Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons
Jason Howitt, Ulrich Putz, Jenny Lackovic, Anh Doan, Loretta Dorstyn, Hong Cheng, Baoli Yang, Chan-Ling Tailoi, John Silke, Sharad Kumar, Seong-Seng Tan
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | NATL ACAD SCIENCES | Published : 2009
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 neuro..View full abstract
This work was supported by a grant from the Victorian Neurotrauma Initiative, a joint venture between the Transport Accident Commission of Victoria with the Department of Innovation, Industry and Regional Development, and the National Health and Medical Research Council (NHMRC). J. H. is supported by a Howard Florey Centenary Fellowship awarded by the NHMRC. This work was carried out under the NHMRC National Statement on Ethical Conduct in research involving humans and approved by Melbourne Health Human Research Ethics committee.