FBXL5: Sensor and Regulator of Mammalian Iron Homeostasis
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While iron is an important cofactor for many proteins, the chemical properties of iron that favor its biological roles can lead to toxic side reactions that damage macromolecules. Cellular iron homeostasis is maintained by the coordinate posttranscriptional regulation of gene products responsible for iron uptake, release, utilization, and storage. This process is mediated by Iron Regulatory Proteins (IRPs) that bind to Iron Responsive Elements (IREs) in the mRNAs of these genes. When iron bioavailability is low IRPs bind IREs within these mRNAs, affecting their subsequent translation or stability. When cellular free iron availability is high, IRPs are preferentially degraded by the proteasome. An SCF E3 ubiquitin ligase complex containing the FBXL5 protein regulates this process as a function of cellular iron and oxygen concentrations. This process occurs through the stability of FBXL5, which accumulates under iron and oxygen replete conditions and is targeted for degradation upon iron depletion. FBXL5 contains an iron- and oxygen -sensing hemerythrin domain that acts as a ligand-binding regulatory switch mediating its stability. As a result, FBXL5 directly senses iron and oxygen levels to serve as a regulator of cellular iron homeostasis.