Iron regulatory protein 1 promotes ferroptosis by sustaining cellular iron homeostasis in melanoma

AbstractIron Regulatory Protein 1 (IRP1) is a bifunctional cytosolic iron sensor. When iron levels are normal, IRP1 harbours an iron-sulphur cluster (holo-IRP1), an enzyme with aconitase activity. When iron levels fall, IRP1 loses the cluster (apo-IRP1) and binds to iron-responsive elements (IREs) in messenger RNAs (mRNAs) encoding proteins involved in cellular iron uptake, distribution, and storage. Here we show that mutations in the Drosophila 1,4-Alpha-Glucan Branching Enzyme (AGBE) gene cause porphyria. AGBE was hitherto only linked to glycogen metabolism and a fatal human disorder known as glycogen storage disease type IV. AGBE binds specifically to holo-IRP1 and to mitoNEET, a protein capable of repairing IRP1 iron-sulphur clusters. This interaction ensures nuclear translocation of holo-IRP1 and downregulation of iron-dependent processes, demonstrating that holo-IRP1 functions not just as an aconitase, but throttles target gene expression in anticipation of declining iron requirements.

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Catecholamine Stress Hormones Regulate Cellular Iron Homeostasis by a Posttranscriptional Mechanism Mediated by Iron Regulatory Protein

Journal of Biological Chemistry ◽

10.1074/jbc.m114.592519 ◽

2015 ◽

Vol 290 (12) ◽

pp. 7634-7646 ◽

Cited By ~ 12

Author(s):

Nisha Tapryal ◽

Vishnu Vivek G ◽

Chinmay K. Mukhopadhyay

Keyword(s):

Iron Homeostasis ◽

Stress Hormones ◽

Regulatory Protein ◽

Iron Regulatory Protein ◽

Cellular Iron ◽

Cellular Iron Homeostasis

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Involvement of the Iron Regulatory Protein from Eisenia andrei Earthworms in the Regulation of Cellular Iron Homeostasis

PLoS ONE ◽

10.1371/journal.pone.0109900 ◽

2014 ◽

Vol 9 (10) ◽

pp. e109900

Author(s):

Petra Procházková ◽

František Škanta ◽

Radka Roubalová ◽

Marcela Šilerová ◽

Jiří Dvořák ◽

...

Keyword(s):

Iron Homeostasis ◽

Regulatory Protein ◽

Iron Regulatory Protein ◽

Eisenia Andrei ◽

Cellular Iron ◽

Cellular Iron Homeostasis

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Faculty Opinions recommendation of Catecholamine stress hormones regulate cellular iron homeostasis by a posttranscriptional mechanism mediated by iron regulatory protein: implication in energy homeostasis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725308973.793504437 ◽

2015 ◽

Author(s):

Anirban Basu ◽

Sourish Ghosh

Keyword(s):

Energy Homeostasis ◽

Iron Homeostasis ◽

Stress Hormones ◽

Regulatory Protein ◽

Iron Regulatory Protein ◽

Cellular Iron ◽

Cellular Iron Homeostasis

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Chlamydia trachomatisAlters Iron-Regulatory Protein-1 Binding Capacity and Modulates Cellular Iron Homeostasis in HeLa-229 Cells

Journal of Biomedicine and Biotechnology ◽

10.1155/2009/342032 ◽

2009 ◽

Vol 2009 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Harsh Vardhan ◽

Apurb R. Bhengraj ◽

Rajneesh Jha ◽

Aruna Singh Mittal

Keyword(s):

Iron Homeostasis ◽

Binding Capacity ◽

Regulatory Protein ◽

Binding Activity ◽

Iron Regulatory Protein ◽

Mobility Shift ◽

Cellular Iron ◽

Infected Cells ◽

Mobility Shift Assay ◽

Cellular Iron Homeostasis

Chlamydia trachomatis(CT) is the leading cause of diseases related to reproductive health and iron plays important role in chlamydial pathogenesis. Iron homeostasis in chlamydia-infected cells is not clear thus far. This study shows that expression of the transferrin receptor (TfR) is downregulated, whereas expression of the ferritin heavy chain is upregulated in CT-infected HeLa-229 cells. Expression of iron-regulatory protein (IRP)-1 predominates over IRP-2 in infected cells. In infected cells, attenuated binding activity of IRP-iron responsive elements (IREs) is observed using the electrophoretic mobility-shift assay. These results suggest that iron homeostasis is modulated in CT-infected HeLa cells at the interface of acquisition and commensal use of iron.

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Function and crystal structure of the dimeric P-loop ATPase CFD1 coordinating an exposed [4Fe-4S] cluster for transfer to apoproteins

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1807762115 ◽

2018 ◽

Vol 115 (39) ◽

pp. E9085-E9094 ◽

Cited By ~ 11

Author(s):

Oliver Stehling ◽

Jae-Hun Jeoung ◽

Sven A. Freibert ◽

Viktoria D. Paul ◽

Sebastian Bänfer ◽

...

