Review
Cellular iron sensing and regulation: Nuclear IRP1 extends a classic paradigm

https://doi.org/10.1016/j.bbamcr.2020.118705Get rights and content
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Highlights

  • Drosophila IRP1 homolog translocates to nucleus when carrying its [4Fesingle bond4S] cluster.

  • Physical interaction of nuclear IRP1 with histones regulates iron-related genes.

  • Fly mitoNEET homolog requires glycogen branching enzyme for [3Fesingle bond4S] cluster repair.

  • Ferritin could be a cellular iron sensor by contributing to the IRP1 repair process.

  • Drosophila Zip13 transports iron to the ER and Golgi.

Abstract

The classic view is that iron regulatory proteins operate at the post-transcriptional level. Iron Regulatory Protein 1 (IRP1) shifts between an apo-form that binds mRNAs and a holo-form that harbors a [4Fesingle bond4S] cluster. The latter form is not considered relevant to iron regulation, but rather thought to act as a non-essential cytosolic aconitase. Recent work in Drosophila, however, shows that holo-IRP1 can also translocate to the nucleus, where it appears to downregulate iron metabolism genes, preparing the cell for a decline in iron uptake. The shifting of IRP1 between states requires a functional mitoNEET pathway that includes a glycogen branching enzyme for the repair or disassembly of IRP1's oxidatively damaged [3Fesingle bond4S] cluster. The new findings add to the notion that glucose metabolism is modulated by iron metabolism. Furthermore, we propose that ferritin ferroxidase activity participates in the repair of the IRP1 [3Fesingle bond4S] cluster leading to the hypothesis that cytosolic ferritin directly contributes to cellular iron sensing.

Keywords

IRP2
Iron-sulfur cluster
Heme
Glycogen storage disease
Prothoracic gland
Steroidogenesis

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