{"gene":"IREB2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1995,"finding":"IRP2 binds to iron-responsive elements (IREs) in the 5' or 3' UTRs of target mRNAs; binding to 5'-IREs inhibits translation while binding to 3'-IREs stabilizes mRNA. IRP2 was shown to inhibit translation of ferritin mRNAs in vitro with molar efficacy equal to IRP1, and unlike IRP1, is not inactivated for RNA binding by alkylation with N-ethylmaleimide.","method":"In vitro translation assay, gel retardation (EMSA), recombinant protein purification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of translational repression with purified recombinant IRP2, replicated across multiple studies","pmids":["7890603","7622457"],"is_preprint":false},{"year":1995,"finding":"IRP2 activation requires de novo protein synthesis (new IRP2 protein accumulation), in contrast to IRP1 which is regulated post-translationally. Iron-induced inactivation/degradation of IRP2 also requires translation of another protein, indicating an independent regulator controls IRP2 stability.","method":"Translation inhibitor (cycloheximide) and transcription inhibitor (actinomycin D) treatment, immunoblot analysis in Ltk- cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus immunoblotting, single lab with two orthogonal approaches","pmids":["7544791"],"is_preprint":false},{"year":1999,"finding":"c-MYC transcriptionally stimulates IRP2 expression, increasing the intracellular iron pool, as part of a coordinated regulation of iron-controlling genes required for cell proliferation and transformation.","method":"Gene expression analysis, c-MYC gain/loss-of-function in cell transformation assays","journal":"Science (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiments and transformation assays, single lab","pmids":["9924025"],"is_preprint":false},{"year":1999,"finding":"Aluminum stabilizes IRP2 by interfering with iron-catalyzed oxidation of IRP2, preventing its degradation and thereby perturbing iron metabolism.","method":"IRE binding activity assay, in vitro oxidation assay with aluminum treatment","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vitro oxidation assay plus IRE binding, single lab two methods","pmids":["10580122"],"is_preprint":false},{"year":2003,"finding":"The RING finger protein HOIL-1 (heme-oxidized IRP2 ubiquitin ligase-1) functions as an E3 ubiquitin ligase for oxidized IRP2. Heme binds IRP2 in iron-rich cells, generating oxidative modification of IRP2 that serves as a recognition signal for HOIL-1-mediated ubiquitination and degradation.","method":"Co-immunoprecipitation, ubiquitination assay, cell-based degradation assay","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay in single lab; later contested by other studies showing HOIL-1 not required in HEK293 cells","pmids":["12629548"],"is_preprint":false},{"year":2004,"finding":"Iron-dependent IRP2 degradation involves 2-oxoglutarate-dependent oxygenase activity, similar to HIF-1alpha degradation. The previously proposed 73-amino-acid degradation domain with cysteine oxidation is not required, as deletion of this domain or triple cysteine mutants remain sensitive to iron-mediated degradation. Dimethyl-oxalylglycine (a 2-oxoglutarate-dependent oxygenase inhibitor) stabilizes IRP2.","method":"Mutagenesis of IRP2 expressed in H1299 cells, pharmacological inhibition, proteasome assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with pharmacological inhibition, directly tested multiple mutants and deletion constructs","pmids":["14729944"],"is_preprint":false},{"year":2004,"finding":"S-nitrosylation of IRP2 at cysteine C178 by nitric oxide leads to IRP2 ubiquitination and proteasomal degradation. Mutation C178S prevents NO-mediated degradation of IRP2.","method":"In vitro and in vivo S-nitrosylation assay, site-directed mutagenesis, ubiquitination assay, proteasome inhibitor treatment in RAW 264.7 cells","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus biochemical assays, single lab; mechanistic claim is contested by later studies showing SNP-induced IRP2 degradation does not require C178","pmids":["14673166"],"is_preprint":false},{"year":2005,"finding":"IRP2 degradation is triggered by heme-mediated oxidation involving the heme regulatory motif (HRM). Cys201 binds ferric heme and His204 is a ferrous heme binding site; both residues are critical for IRP2 degradation and recognition by HOIL-1 ubiquitin ligase. The HRM specifically contributes to oxidative modification and iron concentration sensing after iron is integrated into heme.","method":"Spectroscopic studies (heme binding), site-directed mutagenesis, cell-based degradation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — spectroscopic characterization of heme binding combined with mutagenesis and degradation assays in single rigorous study","pmids":["16039587"],"is_preprint":false},{"year":2005,"finding":"IRP2 deficiency in mice causes microcytic anemia and altered body iron distribution due to failure to stabilize TfR1 mRNA in bone marrow erythroid cells, linking IRP2 to systemic iron homeostasis and erythropoiesis.","method":"Irp2-/- knockout mouse model, hematological analysis, TfR1 mRNA quantification in bone marrow","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout model with multiple defined hematological and molecular phenotype readouts","pmids":["15956281"],"is_preprint":false},{"year":2005,"finding":"Nitric oxide (NO) stabilizes IRP2 protein by inhibiting its proteasomal degradation, without compromising overall proteasome activity. NO produced in neighboring cells can stabilize IRP2 by passive diffusion, acting as an intercellular signal.","method":"SNAP NO-donor treatment, HA-tagged IRP2 stability assay, co-culture system with NO synthase II-expressing cells, proteasome activity assay in B6 fibroblasts and H1299 cells","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell lines and co-culture system, but single lab","pmids":["15684386"],"is_preprint":false},{"year":2006,"finding":"Sodium nitroprusside (SNP) promotes IRP2 degradation by donating iron into cells and raising the labile iron pool (>4-fold increase), rather than via S-nitrosylation at C178. IRP2 mutants lacking C178 or the 73-aa domain remain sensitive to SNP-induced degradation, and SNP-induced degradation shares the same mechanism as ferric ammonium citrate-induced degradation.","method":"IRP2 mutagenesis (C178S, Delta73), calcein-based labile iron pool measurement, pharmacological inhibitors (actinomycin D, cycloheximide, succinylacetone, DMOG) in H1299 cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple mutants, direct labile iron pool measurement, and pharmacological dissection in single rigorous study","pmids":["16479012"],"is_preprint":false},{"year":2007,"finding":"HOIL-1 is not required for iron-mediated IRP2 degradation in HEK293 cells. Although HOIL-1 and IRP2 interact via the 73-aa domain, the interaction is not iron-dependent, does not enhance the rate of iron-mediated IRP2 degradation, and siRNA knockdown of HOIL-1 has no effect on endogenous IRP2 degradation.","method":"Co-immunoprecipitation, siRNA knockdown of HOIL-1, iron-dependent degradation assay, stable HOIL-1 expression in HEK293 cells","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional siRNA knockdown, single lab; directly contradicts HOIL-1 as obligate E3 for IRP2","pmids":["17822790"],"is_preprint":false},{"year":2008,"finding":"The C-terminal domain 4 (amino acids 719-963) of IRP2 is necessary but not sufficient for iron-dependent degradation. Deletion mutants lacking this region are stable even in iron-replete cells; transfer of IRP2 domain 4 to IRP1 confers iron sensitivity on the chimeric protein, while substituting IRP1 domain 4 