Regulation of the divalent metal ion transporter via membrane budding

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 reg...

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Published inCell discovery Vol. 2; no. 1; p. 16011
Main Authors Mackenzie, KimberlyD, Foot, Natalie J, Anand, Sushma, Dalton, Hazel E, Chaudhary, Natasha, Collins, Brett M, Mathivanan, Suresh, Kumar, Sharad
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 21.06.2016
Springer Nature B.V
Nature Publishing Group
Subjects
631/80/313/2162
631/80/313/2380
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell Cycle Analysis
Cell Physiology
Life Sciences
Stem Cells
Arrdc
extracellular vesicles
ubiquitin ligases
ubiquitination
DMT1
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Summary: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.
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KDM, NJF and SK conceptualized and designed the project and wrote the paper; KDM and NJF carried out experimental work; SA and SM generated and analyzed EV data in MEFs; HED contributed to early experimental design and generation of constructs; NC and BMC provided Arrdc constructs and advice. All authors commented on the draft versions of the manuscript.
ISSN:2056-5968
2056-5968
DOI:10.1038/celldisc.2016.11