Journal article
Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons
Proceedings of the National Academy of Sciences - PNAS, Vol.106(36), pp.15489-15494
2009
DOI: 10.1073/pnas.0904880106
PMCID: PMC2741278
PMID: 19706893
Abstract
The regulation of metal ion transport within neurons is critical for normal brain function. Of particular importance is the regulation of redox metals such as iron (Fe), where excess levels can contribute to oxidative stress and protein aggregation, leading to neuronal death. The divalent metal transporter 1 (DMT1) plays a central role in the regulation of Fe as well as other metals; hence, failure of DMT1 regulation is linked to human brain pathology. However, it remains unclear how DMT1 is regulated in the brain. Here, we show that DMT1 is regulated by Ndfip1 (Nedd4 family-interacting protein 1), an adaptor protein that recruits E3 ligases to ubiquitinate target proteins. Using human neurons we show the Ndfip1 is upregulated and binds to DMT1 in response to Fe and cobalt (Co) exposure. This interaction results in the ubiquitination and degradation of DMT1, resulting in reduced metal entry. Induction of Ndfip1 expression protects neurons from metal toxicity, and removal of Ndfip1 by shRNAi results in hypersensitivity to metals. We identify Nedd4-2 as an E3 ligase recruited by Ndfip1 for the ubiquitination of DMT1 within human neurons. Comparison of brains from Ndfip1⁻/⁻ with Ndfip1⁺/⁺ mice exposed to Fe reveals that Ndfip1⁻/⁻ brains accumulate Fe within neurons. Together, this evidence suggests a critical role for Ndfip1 in regulating metal transport in human neurons.
Details
- Title: Subtitle
- Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons
- Creators
- Jason HowittUlrich PutzJenny LackovicAnh DoanLoretta DorstynHong Cheng - University of Michigan–Ann ArborBaoli Yang - University of Iowa, BioVentures CenterTailoi Chan-LingJohn SilkeSharad KumarSeong-Seng Tan
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.106(36), pp.15489-15494
- Publisher
- National Academy of Sciences
- DOI
- 10.1073/pnas.0904880106
- PMID
- 19706893
- PMCID
- PMC2741278
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Language
- English
- Date published
- 2009
- Academic Unit
- BioVentures Center; Obstetrics and Gynecology
- Record Identifier
- 9983557152102771
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