into IRP2 stabilizes the chimeric protein.","method":"Systematic mutagenesis (truncation and domain-swap mutants), expression in H1299 cells, iron treatment stability assays","journal":"BMC molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis and chimeric protein domain swaps establishing structural requirements","pmids":["18226225"],"is_preprint":false},{"year":2008,"finding":"Stat5 directly transcriptionally regulates IRP2 expression in erythroid cells, linking EpoR/Jak2/Stat5 signaling to iron metabolism. Loss of Stat5 reduces IRP2 transcription, which in turn reduces TfR1 mRNA stability and TfR1 cell surface levels, causing microcytic anemia.","method":"Stat5-/- mouse model, chromatin immunoprecipitation (ChIP), transcriptional reporter assays, flow cytometry for TfR1 surface levels","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout model plus ChIP demonstrating direct transcriptional target, multiple orthogonal methods","pmids":["18694996"],"is_preprint":false},{"year":2008,"finding":"Tempol, a stable nitroxide, attenuates neuromuscular impairment in IRP2-/- mice by disassembling the iron-sulfur cluster of IRP1, converting it from cytosolic aconitase to IRE-binding form, which stabilizes TfR1 transcript and represses ferritin synthesis in the brain, partially restoring iron homeostasis.","method":"IRP2-/- mouse dietary Tempol supplementation, IRP1 IRE-binding activity assay, TfR1 mRNA and ferritin protein measurements in brain tissues","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo rescue experiment with defined molecular mechanism validated in multiple brain regions and cell lines","pmids":["18685102"],"is_preprint":false},{"year":2010,"finding":"IRP2 promotes tumor xenograft growth in a manner dependent on its unique 73-amino acid insert; the deletion mutant IRP2-Delta73 fails to promote tumor growth. IRP2 overexpression increases TfR1 levels in xenografts, along with elevated c-MYC and ERK1/2 phosphorylation.","method":"Tetracycline-inducible IRP2 expression in nude mouse xenograft model, IRP2-Delta73 deletion mutant, Western blot for TfR1 and signaling proteins, microarray analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft with inducible transgene and deletion mutant, single lab","pmids":["20405006"],"is_preprint":false},{"year":2011,"finding":"FBXL5-mediated degradation of IRP2 is essential for iron homeostasis in vivo. Fbxl5-/- mice die in utero with excessive iron accumulation, and this lethality is rescued by additional ablation of IRP2, demonstrating that impaired IRP2 degradation is primarily responsible for the phenotype.","method":"Fbxl5-/- knockout mice, Fbxl5-/-;Irp2-/- double-knockout rescue, liver-specific Fbxl5 deletion, high-iron diet challenge","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double knockout rescue in vivo, multiple mouse models","pmids":["21907140"],"is_preprint":false},{"year":2011,"finding":"IRP2 deficiency causes lower motor neuron degeneration with spinal cord axonopathy and mitochondrial dysfunction (decreased Complex I and II activities) due to functional iron starvation from misregulation of TfR1 and ferritin. Restoring IRP activity (via Tempol activating IRP1) or reducing ferritin expression genetically partially rescues motor neuron degeneration.","method":"Irp2-/- mouse model, mitochondrial complex activity assays, histological analysis of spinal cord, genetic ferritin reduction, Tempol dietary rescue","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo rescue experiments with multiple therapeutic approaches, mitochondrial biochemical assays, single lab but multiple orthogonal methods","pmids":["22003390"],"is_preprint":false},{"year":2002,"finding":"YB-1 (Y-box-binding protein) directly interacts with IRP2 in the presence of high iron concentrations. YB-1 reduces IRP2-mRNA complex formation with ferritin IRE and, when co-administered with IRP2, abrogates the translational inhibition exerted by either protein alone, providing a novel translational control mechanism through IRE.","method":"Two-hybrid screen, in vitro binding assay, co-immunoprecipitation, RNA gel shift assay (EMSA), in vitro translation assay with luciferase reporter","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (yeast two-hybrid, Co-IP, EMSA, in vitro translation), single lab","pmids":["12192037"],"is_preprint":false},{"year":2020,"finding":"The C-terminal substrate-binding domain of FBXL5 harbors a [2Fe2S] cluster in the oxidized state that organizes the C-terminal loop responsible for recruiting IRP2. The oxidized state of the cluster maintained by ambient oxygen promotes FBXL5 binding to IRP2, explaining hypoxia-induced IRP2 stabilization. FBXL5 also sterically dislodges IRP2 from IRE RNA to facilitate its ubiquitination and proteasomal turnover.","method":"Cryo-EM structure of IRP2-FBXL5-SKP1 complex, EPR spectroscopy of [2Fe2S] cluster, ubiquitination assay, RNA binding competition assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus biochemical reconstitution plus spectroscopic validation in a single rigorous study","pmids":["32126207"],"is_preprint":false},{"year":2020,"finding":"IRP2 loss in mice causes functional iron deficiency in pancreatic beta cells due to dysregulation of TfR1 and ferritin. This impairs Fe-S cluster biosynthesis, reducing the function of Cdkal1 (an Fe-S cluster enzyme), which catalyzes tRNA methylthiolation (ms2t6A37 in tRNALysUUU), leading to proinsulin misreading and impaired insulin processing. Iron repletion normalizes tRNA modification and restores insulin content.","method":"Irp2-/- mouse model, tRNA modification mass spectrometry, iron supplementation rescue, metabolic phenotyping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with rescue, mass spectrometry validation of tRNA modification, multiple orthogonal methods","pmids":["31941883"],"is_preprint":false},{"year":2021,"finding":"ISC (iron-sulfur cluster) synthesis suppression can activate IRP2 binding to target mRNAs independent of IRP1, FBXL5, and changes in IRP2 protein level, at tissue-level O2 concentrations. Deletion of both IRP1 and IRP2 abolishes the iron-starvation response, preventing its activation by ISC synthesis inhibition.","method":"ISC synthesis inhibition, IRP1/IRP2 double-deletion cell lines, RNA binding activity assay, iron homeostasis measurements","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion of both IRPs plus pharmacological ISC inhibition with direct RNA-binding measurements, multiple orthogonal approaches","pmids":["34039609"],"is_preprint":false},{"year":2020,"finding":"Loss of FDXR increases IRP2 expression (via FDX2), which then binds to an iron response element in the 3'UTR of TP73 mRNA and destabilizes it, repressing p73 protein expression. This FDXR-FDX2-IRP2-TP73 axis regulates aging and tumor suppression.","method":"Genetically modified mouse embryonic fibroblasts, siRNA knockdown of FDXR/IRP2, 3'UTR IRE reporter assay, immunoblotting in multiple human cancer cell lines","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IRE reporter assay and siRNA knockdown with multiple cell lines, single lab","pmids":["32304229"],"is_preprint":false},{"year":2019,"finding":"IRP2 stabilizes Mdm2 mRNA by binding to an iron response element (IRE) in the 3'UTR of Mdm2 mRNA, increasing Mdm2 expression independently of p53. IRP2 knockdown/knockout reduces Mdm2 expression, and IRP2-regulated Mdm2 is required for IRP2-mediated cell proliferation.","method":"IRP2 ectopic expression, siRNA/CRISPR knockout in human cancer cells and MEFs, IRE-3'UTR mRNA stability assay, luciferase reporter","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay and KO/KD with defined molecular mechanism, single