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.
Highlights
Control of intracellular iron levels in animal cells is regulated at the post-transcriptional level by iron regulatory protein 1 (IRP1)2 and its paralog IRP2 [1]
Cell viability was significantly decreased when FBXL5 knockdown was combined with knockdown of either early (NUBP2) or late acting (FAM96A) cytosolic iron-sulfur assembly (CIA) components or with expression of an RNAbinding IRP13CϾ3S mutant that is unable to bind an Fe-S cluster
The authors postulated that when the IRP1 Fe-S switch is not functional, cell viability is dependent on induction of FBXL5 activity to limit apo-IRP1 and IRP2 overaccumulation
Summary
Control of intracellular iron levels in animal cells is regulated at the post-transcriptional level by iron regulatory protein 1 (IRP1)2 and its paralog IRP2 [1]. Because FBXL5 promotes ubiquitination and degradation of IRP2 and apoIRP1 in an iron-dependent manner [4, 5], this study uncovered a potentially intriguing, unexplained connection between the CIA machinery, FBXL5 activity, and iron regulation. FBXL5 and CIA factors were silenced alone or in combination in HEK cells, and the downstream effects were evaluated.
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