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A disease-causing mutation K240E disrupts ferroportin trafficking by SUMO (ferroportin SUMOylation)

Bayele, HK; Srai, SKS; (2021) A disease-causing mutation K240E disrupts ferroportin trafficking by SUMO (ferroportin SUMOylation). Biochemistry and Biophysics Reports , 25 , Article 100873. 10.1016/j.bbrep.2020.100873. Green open access

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Abstract

Ferroportin (Fpn/IREG1/MTP1) is the only known transporter mediating iron efflux from epithelial cells and macrophages, and thus regulates how much iron is released into the circulation. Consequently, Fpn mutations are associated with haemochromatosis. Fpn itself is post-translationally regulated by hepcidin (Hepc) which induces its redistribution and degradation in a ubiquitin-dependent process. Together, the two proteins appear to be the nexus for iron homeostasis. Here we show that a rare gain-of-function mutation (K240E) that is associated with iron overload, impedes Fpn binding and subcellular trafficking by the small ubiquitin-like modifier (SUMO). Whereas wild-type Fpn is ensconced within vesicular bodies, the FpnK240E mutant appeared diffused within the cell when co-expressed with SUMO. Furthermore, compared with wild type Fpn, the sumoylation-defective mutant was constitutively-active, resulting in a lower intracellular labile iron pool than the former. These findings suggest that SUMO may regulate iron homeostasis by controlling Fpn trafficking.

Type: Article
Title: A disease-causing mutation K240E disrupts ferroportin trafficking by SUMO (ferroportin SUMOylation)
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bbrep.2020.100873
Publisher version: https://doi.org/10.1016/j.bbrep.2020.100873
Language: English
Additional information: This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Ferroportin, Iron transport, Subcellular distribution, SUMO, Sumoylation
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10119248
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