lab","pmids":["31907996"],"is_preprint":false},{"year":2022,"finding":"Biallelic loss-of-function IREB2 variants in human patients cause disrupted post-transcriptional regulation of iron metabolism genes (altered ferritin and TfR1 expression), functional iron deficiency, and mitochondrial dysfunction in patient-derived lymphoblasts. Lentiviral restoration of IREB2 expression reverses iron metabolism abnormalities, confirming IRP2 is essential for iron homeostasis in humans.","method":"Patient-derived lymphoblast cell line, western blot for ferritin/TfR1, mitochondrial function assay, lentiviral rescue of IREB2 expression","journal":"Brain communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — human patient cells with molecular rescue experiment demonstrating causality, multiple orthogonal measurements","pmids":["35602653"],"is_preprint":false},{"year":2023,"finding":"G3BP1 stabilizes IRP2 by binding to and suppressing translation of FBXL5 mRNA (the E3 ligase component that mediates IRP2 ubiquitination), thereby preventing IRP2 proteasomal degradation, elevating cellular labile iron, and promoting ferroptosis in response to sodium arsenite.","method":"Co-immunoprecipitation, siRNA knockdown of G3BP1/FBXL5, IRP2 ubiquitination assay, labile iron measurement, ferroptosis assays in HEK293/MEF/HT1080 cells and mouse model","journal":"Journal of hazardous materials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KD, and ubiquitination assay with in vivo validation, single lab","pmids":["38118197"],"is_preprint":false},{"year":2024,"finding":"IRP2 post-transcriptionally upregulates TP53 by binding to an IRE in the 3'UTR of TP53 mRNA, increasing p53 protein levels. Elevated IRP2 in substantia nigra increases TFR1 expression, causes iron deposits and dopaminergic neuronal loss, and induces ferroptosis through the SLC7A11-ALOX12 pathway independently of GPX4.","method":"AAV-mediated IRP2 overexpression in mouse substantia nigra, MPTP-induced PD model, immunofluorescence, western blot, IRE-binding assay for TP53 3'UTR","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV overexpression with molecular pathway validation, single lab","pmids":["38936518"],"is_preprint":false},{"year":2025,"finding":"IRP2 deficiency reduces expression of HIF2α and its transcriptional target EPO, compromising stress erythropoiesis. The HIF2α IRE has a bulge uridine in the upper stem that specifically impairs IRP2 binding but not IRP1 binding, resulting in IRP1-selective regulation of HIF2α and EPO. This explains the distinct erythropoietic phenotypes of IRP1- vs IRP2-deficient mice.","method":"IRP1-/- and IRP2-/- mouse models, in vitro IRE binding assays with wild-type and mutant IREs, EPO measurement, erythropoiesis phenotyping","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assays with mutant IREs plus in vivo genetic models demonstrating differential binding affinity mechanism","pmids":["39316647"],"is_preprint":false},{"year":2024,"finding":"The deubiquitinase OTUD3 stabilizes IRP2 protein expression; OTUD3-mediated IRP2 stabilization reduces hippocampal neuron ferroptosis by inhibiting the p53/PTGS2 pathway.","method":"Lentiviral OTUD3 overexpression and IRP2 knockdown in cerebral ischemia-reperfusion mouse model and OGD/R neuronal model, co-immunoprecipitation, western blot","journal":"European journal of medical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, co-IP and overexpression/KD without direct deubiquitinase activity assay on IRP2","pmids":["39415292"],"is_preprint":false},{"year":2026,"finding":"TRIM28 functions as a novel E3 ubiquitin ligase that directly binds IRP2 and promotes K48-linked ubiquitination at the K877 site, leading to IRP2 degradation, reduced TfR1 expression, suppression of intracellular iron uptake, and attenuation of cardiomyocyte ferroptosis during ischemia/reperfusion injury.","method":"Co-immunoprecipitation coupled with mass spectrometry, ubiquitinome profiling, AAV9-mediated cardiomyocyte-specific TRIM28 overexpression, cardiomyocyte-specific TRIM28 knockout mice, K877 site mutagenesis","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct E3 ligase activity established by ubiquitinome profiling, site-specific mutagenesis, and in vivo genetic models","pmids":["41797698"],"is_preprint":false},{"year":2024,"finding":"The p.Asp826Val (D826V) missense variant in IRP2 causes significant protein degradation leading to misregulation of intracellular iron homeostasis. In a CRISPR-Cas9 knock-in mouse model, this variant causes reduced IRP2 protein levels, dysregulated iron metabolism, synaptic dysfunction (impaired LTP, increased microglial activation, decreased dendritic spine density), and neurobehavioral deficits. Proteasome inhibitor treatment restores IRP2 expression.","method":"CRISPR-Cas9 D826V knock-in mice, behavioral testing (Morris water maze, open field, Y-maze), LTP electrophysiology, proteasome inhibitor rescue, immunoblot in patient-derived cells","journal":"Orphanet journal of rare diseases / Acta biochimica et biophysica Sinica","confidence":"High","confidence_rationale":"Tier 1 / Strong — CRISPR knock-in animal model with functional rescue, multiple orthogonal phenotypic and molecular readouts, human patient variant confirmed","pmids":["39587636","41234066"],"is_preprint":false},{"year":2024,"finding":"FGFR1 stabilizes IRP2 protein through regulation of intracellular protein degradation pathways, leading to increased IRP2 binding to the IRE of TfR1 mRNA, upregulation of TfR1, and expansion of the labile iron pool in prostate cancer cells. Forced IRP2 expression in FGFR1-depleted cells rescues TfR1 expression and tumor growth.","method":"FGFR1 knockout (DU145 cells), IRP2 forced expression rescue, IRP2-IRE binding assay (RNA immunoprecipitation), labile iron pool measurement","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment plus IRE binding assay, single lab","pmids":["39154074"],"is_preprint":false},{"year":2018,"finding":"Leishmania donovani increases IRP2 protein expression and decreases its stability regulator FBXL5 in macrophages/splenocytes, causing increased IRP2 binding to the 5'IRE of ferroportin mRNA and blocking ferroportin translation, thereby retaining iron in macrophages to support intracellular parasite growth.","method":"In vitro (J774 macrophages) and in vivo L. donovani infection models, supershift analysis identifying IRP2 involvement, 35S-methionine pulse-chase labeling, FBXL5/ferroportin siRNA knockdown","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — supershift assay identifying IRP2, siRNA functional knockdown, in vivo infection model, single lab","pmids":["29470856"],"is_preprint":false},{"year":2024,"finding":"Diurnal oscillations in IRE-containing transcript regulation in mouse liver are mediated by feeding rhythms rather than the circadian clock. IRP2 protein levels show diurnal variation peaking at the light-dark transition, but ribosome profiling in IRP2-deficient mice reveals that maximum repression of target mRNAs at dark onset still occurs, indicating temporal redundancy with IRP1.","method":"IRP2-/- mice, ribosome profiling, liver transcript diurnal time-course analysis, circadian clock mutant mice with controlled feeding","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo ribosome profiling in IRP2 knockout with controlled feeding paradigm, single lab","pmids":["38773499"],"is_preprint":false}],"current_model":"IRP2 (IREB2) is a cytosolic RNA-binding protein that post-transcriptionally regulates iron homeostasis by binding iron-responsive elements (IREs) in the 5'-UTR of target mRNAs (ferritin, HIF2α) to repress their translation, and in the 3'-UTR (TfR1, Mdm2, TP73) to stabilize them; its activity and protein stability are controlled by iron- and oxygen-dependent ubiquitin-proteasome degradation mediated primarily by the FBXL5 E3 ligase complex (whose [2Fe2S] cluster senses both iron and oxygen), with additional regulation by TRIM28 and HOIL-1 ubiquitin ligases, ISC availability, nitric oxide, heme-mediated oxidation of its heme regulatory motif (Cys201/His204), and transcriptional stimulation by c-MYC and Stat5; in vivo, IRP2 is the dominant regulator of erythroid TfR1 and systemic iron distribution, and its loss causes microcytic anemia, neurodegeneration, motor neuron dysfunction, and diabetes through functional iron starvation of erythroblasts, neurons, and beta cells respectively."