Copper-induced ferroportin-1 expression in J774 macrophages is associated with increased iron efflux

Chung, Jayong; Haile, David J.; Wessling‐Resnick, Marianne

doi:10.1073/pnas.0306622101

Cited by 46 publications

(43 citation statements)

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“…This suggests that there may be some pivotal interaction between the N terminus and the core of Slc11a proteins, such as occurs in the CPX-type copper-transporting P-type ATPases (68,69). Although there are no obvious ion-binding amino acids in the N terminus of Slc11a proteins, it was recently shown that deletion of the tyrosine-based Slc11a2-specific motif YSCF [62][63][64][65] inactivates transport function in mammalian cells but does not affect the subcellular localization (70). This motif is conserved in all mammalian Slc11a2, but not Slc11a1, homologues and might therefore play a role in determining symport function.…”

Section: Discussionmentioning

confidence: 99%

Evolution of Differences in Transport Function in Slc11a Family Members

Techau

Taubas

Popoff

et al. 2007

Journal of Biological Chemistry

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Slc11a1 (formerly Nramp1) is a proton/divalent cation transporter that regulates cation homeostasis in macrophages. Slc11a2 mediates divalent cation uptake via the gut and delivery into cells. The mode of action of the two transporters remains controversial. Heterologous expression in frog oocytes shows Slc11a2 is a symporter, whereas Slc11a1 is an antiporter fluxing divalent cations against the proton gradient. This explains why Slc11a2, but not Slc11a1, can complement EGTA sensitivity in smf1⌬/smf2⌬/smf3⌬ yeast. However, some studies of transport in mammalian cells suggest Slc11a1 is a symporter. We now demonstrate that Slc11a1, but not Slc11a2, complements a divalent cation stress phenotype in bsd2⌬/rer1⌬ yeast. This is the first description of a yeast complementation assay for Slc11a1 function. Given the prior demonstration in frog oocytes that Slc11a1 acts as an antiporter, the most plausible interpretation of the data is that Slc11a1 is rescuing bsd2⌬/rer1⌬ yeast by exporting divalent cations. Chimaeras define the N terminus, and a segment of the protein core preceding transmembrane domain 9 through transmembrane domain 12, as important in rescuing the divalent cation stress phenotype. EGTA sensitivity and divalent cation stress phenotypes in yeast expressing Slc11a orthologues show that symport activity is ancestral. Molecular changes that mediate rescue of the divalent cation stress phenotype post-date frogs and co-evolved with Slc11a1 orthologues that regulate divalent cation homeostasis in macrophages and resistance to infection in chickens and mammals.Slc11a1 (formerly Ity/Lsh/Bcg/Nramp1) is a proton/divalent cation transporter with 12 putative transmembrane domains (TMD) 4 (1) that localizes to late endosomes and lysosomes of macrophages (2, 3) and dendritic cells (4), and tertiary granules of neutrophils (5). It is recruited to phagosome membranes in macrophages infected with Mycobacterium (2, 3) or Leishmania (3), and regulates cellular divalent cation homeostasis (6, 7). Polymorphisms at murine Slc11a1 and human SLC11A1 contribute to susceptibility to numerous infectious and autoimmune diseases (8, 9). Slc11a2 (also Nramp2/DMT1/DCT1) shares 64% amino acid identity with Slc11a1 (10) and regulates divalent cation uptake via the gut and delivery of iron into multiple cell types (11,12). Different isoforms can be distinguished by different C-terminal amino acid sequences, and by the presence or absence of an iron response element located in the 3Ј-untranslated region of the mRNA (13). The IRE-containing isoform (Slc11a2-IRE) is expressed predominantly in epithelial cells and localizes to late endosome/lysosomes, whereas the non-IRE-containing isoform (Slc11a2-nonIRE) is expressed in blood cell lineages and localizes to early endosomes (13). Both isoforms localize to their respective endosomal compartments and to apical membranes when expressed in polarized MadinDarby canine kidney cells (13). Mutation at Slc11a2 in mice and rats is associated with microcytic anemia (14, 15).Fe 2ϩ , Zn 2ϩ , Mn 2ϩ , Co ...

