Journal article
Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2
Blood, Vol.112(10), pp.4268-4275
11/15/2008
DOI: 10.1182/blood-2008-04-150953
PMID: 18776082
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. (Blood. 2008; 112: 4268-4275)
Details
- Title: Subtitle
- Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2
- Creators
- Natalie J. Foot - Hanson Inst, Dept Haematol, Adelaide, SA 5000, AustraliaHazel E. Dalton - Hanson Inst, Dept Haematol, Adelaide, SA 5000, AustraliaLinda M. Shearwin-Whyatt - Hanson Inst, Dept Haematol, Adelaide, SA 5000, AustraliaLoretta Dorstyn - Hanson Inst, Dept Haematol, Adelaide, SA 5000, AustraliaSeong-Seng Tan - Howard Florey Inst, Brain Dev Grp, Melbourne, Vic, AustraliaBaoli Yang - University of Iowa, BioVentures CenterSharad Kumar - Hanson Inst, Dept Haematol, Adelaide, SA 5000, Australia
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.112(10), pp.4268-4275
- Publisher
- Amer Soc Hematology
- DOI
- 10.1182/blood-2008-04-150953
- PMID
- 18776082
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Number of pages
- 8
- Grant note
- National Health and Medical Research Council of Australia; National Health and Medical Research Council (NHMRC) of Australia
- Language
- English
- Date published
- 11/15/2008
- Academic Unit
- BioVentures Center; Obstetrics and Gynecology
- Record Identifier
- 9983557562602771
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