},"narrative":{"mechanistic_narrative":"IREB2 (IRP2) is a cytosolic RNA-binding protein that serves as a central post-transcriptional regulator of cellular and systemic iron homeostasis by binding iron-responsive elements (IREs) in target mRNAs: occupancy of 5'-UTR IREs represses translation (ferritin) while binding of 3'-UTR IREs stabilizes transcripts such as TfR1 [PMID:7890603, PMID:7622457, PMID:15956281]. IRP2 binds ferritin IREs with molar efficacy equal to IRP1 but, unlike IRP1, retains RNA-binding activity after alkylation, marking it as a distinct iron sensor [PMID:7890603, PMID:7622457]. Its RNA-binding output is governed chiefly by iron- and oxygen-dependent control of its own abundance: under iron- and oxygen-replete conditions IRP2 is targeted for ubiquitin-proteasome degradation, and the FBXL5 E3 ligase complex is the dominant route, with FBXL5 using a [2Fe2S] cluster (oxidized state stabilized by ambient oxygen) to recruit IRP2, sterically dislodge it from IRE RNA, and drive its ubiquitination — accounting for hypoxia-induced IRP2 stabilization [PMID:21907140, PMID:32126207]. Degradation requires the C-terminal domain 4, which is necessary and, when transferred, sufficient to confer iron sensitivity on IRP1 [PMID:18226225], and is potentiated by heme binding through the heme regulatory motif (Cys201/His204) that licenses oxidative modification [PMID:16039587]; degradation also depends on 2-oxoglutarate-dependent oxygenase activity [PMID:14729944], while raising the labile iron pool is the proximal trigger [PMID:16479012]. Additional E3 ligase input from TRIM28, which ubiquitinates IRP2 at K877, and deubiquitinase OTUD3 tune IRP2 levels [PMID:41797698]. Beyond protein stability, suppression of iron-sulfur cluster synthesis activates IRP2 RNA binding independently of protein level, FBXL5, and IRP1 [PMID:34039609], and IRP2 transcription is driven by c-MYC and by EpoR/Jak2/Stat5 signaling in erythroid cells [PMID:9924025, PMID:18694996]. In vivo, IRP2 is the dominant regulator of erythroid TfR1 and systemic iron distribution, and its loss causes microcytic anemia, motor neuron degeneration with mitochondrial dysfunction, and beta-cell dysfunction through functional iron starvation [PMID:15956281, PMID:22003390, PMID:31941883]. Biallelic loss-of-function IREB2 variants in humans cause functional iron deficiency, mitochondrial dysfunction, and neurological disease, with phenotypes reversed by restoring IREB2 expression [PMID:35602653, PMID:39587636, PMID:41234066]. IRP2 additionally regulates an expanding set of 3'-UTR IRE-bearing transcripts (Mdm2, TP73, TP53) and HIF2α/EPO, where an IRP2-impairing IRE bulge uridine renders HIF2α regulation IRP1-selective [PMID:31907996, PMID:32304229, PMID:38936518, PMID:39316647].","teleology":[{"year":1995,"claim":"Established that IRP2 is a bona fide IRE-binding regulator that represses translation via 5'-IREs and stabilizes mRNA via 3'-IREs, distinguishing it biochemically from IRP1.","evidence":"in vitro translation assay and EMSA with purified recombinant IRP2","pmids":["7890603","7622457"],"confidence":"High","gaps":["In vitro repression did not resolve which endogenous transcripts dominate in vivo","Structural basis of IRE recognition not defined"]},{"year":1995,"claim":"Showed IRP2 is regulated through protein accumulation/degradation rather than the post-translational switch used by IRP1, predicting an independent stability regulator.","evidence":"cycloheximide/actinomycin D treatment with immunoblotting in Ltk- cells","pmids":["7544791"],"confidence":"Medium","gaps":["The proposed protein controlling IRP2 stability was not identified","Pharmacological inhibition is indirect"]},{"year":1999,"claim":"Connected IRP2 to proliferative signaling by identifying it as a c-MYC transcriptional target that expands the intracellular iron pool.","evidence":"c-MYC gain/loss-of-function and transformation assays","pmids":["9924025"],"confidence":"Medium","gaps":["Direct promoter binding by c-MYC at IREB2 not shown","Single lab"]},{"year":2003,"claim":"Proposed HOIL-1 as an E3 ligase recognizing heme-oxidized IRP2, offering a mechanism linking heme/iron status to IRP2 turnover.","evidence":"co-IP, ubiquitination and cell-based degradation assays","pmids":["12629548"],"confidence":"Medium","gaps":["Later contested as non-obligate for iron-mediated degradation","Single lab"]},{"year":2004,"claim":"Reframed the degradation mechanism by showing it depends on 2-oxoglutarate-dependent oxygenase activity and not the previously proposed cysteine-oxidation domain.","evidence":"deletion/cysteine-mutant analysis with DMOG inhibition in H1299 cells","pmids":["14729944"],"confidence":"High","gaps":["The relevant oxygenase was not identified","Direct hydroxylation of IRP2 not demonstrated"]},{"year":2004,"claim":"Proposed S-nitrosylation at C178 as a route for NO-induced IRP2 degradation.","evidence":"S-nitrosylation assay, C178S mutagenesis and ubiquitination assay in RAW 264.7 cells","pmids":["14673166"],"confidence":"Medium","gaps":["Later contested by data showing NO-donor degradation is iron-mediated and C178-independent","Single lab"]},{"year":2005,"claim":"Defined the heme regulatory motif (Cys201/His204) as the heme-sensing element whose oxidative modification triggers degradation and HOIL-1 recognition.","evidence":"spectroscopic heme-binding studies, site-directed mutagenesis, degradation assays","pmids":["16039587"],"confidence":"High","gaps":["Relationship of HRM-dependent degradation to FBXL5 pathway not resolved","In vivo relevance of HRM not tested"]},{"year":2005,"claim":"Demonstrated in vivo that IRP2 is the dominant stabilizer of erythroid TfR1 mRNA and governs systemic iron distribution.","evidence":"Irp2-/- knockout mice with hematology and TfR1 mRNA quantification","pmids":["15956281"],"confidence":"High","gaps":["Cell-autonomous vs systemic contributions not fully separated","Degradation machinery in vivo not addressed"]},{"year":2005,"claim":"Showed NO can stabilize IRP2 and act as a diffusible intercellular iron-signaling cue, complicating the earlier S-nitrosylation degradation model.","evidence":"NO-donor treatment and co-culture with NOS II-expressing cells, proteasome assays","pmids":["15684386"],"confidence":"Medium","gaps":["Mechanistic reconciliation of NO stabilizing vs degrading IRP2 unresolved","Single lab"]},{"year":2006,"claim":"Resolved the NO controversy by showing SNP-induced IRP2 degradation acts by raising the labile iron pool, not via C178 S-nitrosylation.","evidence":"C178S/Delta73 mutants, calcein labile-iron measurement, inhibitor dissection in H1299 cells","pmids":["16479012"],"confidence":"High","gaps":["Did not identify the iron-sensing degradation machinery","Single cell-line context"]},{"year":2007,"claim":"Challenged HOIL-1 as the obligate IRP2 E3 ligase by showing its knockdown does not affect endogenous iron-mediated IRP2 degradation.","evidence":"reciprocal co-IP and HOIL-1 siRNA knockdown in HEK293 cells","pmids":["17822790"],"confidence":"Medium","gaps":["Did not identify the true iron-dependent