title: Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2.
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.
authors.affiliation: Department of Haematology, Hanson Institute, Adelaide, Australia.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Foot
authors.forename: Hazel E
authors.initials: HE
authors.lastname: Dalton
authors.forename: Linda M
authors.initials: LM
authors.lastname: Shearwin-Whyatt
authors.forename: Loretta
authors.initials: L
authors.lastname: Dorstyn
authors.forename: Seong-Seng
authors.initials: SS
authors.lastname: Tan
authors.forename: Baoli
authors.initials: B
authors.lastname: Yang
authors.forename: Sharad
authors.initials: S
authors.lastname: Kumar
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D056827:Endosomal Sorting Complexes Required for Transport; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D017136:Ion Transport / Q000502:physiology; D007501:Iron / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000075702:Nedd4 Ubiquitin Protein Ligases; D017434:Protein Structure, Tertiary / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D036341:Intercellular Signaling Peptides and Proteins; D007501:Iron; D008565:Membrane Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; D044767:Ubiquitin-Protein Ligases; D000099236:Solute Carrier Family 11, Member 2; C499188:Ndfip1 protein, mouse; C000618461:Nedd4l protein, mouse; C487995:Wwp2 protein, mouse