouse strains in susceptibility to intracellular infections with Leishmania, Mycobacteria and Salmonella, but not virulent Mycobacterium tuberculosis.
“Early studies of the genetic basis of resistance to infections uncovered differences among mouse strains in their susceptibility to intracellular infections with a group of diverse microbes that included Leishmania, Mycobacteria and Salmonella [43] but not virulent strains of Mycobacterium tuberculosis [44].”
From Iron and infection (2018) · cites this paper as [43]
NRAMP1 has been identified as an important gene conferring resistance against Salmonella, Mycobacteria and Leishmania spp., all of which reside within the phagolysosome.
“It has been identified as an important gene to confer resistance against Salmonella, Mycobacteria and Leishmania spp., all of which residing within the phagolyosome”
From Iron in immune cell function and host defense (2021) · cites this paper as [19]
Nramp1 lowers phagosomal iron and restricts vacuolar growth of Salmonella Typhimurium, Leishmania donovani, and Mycobacterium bovis, but not cytosolic Listeria monocytogenes.
“Nramp1 reduces Fe concentration in phagosomes, restricting the vacuolar growth of intracellular pathogens such as Salmonella enterica serovar Typhimurium (Salmonella), Leishmania donovani and Mycobacteriun bovis, but not Listeria monocytogenes that exhibit a cytosolic life style (56–60).”
From Innate Nutritional Immunity (2018) · cites this paper as [59]
Another defense strategy lowering intracellular iron depends on post-transcriptional regulation of iron-responsive genes by IRPs.
“Other defense strategies reducing intracellular Fe content rely on post-transcriptional regulation of Fe-responsive genes, afforded by the concerted action of iron regulatory proteins (IRPs) (59).”
From Innate Nutritional Immunity (2018) · cites this paper as [59]
IRPs sense intracellular iron and bind iron-responsive elements on target mRNAs including TFR1, ferritin, and ferroportin, controlling their stability.
“IRPs sense intracellular Fe content and bind cis-regulatory iron responsive elements (IREs) on target mRNAs including TFR1, ferritin and ferroportin, regulating their stability (59).”
From Innate Nutritional Immunity (2018) · cites this paper as [59]
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The Thlaspi caerulescens NRAMP homologue TcNRAMP3 is capable of divalent cation transport
Wei, W., Chai, T., Zhang, Y., Han, L., Xu, J., & Guan, Z. (2009) · Molecular Biotechnology · doi:10.1007/s12033-008-9088-x · Cited by 94 · see citing works
‘Ride on the ferrous wheel’ – The cycle of iron in macrophages in health and disease
Nairz, M., Schroll, A., Demetz, E., Tancevski, I., Theurl, I., & Weiss, G. (2015) · Immunobiology · doi:10.1016/j.imbio.2014.09.010 · Cited by 89 · see citing works
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Copper intoxication inhibits aerobic nucleotide synthesis in Streptococcus pneumoniae
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Transcriptional riboswitches integrate timescales for bacterial gene expression control
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“Once sufficient Mn2+ has been imported, binding of excess Mn2+ to the Mn2+ riboswitch turns “off” expression of mntH so that concentration levels of the divalent cation do not result in cytotoxicity (Forbes and Gros, 2001; Shi et al., 2014).”
BackgroundNeisseria gonorrhoeae modulates iron-limiting innate immune defenses in macrophages
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Competition for Manganese at the Host–Pathogen Interface
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Natural history of SLC11 genes in vertebrates: tales from the fish world
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- Authors
- Forbes, J. R., & Gros, P.
- Affiliations
- McGill University (CA)
- Corresponding author
- Gros, Phillippe
- Venue
- Trends in Microbiology
- Publisher
- Elsevier BV
- Published
- 2001-08
- Volume
- 9
- Issue
- 8
- Pages
- 397-403
- ISSN
- 0966-842X (ISSN-L)
- OpenAlex
- W2093427530
- Cited by
- 424
- References
- 68
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 5 · 2023: 8 · 2022: 12 · 2021: 15 · 2020: 8 · 2019: 9 · 2018: 14 · 2017: 13 · 2016: 16 · 2015: 16 · 2014: 19 · 2013: 25 · 2012: 21
- FWCI
- 3.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Microbiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- NRAMP1, DMT1, iron homeostasis, host-pathogen interaction, intracellular pathogens, phagosome, metal transporters
- MeSH terms
- Natural Resistance-associated Macrophage Protein 1, Animals, Bacteria, Bacterial Infections, Carrier Proteins, Cations, Divalent, Humans, Iron, Macrophages, Membrane Proteins, Phagocytosis, Phagosomes, Cation Transport Proteins, Mice
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