E3 ligase","Cell-type-specific roles not excluded"]},{"year":2008,"claim":"Mapped the C-terminal domain 4 as necessary and transferable for iron-dependent degradation, localizing the degron.","evidence":"truncation and IRP1/IRP2 domain-swap chimeras in H1299 cells","pmids":["18226225"],"confidence":"High","gaps":["The recognizing ligase was still unknown","Structural detail of domain 4 not defined"]},{"year":2008,"claim":"Linked erythropoietin signaling to iron metabolism by identifying IRP2 as a direct Stat5 transcriptional target whose loss causes microcytic anemia.","evidence":"Stat5-/- mice, ChIP, reporter assays, TfR1 surface flow cytometry","pmids":["18694996"],"confidence":"High","gaps":["Contribution relative to c-MYC-driven transcription unclear","Direct vs indirect effects on TfR1 not fully separated"]},{"year":2008,"claim":"Provided proof-of-principle rescue showing IRP1 activation by Tempol can compensate for IRP2 loss in brain, restoring iron homeostasis and neuromuscular function.","evidence":"dietary Tempol in Irp2-/- mice, IRP1 IRE-binding and brain TfR1/ferritin assays","pmids":["18685102"],"confidence":"High","gaps":["Long-term and disease-stage efficacy not established","Mechanism of Tempol on IRP1 cluster not fully defined"]},{"year":2010,"claim":"Implicated IRP2 in tumor growth in a manner dependent on its unique 73-aa insert, linking iron handling to proliferation.","evidence":"tetracycline-inducible IRP2 and Delta73 in nude mouse xenografts","pmids":["20405006"],"confidence":"Medium","gaps":["Mechanistic role of the 73-aa insert in tumorigenesis unresolved","Single lab"]},{"year":2011,"claim":"Established FBXL5 as the physiologically dominant IRP2 degradation pathway through genetic epistasis, since Irp2 ablation rescues Fbxl5-/- iron-overload lethality.","evidence":"Fbxl5-/- and Fbxl5-/-;Irp2-/- mice with iron-diet challenge","pmids":["21907140"],"confidence":"High","gaps":["Molecular basis of FBXL5 iron/oxygen sensing not yet structural","Tissue-specific contributions only partially mapped"]},{"year":2011,"claim":"Defined the neurodegenerative consequences of IRP2 loss as functional iron starvation with mitochondrial complex dysfunction, partially rescuable by IRP reactivation or ferritin reduction.","evidence":"Irp2-/- mice, mitochondrial complex assays, genetic ferritin reduction, Tempol","pmids":["22003390"],"confidence":"High","gaps":["Selective neuronal vulnerability not fully explained","Link to human disease still pending at this point"]},{"year":2002,"claim":"Identified YB-1 as a direct iron-dependent IRP2 partner that modulates IRE-dependent translational control.","evidence":"yeast two-hybrid, co-IP, EMSA and in vitro translation reporter","pmids":["12192037"],"confidence":"Medium","gaps":["In vivo significance of YB-1 modulation unknown","Single lab"]},{"year":2020,"claim":"Provided the structural and biophysical basis for iron/oxygen sensing, showing FBXL5's oxidized [2Fe2S] cluster organizes IRP2 recruitment and sterically displaces it from IRE RNA.","evidence":"cryo-EM of IRP2-FBXL5-SKP1, EPR spectroscopy, ubiquitination and RNA competition assays","pmids":["32126207"],"confidence":"High","gaps":["Kinetics of cluster oxidation in cells not measured","Non-FBXL5 ligase contributions not addressed"]},{"year":2020,"claim":"Extended IRP2's physiological reach to beta-cell function by linking iron starvation to defective Fe-S enzyme Cdkal1 and proinsulin misreading.","evidence":"Irp2-/- mice, tRNA modification mass spectrometry, iron-repletion rescue","pmids":["31941883"],"confidence":"High","gaps":["Human diabetes relevance not established","Other Fe-S enzymes affected not catalogued"]},{"year":2021,"claim":"Showed IRP2 RNA-binding can be activated by ISC synthesis suppression independently of protein level, FBXL5, and IRP1, expanding sensing beyond degradation control.","evidence":"ISC inhibition, IRP1/IRP2 double-deletion cells, direct RNA-binding assays","pmids":["34039609"],"confidence":"High","gaps":["Molecular switch converting ISC status to IRP2 binding undefined","In vivo significance at tissue O2 not fully tested"]},{"year":2020,"claim":"Placed IRP2 within a tumor-suppressor/aging axis by showing it destabilizes TP73 mRNA via a 3'-UTR IRE downstream of FDXR/FDX2.","evidence":"MEFs, FDXR/IRP2 siRNA, 3'UTR IRE reporter assays","pmids":["32304229"],"confidence":"Medium","gaps":["Physiological setting where this axis dominates unclear","Single lab"]},{"year":2019,"claim":"Identified Mdm2 mRNA as a 3'-UTR IRE target stabilized by IRP2, coupling iron regulation to proliferation control.","evidence":"ectopic IRP2, siRNA/CRISPR KO, IRE-3'UTR stability and reporter assays","pmids":["31907996"],"confidence":"Medium","gaps":["In vivo relevance of IRP2-Mdm2 axis untested","Single lab"]},{"year":2024,"claim":"Added TP53 as an IRP2-upregulated IRE target and implicated IRP2-driven iron deposition in dopaminergic neuron ferroptosis via SLC7A11-ALOX12.","evidence":"AAV IRP2 overexpression in substantia nigra, MPTP PD model, TP53 3'UTR IRE assay","pmids":["38936518"],"confidence":"Medium","gaps":["Apparent opposing effects on p73 vs p53 not reconciled","Single lab"]},{"year":2025,"claim":"Explained divergent IRP1 vs IRP2 erythropoietic phenotypes by an HIF2α IRE bulge uridine that selectively impairs IRP2 binding.","evidence":"IRP1-/-/IRP2-/- mice and in vitro binding with wild-type/mutant IREs, EPO measurement","pmids":["39316647"],"confidence":"High","gaps":["Generalizability of IRE sequence selectivity across targets not mapped","Structural basis of bulge discrimination not solved"]},{"year":2024,"claim":"Demonstrated human disease causality of biallelic IREB2 loss-of-function through patient cells and lentiviral rescue of iron metabolism defects.","evidence":"patient-derived lymphoblasts, ferritin/TfR1 immunoblot, mitochondrial assays, lentiviral rescue","pmids":["35602653"],"confidence":"High","gaps":["Genotype-phenotype spectrum across patients not fully defined","Tissue-specific vulnerability mechanisms incomplete"]},{"year":2024,"claim":"Modeled a specific IREB2 missense variant (D826V) causing destabilization, synaptic dysfunction, and behavioral deficits rescuable by proteasome inhibition.","evidence":"CRISPR knock-in mice, behavioral and LTP testing, proteasome-inhibitor rescue, patient cells","pmids":["39587636","41234066"],"confidence":"High","gaps":["Why D826V destabilizes IRP2 mechanistically not fully defined","Translation to patient therapy untested"]},{"year":2024,"claim":"Identified additional inputs to IRP2 stability and binding via upstream regulators G3BP1 (suppressing FBXL5 translation) and FGFR1 (stabilizing IRP2), tying IRP2 to ferroptosis and cancer iron expansion.","evidence":"co-IP, siRNA, ubiquitination, labile iron and IRE-binding assays in multiple cell lines","pmids":["38118197","39154074"],"confidence":"Medium","gaps":["Direct vs indirect effects on IRP2 stability not fully separated","Single lab per axis"]},{"year":2026,"claim":"Defined TRIM28 as a direct K48-linked E3 ligase ubiquitinating IRP2 at K877, controlling cardiomyocyte iron uptake and ferroptosis.","evidence":"co-IP/MS, ubiquitinome profiling, K877 mutagenesis, cardiomyocyte-specific TRIM28 mouse models","pmids":["41797698"],"confidence":"High","gaps":["Relationship of TRIM28 to FBXL5 pathway hierarchy unresolved","Iron/oxygen dependence of TRIM28 targeting not addressed"]},{"year":null,"claim":"How the multiple, partly conflicting IRP2 stability inputs (FBXL5, TRIM28, OTUD3, heme/HRM oxidation, ISC sensing, NO) are hierarchically integrated across tissues and oxygen tensions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model ranks the relative contribution of each ligase/DUB in a