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https://hdl.handle.net/2440/134416
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Type: | Journal article |
Title: | K-29 linked ubiquitination of Arrdc4 regulates its function in extracellular vesicle biogenesis |
Author: | Farooq, A.U. Gembus, K. Sandow, J.J. Webb, A. Mathivanan, S. Manning, J.A. Shah, S.S. Foot, N.J. Kumar, S. |
Citation: | Journal of Extracellular Vesicles, 2022; 11(2):e12188-1-e12188-15 |
Publisher: | Wiley |
Issue Date: | 2022 |
ISSN: | 2001-3078 2001-3078 |
Statement of Responsibility: | Ammara Usman Farooq, Kelly Gembus, Jarrod J. Sandow, Andrew Webb, Suresh Mathivanan, Jantina A. Manning, Sonia S. Shah, Natalie J. Foot, Sharad Kumar |
Abstract: | Extracellular vesicles (EVs) are important mediators of intercellular communication. However, EV biogenesis remains poorly understood. We previously defined a role for Arrdc4 (Arrestin domain containing protein 4), an adaptor for Nedd4 family ubiquitin ligases, in the biogenesis of EVs. Here we report that ubiquitination of Arrdc4 is critical for its role in EV secretion. We identified five potential ubiquitinated lysine residues in Arrdc4 using mass spectrometry. By analysing Arrdc4 lysine mutants we discovered that lysine 270 (K270) is critical for Arrdc4 function in EV biogenesis. Arrdc4(K270R) mutation caused a decrease in the number of EVs released by cells compared to Arrdc4(WT), and a reduction in trafficking of divalent metal transporter (DMT1) into EVs. Furthermore, we also observed a decrease in DMT1 activity and an increase in its intracellular degradation in the presence of Arrdc4(K270R). K270 was found to be ubiquitinated with K-29 polyubiquitin chains by the ubiquitin ligase Nedd4-2. Thus, our results uncover a novel role of K-29 polyubiquitin chains in Arrdc4-mediated EV biogenesis and protein trafficking. |
Keywords: | DMT1; extracellular vesicles; Nedd4-2; Ubiquitin K-29 chains; ubiquitination |
Rights: | © 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles. This is an open access article under the terms of the Creative Commons Attribution-Non-Commercial-No-Derivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
DOI: | 10.1002/jev2.12188 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/GNT1122437 http://purl.org/au-research/grants/nhmrc/GNT1099307 http://purl.org/au-research/grants/nhmrc/GNT1103006 http://purl.org/au-research/grants/nhmrc/GNT2007739 |
Published version: | http://dx.doi.org/10.1002/jev2.12188 |
Appears in Collections: | Medicine publications |
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hdl_134416.pdf | Published version | 5.47 MB | Adobe PDF | View/Open |
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