The role of cellular iron deficiency in controlling iron export.
Cation Transport Proteins
/ genetics
Cycloheximide
/ pharmacology
Deferoxamine
/ pharmacology
Gene Expression Regulation
HeLa Cells
Hepcidins
/ genetics
Humans
Ion Transport
/ drug effects
Iron Chelating Agents
/ pharmacology
Iron Deficiencies
Protein Binding
/ drug effects
Protein Synthesis Inhibitors
/ pharmacology
Protein Transport
/ drug effects
Proteolysis
/ drug effects
Signal Transduction
Ferroportin
Hepcidin
Iron deficiency
Iron metabolism
Ligand-induced degradation
SLC40A1
Journal
Biochimica et biophysica acta. General subjects
ISSN: 1872-8006
Titre abrégé: Biochim Biophys Acta Gen Subj
Pays: Netherlands
ID NLM: 101731726
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
30
06
2020
revised:
25
11
2020
accepted:
14
12
2020
pubmed:
20
12
2020
medline:
15
4
2021
entrez:
19
12
2020
Statut:
ppublish
Résumé
Iron export via the transport protein ferroportin (Fpn) plays a critical role in the regulation of dietary iron absorption and iron recycling in macrophages. Fpn plasma membrane expression is controlled by the hepatic iron-regulated hormone hepcidin in response to high iron availability and inflammation. Hepcidin binds to the central cavity of the Fpn transporter to block iron export either directly or by inducing Fpn internalization and lysosomal degradation. Here, we investigated whether iron deficiency affects Fpn protein turnover. We ectopically expressed Fpn in HeLa cells and used cycloheximide chase experiments to study basal and hepcidin-induced Fpn degradation under extracellular and intracellular iron deficiency. We show that iron deficiency does not affect basal Fpn turnover but causes a significant delay in hepcidin-induced degradation when cytosolic iron levels are low. These data have important mechanistic implications supporting the hypothesis that iron export is required for efficient targeting of Fpn by hepcidin. Additionally, we show that Fpn degradation is not involved in protecting cells from intracellular iron deficiency.
Sections du résumé
BACKGROUND
Iron export via the transport protein ferroportin (Fpn) plays a critical role in the regulation of dietary iron absorption and iron recycling in macrophages. Fpn plasma membrane expression is controlled by the hepatic iron-regulated hormone hepcidin in response to high iron availability and inflammation. Hepcidin binds to the central cavity of the Fpn transporter to block iron export either directly or by inducing Fpn internalization and lysosomal degradation. Here, we investigated whether iron deficiency affects Fpn protein turnover.
METHODS
We ectopically expressed Fpn in HeLa cells and used cycloheximide chase experiments to study basal and hepcidin-induced Fpn degradation under extracellular and intracellular iron deficiency.
CONCLUSIONS/GENERAL SIGNIFICANCE
We show that iron deficiency does not affect basal Fpn turnover but causes a significant delay in hepcidin-induced degradation when cytosolic iron levels are low. These data have important mechanistic implications supporting the hypothesis that iron export is required for efficient targeting of Fpn by hepcidin. Additionally, we show that Fpn degradation is not involved in protecting cells from intracellular iron deficiency.
Identifiants
pubmed: 33340587
pii: S0304-4165(20)30340-8
doi: 10.1016/j.bbagen.2020.129829
pii:
doi:
Substances chimiques
Cation Transport Proteins
0
HAMP protein, human
0
Hepcidins
0
Iron Chelating Agents
0
Protein Synthesis Inhibitors
0
metal transporting protein 1
0
Cycloheximide
98600C0908
Deferoxamine
J06Y7MXW4D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
129829Informations de copyright
Copyright © 2020. Published by Elsevier B.V.