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Cited by 148Extracellular vesicles in diseaseIron Metabolism and DisordersCellular transport and secretion

CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles

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Yanatori, Izumi, Richardson, Des R., Dhekne, Herschel S., Toyokuni, Shinya, Kishi, Fumio·2021·Blood
DOI 10.1182/blood.2021010995PMC PMC8667049
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Abstract

Extracellular vesicles (EVs) transfer functional molecules between cells. CD63 is a widely recognized EV marker that contributes to EV secretion from cells. However, the regulation of its expression remains largely unknown. Ferritin is a cellular iron storage protein that can also be secreted by the exosome pathway, and serum ferritin levels classically reflect body iron stores. Iron metabolism-associated proteins such as ferritin are intricately regulated by cellular iron levels via the iron responsive element-iron regulatory protein (IRE-IRP) system. Herein, we present a novel mechanism demonstrating that the expression of the EV-associated protein CD63 is under the regulation of the IRE-IRP system. We discovered a canonical IRE in the 5' untranslated region of CD63 messenger RNA that is responsible for regulating its expression in response to increased iron. Cellular iron loading caused a marked increase in CD63 expression and the secretion of CD63+ EVs from cells, which were shown to contain ferritin-H and ferritin-L. Our results demonstrate that under iron loading, intracellular ferritin is transferred via nuclear receptor coactivator 4 (NCOA4) to CD63+ EVs that are then secreted. Such iron-regulated secretion of the major iron storage protein ferritin via CD63+ EVs, is significant for understanding the local cell-to-cell exchange of ferritin and iron.

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Cited by

Sorted by citations

Authors
Yanatori, I., Richardson, D. R., Dhekne, H. S., Toyokuni, S., & Kishi, F.
Affiliations
  • Nagoya University (JP)
  • Griffith University (AU)
  • Stanford Medicine (US)
  • Center for Low-temperature Plasma Sciences, Nagoya University (JP)
  • Kenjinkai Healthcare Corporation, Yamaguchi, Japan
Corresponding author
  • Richardson, Des R.
  • Toyokuni, Shinya
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2021-10-21
Volume
138
Issue
16
Pages
1490-1503
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2021010995
PMC
PMC8667049
OpenAlex
W3177874667
Cited by
148
References
12
Citations by year
2026: 19 · 2025: 38 · 2024: 34 · 2023: 38 · 2022: 14 · 2021: 5
FWCI
7.93
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Griffith Research Online (submittedVersion, other-oa)
Funders
  • Medical Research Council
  • Australian Research Council (DP200103530)
  • National Health and Medical Research Council (1144456, 1144829, 1159596)
  • Japan Society for the Promotion of Science (JP20H05502, 20K07309, CREST, 19K23722, 20H05502)
  • Japan Science and Technology Agency (JPMJCR19H4, CREST)
  • Core Research for Evolutional Science and Technology (JPMJCR19H4)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
CD63, extracellular vesicles, iron metabolism, iron-responsive element, NCOA4, H-ferritin, iron loading, 5' untranslated region
MeSH terms
Extracellular Vesicles, Apoferritins, Cell Line, Ferritins, Humans, Iron, Oxidoreductases, RNA, Messenger, Up-Regulation, Gene Silencing, Protein Transport, Iron Regulatory Protein 1, Iron Regulatory Protein 2, Tetraspanin 30

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