given tissue","Crosstalk between protein-level control and ISC-driven RNA-binding activation undefined","Full IRE-target repertoire and sequence determinants of IRP2 vs IRP1 selectivity incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,8,19,21,23,27]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,18,33]},{"term_id":"GO:0140299","term_label":"molecular sensor 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(IRES), which are stem-loop structures found in the 5'-UTR of ferritin, and delta aminolevulinic acid synthase mRNAs, and in the 3'-UTR of transferrin receptor mRNA. Binding to the IRE element in ferritin results in the repression of its mRNA translation. Binding of the protein to the transferrin receptor mRNA inhibits the degradation of this otherwise rapidly degraded mRNA","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P48200/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IREB2","classification":"Not Classified","n_dependent_lines":193,"n_total_lines":1208,"dependency_fraction":0.1597682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TFRC","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IREB2","total_profiled":1310},"omim":[{"mim_id":"618451","title":"NEURODEGENERATION, EARLY-ONSET, WITH CHOREOATHETOID MOVEMENTS AND MICROCYTIC ANEMIA; NDCAMA","url":"https://www.omim.org/entry/618451"},{"mim_id":"618382","title":"CYTOSOLIC IRON-SULFUR ASSEMBLY COMPONENT 2A; CIAO2A","url":"https://www.omim.org/entry/618382"},{"mim_id":"616860","title":"ANEMIA, SIDEROBLASTIC, 3, PYRIDOXINE-REFRACTORY; SIDBA3","url":"https://www.omim.org/entry/616860"},{"mim_id":"614303","title":"EDICT SYNDROME; EDICT","url":"https://www.omim.org/entry/614303"},{"mim_id":"613311","title":"LYR MOTIF-CONTAINING PROTEIN 4; LYRM4","url":"https://www.omim.org/entry/613311"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cell Junctions","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IREB2"},"hgnc":{"alias_symbol":["IRP2"],"prev_symbol":[]},"alphafold":{"accession":"P48200","domains":[{"cath_id":"-","chopping":"12-81","consensus_level":"medium","plddt":92.9451,"start":12,"end":81},{"cath_id":"3.30.499.10","chopping":"86-140_200-263_277-312","consensus_level":"medium","plddt":86.873,"start":86,"end":312},{"cath_id":"3.30.499.10","chopping":"446-680","consensus_level":"high","plddt":90.0626,"start":446,"end":680},{"cath_id":"3.20.19.10","chopping":"738-757_839-963","consensus_level":"high","plddt":93.8652,"start":738,"end":963},{"cath_id":"-","chopping":"762-798","consensus_level":"medium","plddt":92.8795,"start":762,"end":798}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48200","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48200-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48200-F1-predicted_aligned_error_v6.png","plddt_mean":86.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IREB2","jax_strain_url":"https://www.jax.org/strain/search?query=IREB2"},"sequence":{"accession":"P48200","fasta_url":"https://rest.uniprot.org/uniprotkb/P48200.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48200/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48200"}},"corpus_meta":[{"pmid":"9924025","id":"PMC_9924025","title":"Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC.","date":"1999","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9924025","citation_count":288,"is_preprint":false},{"pmid":"15956281","id":"PMC_15956281","title":"Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (IRP2).","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15956281","citation_count":177,"is_preprint":false},{"pmid":"34039609","id":"PMC_34039609","title":"Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/34039609","citation_count":158,"is_preprint":false},{"pmid":"32126207","id":"PMC_32126207","title":"FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/32126207","citation_count":145,"is_preprint":false},{"pmid":"12629548","id":"PMC_12629548","title":"Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2.","date":"2003","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12629548","citation_count":143,"is_preprint":false},{"pmid":"21907140","id":"PMC_21907140","title":"The FBXL5-IRP2 axis is integral to control of iron metabolism in vivo.","date":"2011","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/21907140","citation_count":142,"is_preprint":false},{"pmid":"19800047","id":"PMC_19800047","title":"Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19800047","citation_count":136,"is_preprint":false},{"pmid":"36828914","id":"PMC_36828914","title":"N6-Methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2.","date":"2023","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/36828914","citation_count":131,"is_preprint":false},{"pmid":"16039587","id":"PMC_16039587","title":"Involvement of heme regulatory motif in heme-mediated ubiquitination and degradation of IRP2.","date":"2005","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16039587","citation_count":126,"is_preprint":false},{"pmid":"24285726","id":"PMC_24285726","title":"IRP2 regulates breast tumor growth.","date":"2013","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24285726","citation_count":118,"is_preprint":false},{"pmid":"7622457","id":"PMC_7622457","title":"Characterization and expression of iron regulatory protein 2 (IRP2). 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IRP2 was shown to inhibit translation of ferritin mRNAs in vitro with molar efficacy equal to IRP1, and unlike IRP1, is not inactivated for RNA binding by alkylation with N-ethylmaleimide.\",\n      \"method\": \"In vitro translation assay, gel retardation (EMSA), recombinant protein purification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of translational repression with purified recombinant IRP2, replicated across multiple studies\",\n      \"pmids\": [\"7890603\", \"7622457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"IRP2 activation requires de novo protein synthesis (new IRP2 protein accumulation), in contrast to IRP1 which is regulated post-translationally. Iron-induced inactivation/degradation of IRP2 also requires translation of another protein, indicating an independent regulator controls IRP2 stability.\",\n      \"method\": \"Translation inhibitor (cycloheximide) and transcription inhibitor (actinomycin D) treatment, immunoblot analysis in Ltk- cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus immunoblotting, single lab with two orthogonal approaches\",\n      \"pmids\": [\"7544791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"c-MYC transcriptionally stimulates IRP2 expression, increasing the intracellular iron pool, as part of a coordinated regulation of iron-controlling genes required for cell proliferation and transformation.\",\n      \"method\": \"Gene expression analysis, c-MYC gain/loss-of-function in cell transformation assays\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiments and transformation assays, single lab\",\n      \"pmids\": [\"9924025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Aluminum stabilizes IRP2 by interfering with iron-catalyzed oxidation of IRP2, preventing its degradation and thereby perturbing iron metabolism.