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Glycogen branching enzyme controls cellular iron homeostasis via Iron Regulatory Protein 1 and mitoNEET

Author

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  • Nhan Huynh

    (University of Alberta, G-504 Biological Sciences Bldg)

  • Qiuxiang Ou

    (University of Alberta, G-504 Biological Sciences Bldg)

  • Pendleton Cox

    (University of Alberta, G-504 Biological Sciences Bldg)

  • Roland Lill

    (Philipps-Universität Marburg, Robert-Koch-Strasse 6
    Philipps-Universität Marburg, Hans-Meerwein-Straße)

  • Kirst King-Jones

    (University of Alberta, G-504 Biological Sciences Bldg)

Abstract

Iron Regulatory Protein 1 (IRP1) is a bifunctional cytosolic iron sensor. When iron levels are normal, IRP1 harbours an iron-sulphur cluster (holo-IRP1), an enzyme with aconitase activity. When iron levels fall, IRP1 loses the cluster (apo-IRP1) and binds to iron-responsive elements (IREs) in messenger RNAs (mRNAs) encoding proteins involved in cellular iron uptake, distribution, and storage. Here we show that mutations in the Drosophila 1,4-Alpha-Glucan Branching Enzyme (AGBE) gene cause porphyria. AGBE was hitherto only linked to glycogen metabolism and a fatal human disorder known as glycogen storage disease type IV. AGBE binds specifically to holo-IRP1 and to mitoNEET, a protein capable of repairing IRP1 iron-sulphur clusters. This interaction ensures nuclear translocation of holo-IRP1 and downregulation of iron-dependent processes, demonstrating that holo-IRP1 functions not just as an aconitase, but throttles target gene expression in anticipation of declining iron requirements.

Suggested Citation

  • Nhan Huynh & Qiuxiang Ou & Pendleton Cox & Roland Lill & Kirst King-Jones, 2019. "Glycogen branching enzyme controls cellular iron homeostasis via Iron Regulatory Protein 1 and mitoNEET," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13237-8
    DOI: 10.1038/s41467-019-13237-8
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    Cited by:

    1. Sattar Soltani & Samuel M. Webb & Thomas Kroll & Kirst King-Jones, 2024. "Drosophila Evi5 is a critical regulator of intracellular iron transport via transferrin and ferritin interactions," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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