Keyword(s):

Crystal Structure ◽

Iron Homeostasis ◽

De Novo ◽

Regulatory Protein ◽

Protein Translation ◽

Cluster Assembly ◽

Cellular Iron ◽

Chaetomium Thermophilum ◽

Cellular Iron Homeostasis ◽

S Proteins

Maturation of iron-sulfur (Fe-S) proteins in eukaryotes requires complex machineries in mitochondria and cytosol. Initially, Fe-S clusters are assembled on dedicated scaffold proteins and then are trafficked to target apoproteins. Within the cytosolic Fe-S protein assembly (CIA) machinery, the conserved P-loop nucleoside triphosphatase Nbp35 performs a scaffold function. In yeast, Nbp35 cooperates with the related Cfd1, which is evolutionary less conserved and is absent in plants. Here, we investigated the potential scaffold function of human CFD1 (NUBP2) in CFD1-depleted HeLa cells by measuring Fe-S enzyme activities or 55Fe incorporation into Fe-S target proteins. We show that CFD1, in complex with NBP35 (NUBP1), performs a crucial role in the maturation of all tested cytosolic and nuclear Fe-S proteins, including essential ones involved in protein translation and DNA maintenance. CFD1 also matures iron regulatory protein 1 and thus is critical for cellular iron homeostasis. To better understand the scaffold function of CFD1-NBP35, we resolved the crystal structure of Chaetomium thermophilum holo-Cfd1 (ctCfd1) at 2.6-Å resolution as a model Cfd1 protein. Importantly, two ctCfd1 monomers coordinate a bridging [4Fe-4S] cluster via two conserved cysteine residues. The surface-exposed topology of the cluster is ideally suited for both de novo assembly and facile transfer to Fe-S apoproteins mediated by other CIA factors. ctCfd1 specifically interacted with ATP, which presumably associates with a pocket near the Cfd1 dimer interface formed by the conserved Walker motif. In contrast, ctNbp35 preferentially bound GTP, implying differential regulation of the two fungal scaffold components during Fe-S cluster assembly and/or release.

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Nickel decreases cellular iron level and converts cytosolic aconitase to iron-regulatory protein 1 in A549 cells

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2004.11.011 ◽

2005 ◽

Vol 206 (3) ◽

pp. 275-287 ◽

Cited By ~ 52

Author(s):

Haobin Chen ◽

Todd Davidson ◽

Steven Singleton ◽

Michael D. Garrick ◽

Max Costa

Keyword(s):

Regulatory Protein ◽

A549 Cells ◽

Iron Level ◽

Iron Regulatory Protein ◽

Cellular Iron ◽

Iron Regulatory Protein 1

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Inflaming the Brain with Iron

Antioxidants ◽

10.3390/antiox10010061 ◽

2021 ◽

Vol 10 (1) ◽

pp. 61

Author(s):

Pamela J. Urrutia ◽

Daniel A. Bórquez ◽

Marco Tulio Núñez

Keyword(s):

Nitric Oxide ◽

Iron Homeostasis ◽

Regulatory Protein ◽

Iron Accumulation ◽

Cellular Iron ◽

Bidirectional Relationship ◽

Inflammatory Phenotype ◽

Related Proteins ◽

Cellular Iron Homeostasis ◽

The Brain

Iron accumulation and neuroinflammation are pathological conditions found in several neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Iron and inflammation are intertwined in a bidirectional relationship, where iron modifies the inflammatory phenotype of microglia and infiltrating macrophages, and in turn, these cells secrete diffusible mediators that reshape neuronal iron homeostasis and regulate iron entry into the brain. Secreted inflammatory mediators include cytokines and reactive oxygen/nitrogen species (ROS/RNS), notably hepcidin and nitric oxide (·NO). Hepcidin is a small cationic peptide with a central role in regulating systemic iron homeostasis. Also present in the cerebrospinal fluid (CSF), hepcidin can reduce iron export from neurons and decreases iron entry through the blood–brain barrier (BBB) by binding to the iron exporter ferroportin 1 (Fpn1). Likewise, ·NO selectively converts cytosolic aconitase (c-aconitase) into the iron regulatory protein 1 (IRP1), which regulates cellular iron homeostasis through its binding to iron response elements (IRE) located in the mRNAs of iron-related proteins. Nitric oxide-activated IRP1 can impair cellular iron homeostasis during neuroinflammation, triggering iron accumulation, especially in the mitochondria, leading to neuronal death. In this review, we will summarize findings that connect neuroinflammation and iron accumulation, which support their causal association in the neurodegenerative processes observed in AD and PD.

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