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Section: Discussionmentioning

confidence: 99%

Evolution of Differences in Transport Function in Slc11a Family Members

Techau

Taubas

Popoff

et al. 2007

Journal of Biological Chemistry

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“…5A, compare Lp02 to ΔmavN). As copper treatment has been linked to decreased intracellular iron stores, the ΔmavN-specific defect could be the result of copper aggravating the iron starvation experienced by the ΔmavN mutant (54).…”

Section: Resultsmentioning

confidence: 99%

MavN is a Legionella pneumophila vacuole-associated protein required for efficient iron acquisition during intracellular growth

Isaac

Laguna

Valtz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Iron is essential for the growth and virulence of most intravacuolar pathogens. The mechanisms by which microbes bypass host iron restriction to gain access to this metal across the host vacuolar membrane are poorly characterized. In this work, we identify a unique intracellular iron acquisition strategy used by Legionella pneumophila. The bacterial Icm/Dot (intracellular multiplication/ defect in organelle trafficking) type IV secretion system targets the bacterial-derived MavN (more regions allowing vacuolar colocalization N) protein to the surface of the Legionella-containing vacuole where this putative transmembrane protein facilitates intravacuolar iron acquisition. The ΔmavN mutant exhibits a transcriptional iron-starvation signature before its growth is arrested during the very early stages of macrophage infection. This intracellular growth defect is rescued only by the addition of excess exogenous iron to the culture medium and not a variety of other metals. Consistent with MavN being a translocated substrate that plays an exclusive role during intracellular growth, the mutant shows no defect for growth in broth culture, even under severe iron-limiting conditions. Putative iron-binding residues within the MavN protein were identified, and point mutations in these residues resulted in defects specific for intracellular growth that are indistinguishable from the ΔmavN mutant. This model of a bacterial protein inserting into host membranes to mediate iron transport provides a paradigm for how intravacuolar pathogens can use virulence-associated secretion systems to manipulate and acquire host iron.

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“…Poor biologic availability may also be caused by an unfavorable oxidation state of the copper ion, which can be altered by macrophage-secreted molecules such as nitric oxide (37). Alternatively, minimization of copper stores in macrophages could represent a regulatory phenomenon, as copper has been shown to induce release of iron stores through a regulation of macrophage FPN1 expression (38). High expression levels of CTR4 were also exhibited by cryptococcal cells recovered from mouse brains, consistent with low levels of available copper in this organ.…”

Section: Discussionmentioning

confidence: 99%

Role of a CUF1/CTR4 copper regulatory axis in the virulence of Cryptococcus neoformans

Waterman

Hacham²,

Hu³

et al. 2007

J. Clin. Invest.

125

182

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The study of regulatory networks in human pathogens such as Cryptococcus neoformans provides insights into host-pathogen interactions that may allow for correlation of gene expression patterns with clinical outcomes. In the present study, deletion of the cryptococcal copper-dependent transcription factor 1 (Cuf1) led to defects in growth and virulence factor expression in low copper conditions. In mouse models, cuf1Δ strains exhibited reduced dissemination to the brain, but no change in lung growth, suggesting copper is limiting in neurologic infections. To examine this further, a biologic probe of available copper was constructed using the cryptococcal CUF1-dependent copper transporter, CTR4. Fungal cells demonstrated high CTR4 expression levels after phagocytosis by macrophage-like J774.16 cells and during infection of mouse brains, but not lungs, consistent with limited copper availability during neurologic infection. This was extended to human brain infections by demonstrating CTR4 expression during C. neoformans infection of an AIDS patient. Moreover, high CTR4 expression by cryptococcal strains from 24 solid organ transplant patients was associated with dissemination to the CNS. Our results suggest that copper acquisition plays a central role in fungal pathogenesis during neurologic infection and that measurement of stable traits such as CTR4 expression may be useful for risk stratification of individuals with cryptococcosis.

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Copper-induced ferroportin-1 expression in J774 macrophages is associated with increased iron efflux

Cited by 46 publications

References 46 publications

Evolution of Differences in Transport Function in Slc11a Family Members

Evolution of Differences in Transport Function in Slc11a Family Members

MavN is a Legionella pneumophila vacuole-associated protein required for efficient iron acquisition during intracellular growth

Role of a CUF1/CTR4 copper regulatory axis in the virulence of Cryptococcus neoformans

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