\",\n      \"method\": \"IRE binding activity assay, in vitro oxidation assay with aluminum treatment\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vitro oxidation assay plus IRE binding, single lab two methods\",\n      \"pmids\": [\"10580122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The RING finger protein HOIL-1 (heme-oxidized IRP2 ubiquitin ligase-1) functions as an E3 ubiquitin ligase for oxidized IRP2. Heme binds IRP2 in iron-rich cells, generating oxidative modification of IRP2 that serves as a recognition signal for HOIL-1-mediated ubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, cell-based degradation assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay in single lab; later contested by other studies showing HOIL-1 not required in HEK293 cells\",\n      \"pmids\": [\"12629548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Iron-dependent IRP2 degradation involves 2-oxoglutarate-dependent oxygenase activity, similar to HIF-1alpha degradation. The previously proposed 73-amino-acid degradation domain with cysteine oxidation is not required, as deletion of this domain or triple cysteine mutants remain sensitive to iron-mediated degradation. Dimethyl-oxalylglycine (a 2-oxoglutarate-dependent oxygenase inhibitor) stabilizes IRP2.\",\n      \"method\": \"Mutagenesis of IRP2 expressed in H1299 cells, pharmacological inhibition, proteasome assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with pharmacological inhibition, directly tested multiple mutants and deletion constructs\",\n      \"pmids\": [\"14729944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"S-nitrosylation of IRP2 at cysteine C178 by nitric oxide leads to IRP2 ubiquitination and proteasomal degradation. Mutation C178S prevents NO-mediated degradation of IRP2.\",\n      \"method\": \"In vitro and in vivo S-nitrosylation assay, site-directed mutagenesis, ubiquitination assay, proteasome inhibitor treatment in RAW 264.7 cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus biochemical assays, single lab; mechanistic claim is contested by later studies showing SNP-induced IRP2 degradation does not require C178\",\n      \"pmids\": [\"14673166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IRP2 degradation is triggered by heme-mediated oxidation involving the heme regulatory motif (HRM). Cys201 binds ferric heme and His204 is a ferrous heme binding site; both residues are critical for IRP2 degradation and recognition by HOIL-1 ubiquitin ligase. The HRM specifically contributes to oxidative modification and iron concentration sensing after iron is integrated into heme.\",\n      \"method\": \"Spectroscopic studies (heme binding), site-directed mutagenesis, cell-based degradation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — spectroscopic characterization of heme binding combined with mutagenesis and degradation assays in single rigorous study\",\n      \"pmids\": [\"16039587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IRP2 deficiency in mice causes microcytic anemia and altered body iron distribution due to failure to stabilize TfR1 mRNA in bone marrow erythroid cells, linking IRP2 to systemic iron homeostasis and erythropoiesis.\",\n      \"method\": \"Irp2-/- knockout mouse model, hematological analysis, TfR1 mRNA quantification in bone marrow\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout model with multiple defined hematological and molecular phenotype readouts\",\n      \"pmids\": [\"15956281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Nitric oxide (NO) stabilizes IRP2 protein by inhibiting its proteasomal degradation, without compromising overall proteasome activity. NO produced in neighboring cells can stabilize IRP2 by passive diffusion, acting as an intercellular signal.\",\n      \"method\": \"SNAP NO-donor treatment, HA-tagged IRP2 stability assay, co-culture system with NO synthase II-expressing cells, proteasome activity assay in B6 fibroblasts and H1299 cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell lines and co-culture system, but single lab\",\n      \"pmids\": [\"15684386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Sodium nitroprusside (SNP) promotes IRP2 degradation by donating iron into cells and raising the labile iron pool (>4-fold increase), rather than via S-nitrosylation at C178. IRP2 mutants lacking C178 or the 73-aa domain remain sensitive to SNP-induced degradation, and SNP-induced degradation shares the same mechanism as ferric ammonium citrate-induced degradation.\",\n      \"method\": \"IRP2 mutagenesis (C178S, Delta73), calcein-based labile iron pool measurement, pharmacological inhibitors (actinomycin D, cycloheximide, succinylacetone, DMOG) in H1299 cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple mutants, direct labile iron pool measurement, and pharmacological dissection in single rigorous study\",\n      \"pmids\": [\"16479012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HOIL-1 is not required for iron-mediated IRP2 degradation in HEK293 cells. Although HOIL-1 and IRP2 interact via the 73-aa domain, the interaction is not iron-dependent, does not enhance the rate of iron-mediated IRP2 degradation, and siRNA knockdown of HOIL-1 has no effect on endogenous IRP2 degradation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of HOIL-1, iron-dependent degradation assay, stable HOIL-1 expression in HEK293 cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional siRNA knockdown, single lab; directly contradicts HOIL-1 as obligate E3 for IRP2\",\n      \"pmids\": [\"17822790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The C-terminal domain 4 (amino acids 719-963) of IRP2 is necessary but not sufficient for iron-dependent degradation. Deletion mutants lacking this region are stable even in iron-replete cells; transfer of IRP2 domain 4 to IRP1 confers iron sensitivity on the chimeric protein, while substituting IRP1 domain 4 into IRP2 stabilizes the chimeric protein.\",\n      \"method\": \"Systematic mutagenesis (truncation and domain-swap mutants), expression in H1299 cells, iron treatment stability assays\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis and chimeric protein domain swaps establishing structural requirements\",\n      \"pmids\": [\"18226225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Stat5 directly transcriptionally regulates IRP2 expression in erythroid cells, linking EpoR/Jak2/Stat5 signaling to iron metabolism. Loss of Stat5 reduces IRP2 transcription, which in turn reduces TfR1 mRNA stability and TfR1 cell surface levels, causing microcytic anemia.\",\n      \"method\": \"Stat5-/- mouse model, chromatin immunoprecipitation (ChIP), transcriptional reporter assays, flow cytometry for TfR1 surface levels\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout model plus ChIP demonstrating direct transcriptional target, multiple orthogonal methods\",\n      \"pmids\": [\"18694996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tempol, a stable nitroxide, attenuates neuromuscular impairment in IRP2-/- mice by disassembling the iron-sulfur cluster of IRP1, converting it from cytosolic aconitase to IRE-binding form, which stabilizes TfR1 transcript and represses ferritin synthesis in the brain, partially restoring iron homeostasis.\",\n      \"method\": \"IRP2-/- mouse dietary Tempol supplementation, IRP1 IRE-binding activity assay, TfR1 mRNA and ferritin protein measurements in brain tissues\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo rescue experiment with defined molecular mechanism validated in multiple brain regions and cell lines\",\n      \"pmids\": [\"18685102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IRP2 promotes tumor xenograft growth in a manner dependent on its unique 73-amino acid insert; the deletion mutant IRP2-Delta73 fails to promote tumor growth. IRP2 overexpression increases TfR1 levels in xenografts, along with elevated c-MYC and ERK1/2 phosphorylation.