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 Blood, 15 November 2008, Vol. 112, No. 10, pp. 4268-4275.
Prepublished online as a Blood First Edition Paper on September 5, 2008; DOI 10.1182/blood-2008-04-150953.

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RED CELLS

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

Natalie J. Foot1,*, Hazel E. Dalton1,*, Linda M. Shearwin-Whyatt1, Loretta Dorstyn1, Seong-Seng Tan2, Baoli Yang3, and Sharad Kumar1

1 Department of Haematology, Hanson Institute, Adelaide, Australia; 2 Brain Development Group, Howard Florey Institute, Melbourne, Australia; and 3 Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City

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.


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J. Howitt, U. Putz, J. Lackovic, A. Doan, L. Dorstyn, H. Cheng, B. Yang, T. Chan-Ling, J. Silke, S. Kumar, et al.
Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons
PNAS, September 8, 2009; 106(36): 15489 - 15494.
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