Parkin regulates metal transport via proteasomal degradation of the 1B isoforms of divalent metal transporter 1.
Abnormal iron accumulation is linked to a variety of neurological disorders and may contribute to the progressive damage seen in these diseases. The biochemical processes responsible for iron accumulation are not known but are likely to entail alteration in transport into injured brain areas. The major transport protein responsible for ... uptake of iron is divalent metal transporter 1 (DMT1) and recent studies demonstrate that the 1B species is regulated post-translationally by degradation via the proteasomal pathway. As reported in this paper, the E3 ligase, parkin, when over-expressed in SH-SY5Y cells, results in a decrease in 1B-DMT1 isoforms and also a significant reduction in manganese transport and toxicity. Incubating cells over-expressing parkin with the proteasomal inhibitor, MG-132, restores 1B-DMT1 levels emphasizing that the observed changes are caused by degradation via the proteasomal pathway. Expression of the 1B species of DMT1 was also shown to be elevated in human lymphocytes containing a homozygous deletion of exon 4 of parkin and in brains of parkin knockout animals. Immunoprecipitation and immunofluorescent studies confirm that parkin co-localizes with DMT1 in SH-SY5Y cells transfected with wild-type parkin. These results demonstrate that parkin is the E3 ligase responsible for ubiquitination of the 1B species of DMT1.
Mesh Terms:
Adult, Animals, B-Lymphocytes, Cation Transport Proteins, Cell Death, Cells, Cultured, Chlorides, Cysteine Proteinase Inhibitors, Exons, Gene Expression Regulation, Humans, Immunoprecipitation, Leupeptins, Male, Manganese, Manganese Compounds, Mice, Mice, Knockout, Mutation, Neuroblastoma, Parkinson Disease, Proteasome Endopeptidase Complex, Protein Isoforms, Transfection, Ubiquitin-Protein Ligases
Adult, Animals, B-Lymphocytes, Cation Transport Proteins, Cell Death, Cells, Cultured, Chlorides, Cysteine Proteinase Inhibitors, Exons, Gene Expression Regulation, Humans, Immunoprecipitation, Leupeptins, Male, Manganese, Manganese Compounds, Mice, Mice, Knockout, Mutation, Neuroblastoma, Parkinson Disease, Proteasome Endopeptidase Complex, Protein Isoforms, Transfection, Ubiquitin-Protein Ligases
J. Neurochem.
Date: Apr. 01, 2010
PubMed ID: 20089134
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