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Type: Journal article
Title: Regulation of the divalent metal ion transporter via membrane budding
Author: Mackenzie, K.
Foot, N.
Anand, S.
Dalton, H.
Chaudhary, N.
Collins, B.
Mathivanan, S.
Kumar, S.
Citation: Cell Discovery, 2016; 2(1):16011
Publisher: Nature
Issue Date: 2016
ISSN: 2056-5968
Statement of
Kimberly D Mackenzie, Natalie J Foot, Sushma Anand, Hazel E Dalton, Natasha Chaudhary, Brett M Collins, Suresh Mathivanan and Sharad Kumar
Abstract: The release of extracellular vesicles (EVs) is important for both normal physiology and disease. However, a basic understanding of the targeting of EV cargoes, composition and mechanism of release is lacking. Here we present evidence that the divalent metal ion transporter (DMT1) is unexpectedly regulated through release in EVs. This process involves the Nedd4-2 ubiquitin ligase, and the adaptor proteins Arrdc1 and Arrdc4 via different budding mechanisms. We show that mouse gut explants release endogenous DMT1 in EVs. Although we observed no change in the relative amount of DMT1 released in EVs from gut explants in Arrdc1 or Arrdc4 deficient mice, the extent of EVs released was significantly reduced indicating an adaptor role in biogenesis. Furthermore, using Arrdc1 or Arrdc4 knockout mouse embryonic fibroblasts, we show that both Arrdc1 and Arrdc4 are non-redundant positive regulators of EV release. Our results suggest that DMT1 release from the plasma membrane into EVs may represent a novel mechanism for the maintenance of iron homeostasis, which may also be important for the regulation of other membrane proteins.
Keywords: Arrdc; DMT1; extracellular vesicles; ubiquitin ligases; ubiquitination
Rights: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
RMID: 0030071088
DOI: 10.1038/celldisc.2016.11
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Appears in Collections:Medicine publications

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