Checks and balances for the iron bank

Abstract

The RNA-binding iron regulatory proteins IRP1 and IRP2 are inactivated by either Fe-S cluster insertion or protein degradation mediated by the E3 ligase component FBXL5. However, the mechanisms for coordination between Fe-S cluster assembly, FBXL5, and IRP1/IRP2 activity are poorly defined. A new study reveals that FBXL5 plays a critical role in limiting IRP1 and IRP2 overaccumulation when cytosolic Fe-S cluster assembly is impaired in order to maintain optimal iron levels for cell viability.

Figure 1.

Coordination between CIA, FBXL5, IRP1 and IRP2 in control of iron metabolism. A, when cytosolic iron (Fe) levels are low, Fe-S cluster insertion into IRP1 by the CIA pathway is decreased, driving an increase in the RNA-binding apo-form. Concurrently, FBXL5 is degraded in the absence of iron, leading to increased steady-state levels of its ubiquitination substrate IRP2. The net result is increased RNA binding by both IRP1 and IRP2, resulting in increased iron uptake and decreased iron storage. B, with sufficient cytosolic iron, the CIA pathway inserts an Fe-S cluster in IRP1, preventing RNA binding. Iron binding also stabilizes FBXL5, leading to increased degradation of IRP2. Reduced IRP1/2 RNA-binding activity decreases iron uptake while increasing iron storage, with the net result of lowering cytosolic iron. C, CIA silencing disrupts Fe-S insertion into IRP1 and increases IRP1 phosphorylation, presumably leading to increased cytosolic iron pools that stabilize FBXL5. The expanded FBXL5 pool functions to degrade both apo-IRP1 and IRP2 to curb RNA binding, limiting the increase in cytosolic iron and possibly other downstream effects of CIA dysfunction.