Kirst King-Jones, PhD

Host: Arash Bashirullah

Iron Regulatory Protein 1: A classic textbook example gets an exciting upgrade 

We use the Drosophila prothoracic gland (PG) as a model to study tissues with high and dynamic demands in iron and heme. This is because the synthesis of steroids relies largely on enzymes that require iron-containing cofactors such as heme and iron-sulfur (Fe-S) clusters, most notably heme-bound cytochrome P450 enzymes. Importantly, both the steroidogenic enzymes and their iron cofactors are produced at very high levels in the PG to sustain steroid production. Thus, iron demand in this steroidal gland far exceeds that of most other tissues.

Iron Regulatory Protein 1 (IRP1) is a bifunctional cellular iron sensor. When iron levels are normal, IRP1 harbours an iron-sulphur cluster and forms holo-IRP1, a cytosolic enzyme with aconitase activity. When iron levels fall, IRP1 is free of the cluster (apo-IRP1) and binds to iron-responsive elements (IREs) in selected messenger RNAs (mRNAs) to increase cellular iron availability. Or so the story goes…

In my presentation, I will provide evidence that an enzyme involved in glycogen synthesis has a moonlighting function that is critical for controlling cellular iron homeostasis, and I will show that this occurs via direct interaction with IRP1. I will further show that this interaction revealed hitherto unknown roles for IRP1 that significantly expand the classic paradigm.