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

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.

• Authors: Nhan Huynh, Qiuxiang Ou, Pendleton Cox, Roland Lill, Kirst King-Jones
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 5463 (11 29 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 31784520 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drosophila Proteins
• Ecdysteroids
• Iron-Sulfur Proteins
• Mitochondrial Proteins
• RNA, Messenger
• Heme
• Iron
• 1,4-alpha-Glucan Branching Enzyme
• Iron Regulatory Protein 1

Topics

• 1,4-alpha-Glucan Branching Enzyme (genetics, metabolism)
• Active Transport, Cell Nucleus
• Animals
• Down-Regulation
• Drosophila
• Drosophila Proteins (genetics, metabolism)
• Ecdysteroids (biosynthesis)
• Endocrine Glands (metabolism)
• Gene Expression Regulation (genetics)
• Gene Knock-In Techniques
• Gene Knockout Techniques
• Heme (metabolism)
• Iron (metabolism)
• Iron Regulatory Protein 1 (genetics, metabolism)
• Iron-Sulfur Proteins (metabolism)
• Larva (metabolism)
• Mitochondrial Proteins (genetics, metabolism)
• Porphyrias (genetics, metabolism)
• RNA, Messenger (metabolism)