ArticleThe Journal of biological chemistry2014
HERC2 targets the iron regulator FBXL5 for degradation and modulates iron metabolism.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33 citing papers in PubMed, 58 citations in OpenAlex.
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- Regulation of iron metabolism in ferroptosis: From mechanism research to clinical translation.Journal of pharmaceutical analysis · 2025Review
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- Correlative analysis of metallomic gene expression and metal ion content within the mouse hippocampus.Metallomics : integrated biometal science · 2025Article
- Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance.Molecular cancer · 2025Review
- Macranthoside B Suppresses the Growth of Adenocarcinoma of Esophagogastric Junction by Regulating Iron Homeostasis and Ferroptosis through NRF2 Inhibition.Current cancer drug targets · 2025Article
- Ferritinophagy and Ferroptosis in Cerebral Ischemia Reperfusion Injury.Neurochemical research · 2024Review
- Ferritinophagy: A novel insight into the double-edged sword in ferritinophagy-ferroptosis axis and human diseases.Cell proliferation · 2024Review
- Mechanisms of Ferritinophagy and Ferroptosis in Diseases.Molecular neurobiology · 2024Review
- NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8.Science advances · 2023Article
- The ZZ domain of HERC2 is a receptor of arginylated substrates.Scientific reports · 2022Article
- Ferritinophagy, a form of autophagic ferroptosis: New insights into cancer treatment.Frontiers in pharmacology · 2022Review
- The critical role of ferritinophagy in human disease.Frontiers in pharmacology · 2022Review
- Integrated analysis of the whole transcriptome of skeletal muscle reveals the ceRNA regulatory network related to the formation of muscle fibers in Tan sheep.Frontiers in genetics · 2022Article
- Inflaming the Brain with Iron.Antioxidants (Basel, Switzerland) · 2021Review
- Iron and Ferroptosis as Therapeutic Targets in Alzheimer's Disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
FBXL5 (F-box and leucine-rich repeat protein 5) is the F-box protein subunit of, and therefore responsible for substrate recognition by, the SCF(FBXL5) ubiquitin-ligase complex, which targets iron regulatory protein 2 (IRP2) for proteasomal degradation. IRP2 plays a central role in the maintenance of cellular iron homeostasis in mammals through posttranscriptional regulation of proteins that contribute to control of the intracellular iron concentration. The FBXL5-IRP2 axis is integral to control of iron metabolism in vivo, given that mice lacking FBXL5 die during early embryogenesis as a result of unrestrained IRP2 activity and oxidative stress attributable to excessive iron accumulation. Despite its pivotal role in the control of iron homeostasis, however, little is known of the upstream regulation of FBXL5 activity. We now show that FBXL5 undergoes constitutive ubiquitin-dependent degradation at the steady state. With the use of a proteomics approach to the discovery of proteins that regulate the stability of FBXL5, we identified the large HECT-type ubiquitin ligase HERC2 (HECT and RLD domain containing E3 ubiquitin protein ligase 2) as an FBXL5-associated protein. Inhibition of the HERC2-FBXL5 interaction or depletion of endogenous HERC2 by RNA interference resulted in the stabilization of FBXL5 and a consequent increase in its abundance. Such accumulation of FBXL5 in turn led to a decrease in the intracellular content of ferrous iron. Our results thus suggest that HERC2 regulates the basal turnover of FBXL5, and that this ubiquitin-dependent degradation pathway contributes to the control of mammalian iron metabolism.
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