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PMID:19924247

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Citation

Au, C, Benedetto, A, Anderson, J, Labrousse, A, Erikson, K, Ewbank, JJ and Aschner, M (2009) SMF-1, SMF-2 and SMF-3 DMT1 orthologues regulate and are regulated differentially by manganese levels in C. elegans. PLoS ONE 4:e7792

Abstract

Manganese (Mn) is an essential metal that can exert toxic effects at high concentrations, eventually leading to Parkinsonism. A major transporter of Mn in mammals is the divalent-metal transporter (DMT1). We characterize here DMT1-like proteins in the nematode C. elegans, which regulate and are regulated by Mn and iron (Fe) content. We identified three new DMT1-like genes in C. elegans: smf-1, smf-2 and smf-3. All three can functionally substitute for loss of their yeast orthologues in S. cerevisiae. In the worm, deletion of smf-1 or smf-3 led to an increased Mn tolerance, while loss of smf-2 led to increased Mn sensitivity. smf mRNA levels measured by QRT-PCR were up-regulated upon low Mn and down-regulated upon high Mn exposures. Translational GFP-fusions revealed that SMF-1 and SMF-3 strongly localize to partially overlapping apical regions of the gut epithelium, suggesting a differential role for SMF-1 and SMF-3 in Mn nutritional intake. Conversely, SMF-2 was detected in the marginal pharyngeal epithelium, possibly involved in metal-sensing. Analysis of metal content upon Mn exposure in smf mutants revealed that SMF-3 is required for normal Mn uptake, while smf-1 was dispensable. Higher smf-2 mRNA levels correlated with higher Fe content, supporting a role for SMF-2 in Fe uptake. In smf-1 and smf-3 but not in smf-2 mutants, increased Mn exposure led to decreased Fe levels, suggesting that both metals compete for transport by SMF-2. Finally, SMF-3 was post-translationally and reversibly down-regulated following Mn-exposure. In sum, we unraveled a complex interplay of transcriptional and post-translational regulations of 3 DMT1-like transporters in two adjacent tissues, which regulate metal-content in C. elegans.

Links

PubMed PMC2773845 Online version:10.1371/journal.pone.0007792

Keywords

Amino Acid Sequence; Animals; Animals, Genetically Modified; Biological Transport; Caenorhabditis elegans; Caenorhabditis elegans Proteins/metabolism; Cation Transport Proteins/genetics; Cation Transport Proteins/metabolism; Cloning, Molecular; Gene Deletion; Gene Expression Regulation; Iron/chemistry; Manganese/chemistry; Manganese/metabolism; Metals/chemistry; Molecular Sequence Data; Saccharomyces cerevisiae/metabolism; Sequence Homology, Amino Acid

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:NRAMB

involved_in

GO:0000041: transition metal ion transport

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:O54902

P

Seeded From UniProt

complete

CAEEL:NRAMB

located_in

GO:0043229: intracellular organelle

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:NRAMB

involved_in

GO:0010042: response to manganese ion

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00145540

P

Seeded From UniProt

complete

CAEEL:NRAMB

involved_in

GO:0010038: response to metal ion

ECO:0000316: genetic interaction evidence used in manual assertion

SGD:S000001092
SGD:S000005482

P

Seeded From UniProt

complete

CAEEL:NRAMB

located_in

GO:0016324: apical plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:NRAMB

enables

GO:0046915: transition metal ion transmembrane transporter activity

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:O54902

F

Seeded From UniProt

complete

CAEEL:NRAMB

involved_in

GO:0055072: iron ion homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00145540

P

Seeded From UniProt

complete

CAEEL:NRAMB

involved_in

GO:0055071: manganese ion homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00145540

P

Seeded From UniProt

complete

CAEEL:NRAMA

involved_in

GO:0000041: transition metal ion transport

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:O54902

P

Seeded From UniProt

complete

CAEEL:NRAMA

involved_in

GO:0010042: response to manganese ion

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00145119

P

Seeded From UniProt

complete

CAEEL:NRAMA

involved_in

GO:0010038: response to metal ion

ECO:0000316: genetic interaction evidence used in manual assertion

SGD:S000001092
SGD:S000005482

P

Seeded From UniProt

complete

CAEEL:NRAMA

located_in

GO:0016324: apical plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:NRAMA

enables

GO:0046915: transition metal ion transmembrane transporter activity

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:O54902

F

Seeded From UniProt

complete

CAEEL:NRAMA

involved_in

GO:0055072: iron ion homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00145119

P

Seeded From UniProt

complete

CAEEL:NRAMA

involved_in

GO:0055071: manganese ion homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00145119

P

Seeded From UniProt

complete

CAEEL:NRAMC

involved_in

GO:0000041: transition metal ion transport

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:O54902

P

Seeded From UniProt

complete

CAEEL:NRAMC

involved_in

GO:0010042: response to manganese ion

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00092305

P

Seeded From UniProt

complete

CAEEL:NRAMC

involved_in

GO:0010038: response to metal ion

ECO:0000316: genetic interaction evidence used in manual assertion

SGD:S000001092
SGD:S000005482

P

Seeded From UniProt

complete

CAEEL:NRAMC

located_in

GO:0016324: apical plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:NRAMC

enables

GO:0046915: transition metal ion transmembrane transporter activity

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:O54902

F

Seeded From UniProt

complete

CAEEL:NRAMC

involved_in

GO:0055072: iron ion homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00092305

P

Seeded From UniProt

complete

CAEEL:NRAMC

involved_in

GO:0055071: manganese ion homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00092305

P

Seeded From UniProt

complete


See also

References

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