Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2

Foot, Natalie J., Dalton, Hazel E., Shearwin-Whyatt, Linda M., Dorstyn, Loretta, Tan, Seong-Seng, Yang, Baoli and Kumar, Sharad (2008) Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2. Blood, 112 10: 4268-4275. doi:10.1182/blood-2008-04-150953


Author Foot, Natalie J.
Dalton, Hazel E.
Shearwin-Whyatt, Linda M.
Dorstyn, Loretta
Tan, Seong-Seng
Yang, Baoli
Kumar, Sharad
Title Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
1528-0020
Publication date 2008-11-15
Year available 2008
Sub-type Article (original research)
DOI 10.1182/blood-2008-04-150953
Open Access Status Not yet assessed
Volume 112
Issue 10
Start page 4268
End page 4275
Total pages 8
Place of publication Washington, DC United States
Publisher American Society of Hematology
Language eng
Abstract Many ion channels and transporters are regulated by ubiquitination mediated by the Nedd4 family of HECT-type ubiquitin ligases (E3s). These E3s commonly interact with substrates via their WW domains that bind to specific motifs in target proteins. However, not all potential targets of these E3s contain WW-binding motifs. Therefore, accessory proteins may mediate the interaction between Nedd4 family members and their targets. Here we report that the divalent metal ion transporter DMT1, the primary nonheme iron transporter in mammals, is regulated by ubiquitination mediated by the Nedd4 family member WWP2. DMT1 interacts with 2 WW domain-interacting proteins, Ndfip1 and Ndfip2, previously proposed to have roles in protein trafficking. This promotes DMT1 ubiquitination and degradation by WWP2. Consistent with these observations, Ndfip1 -/- mice show increased DMT1 activity and a concomitant increase in hepatic iron deposition, indicating an essential function of Ndfip1 in iron homeostasis. This novel mechanism of regulating iron homeostasis suggests that Ndfips and WWP2 may contribute to diseases involving aberrant iron transport.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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Created: Tue, 28 Oct 2014, 03:19:28 EST by Sylvie Pichelin on behalf of Queensland Brain Institute