\",\n      \"method\": \"Tetracycline-inducible IRP2 expression in nude mouse xenograft model, IRP2-Delta73 deletion mutant, Western blot for TfR1 and signaling proteins, microarray analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft with inducible transgene and deletion mutant, single lab\",\n      \"pmids\": [\"20405006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FBXL5-mediated degradation of IRP2 is essential for iron homeostasis in vivo. Fbxl5-/- mice die in utero with excessive iron accumulation, and this lethality is rescued by additional ablation of IRP2, demonstrating that impaired IRP2 degradation is primarily responsible for the phenotype.\",\n      \"method\": \"Fbxl5-/- knockout mice, Fbxl5-/-;Irp2-/- double-knockout rescue, liver-specific Fbxl5 deletion, high-iron diet challenge\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double knockout rescue in vivo, multiple mouse models\",\n      \"pmids\": [\"21907140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IRP2 deficiency causes lower motor neuron degeneration with spinal cord axonopathy and mitochondrial dysfunction (decreased Complex I and II activities) due to functional iron starvation from misregulation of TfR1 and ferritin. Restoring IRP activity (via Tempol activating IRP1) or reducing ferritin expression genetically partially rescues motor neuron degeneration.\",\n      \"method\": \"Irp2-/- mouse model, mitochondrial complex activity assays, histological analysis of spinal cord, genetic ferritin reduction, Tempol dietary rescue\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo rescue experiments with multiple therapeutic approaches, mitochondrial biochemical assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22003390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"YB-1 (Y-box-binding protein) directly interacts with IRP2 in the presence of high iron concentrations. YB-1 reduces IRP2-mRNA complex formation with ferritin IRE and, when co-administered with IRP2, abrogates the translational inhibition exerted by either protein alone, providing a novel translational control mechanism through IRE.\",\n      \"method\": \"Two-hybrid screen, in vitro binding assay, co-immunoprecipitation, RNA gel shift assay (EMSA), in vitro translation assay with luciferase reporter\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (yeast two-hybrid, Co-IP, EMSA, in vitro translation), single lab\",\n      \"pmids\": [\"12192037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The C-terminal substrate-binding domain of FBXL5 harbors a [2Fe2S] cluster in the oxidized state that organizes the C-terminal loop responsible for recruiting IRP2. The oxidized state of the cluster maintained by ambient oxygen promotes FBXL5 binding to IRP2, explaining hypoxia-induced IRP2 stabilization. FBXL5 also sterically dislodges IRP2 from IRE RNA to facilitate its ubiquitination and proteasomal turnover.\",\n      \"method\": \"Cryo-EM structure of IRP2-FBXL5-SKP1 complex, EPR spectroscopy of [2Fe2S] cluster, ubiquitination assay, RNA binding competition assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus biochemical reconstitution plus spectroscopic validation in a single rigorous study\",\n      \"pmids\": [\"32126207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IRP2 loss in mice causes functional iron deficiency in pancreatic beta cells due to dysregulation of TfR1 and ferritin. This impairs Fe-S cluster biosynthesis, reducing the function of Cdkal1 (an Fe-S cluster enzyme), which catalyzes tRNA methylthiolation (ms2t6A37 in tRNALysUUU), leading to proinsulin misreading and impaired insulin processing. Iron repletion normalizes tRNA modification and restores insulin content.\",\n      \"method\": \"Irp2-/- mouse model, tRNA modification mass spectrometry, iron supplementation rescue, metabolic phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with rescue, mass spectrometry validation of tRNA modification, multiple orthogonal methods\",\n      \"pmids\": [\"31941883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ISC (iron-sulfur cluster) synthesis suppression can activate IRP2 binding to target mRNAs independent of IRP1, FBXL5, and changes in IRP2 protein level, at tissue-level O2 concentrations. Deletion of both IRP1 and IRP2 abolishes the iron-starvation response, preventing its activation by ISC synthesis inhibition.\",\n      \"method\": \"ISC synthesis inhibition, IRP1/IRP2 double-deletion cell lines, RNA binding activity assay, iron homeostasis measurements\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion of both IRPs plus pharmacological ISC inhibition with direct RNA-binding measurements, multiple orthogonal approaches\",\n      \"pmids\": [\"34039609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of FDXR increases IRP2 expression (via FDX2), which then binds to an iron response element in the 3'UTR of TP73 mRNA and destabilizes it, repressing p73 protein expression. This FDXR-FDX2-IRP2-TP73 axis regulates aging and tumor suppression.\",\n      \"method\": \"Genetically modified mouse embryonic fibroblasts, siRNA knockdown of FDXR/IRP2, 3'UTR IRE reporter assay, immunoblotting in multiple human cancer cell lines\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IRE reporter assay and siRNA knockdown with multiple cell lines, single lab\",\n      \"pmids\": [\"32304229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IRP2 stabilizes Mdm2 mRNA by binding to an iron response element (IRE) in the 3'UTR of Mdm2 mRNA, increasing Mdm2 expression independently of p53. IRP2 knockdown/knockout reduces Mdm2 expression, and IRP2-regulated Mdm2 is required for IRP2-mediated cell proliferation.\",\n      \"method\": \"IRP2 ectopic expression, siRNA/CRISPR knockout in human cancer cells and MEFs, IRE-3'UTR mRNA stability assay, luciferase reporter\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay and KO/KD with defined molecular mechanism, single lab\",\n      \"pmids\": [\"31907996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biallelic loss-of-function IREB2 variants in human patients cause disrupted post-transcriptional regulation of iron metabolism genes (altered ferritin and TfR1 expression), functional iron deficiency, and mitochondrial dysfunction in patient-derived lymphoblasts. Lentiviral restoration of IREB2 expression reverses iron metabolism abnormalities, confirming IRP2 is essential for iron homeostasis in humans.\",\n      \"method\": \"Patient-derived lymphoblast cell line, western blot for ferritin/TfR1, mitochondrial function assay, lentiviral rescue of IREB2 expression\",\n      \"journal\": \"Brain communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human patient cells with molecular rescue experiment demonstrating causality, multiple orthogonal measurements\",\n      \"pmids\": [\"35602653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"G3BP1 stabilizes IRP2 by binding to and suppressing translation of FBXL5 mRNA (the E3 ligase component that mediates IRP2 ubiquitination), thereby preventing IRP2 proteasomal degradation, elevating cellular labile iron, and promoting ferroptosis in response to sodium arsenite.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of G3BP1/FBXL5, IRP2 ubiquitination assay, labile iron measurement, ferroptosis assays in HEK293/MEF/HT1080 cells and mouse model\",\n      \"journal\": \"Journal of hazardous materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KD, and ubiquitination assay with in vivo validation, single lab\",\n      \"pmids\": [\"38118197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IRP2 post-transcriptionally upregulates TP53 by binding to an IRE in the 3'UTR of TP53 mRNA, increasing p53 protein levels. Elevated IRP2 in substantia nigra increases TFR1 expression, causes iron deposits and dopaminergic neuronal loss, and induces ferroptosis through the SLC7A11-ALOX12 pathway independently of GPX4.\",\n      \"method\": \"AAV-mediated IRP2 overexpression in mouse substantia nigra, MPTP-induced PD model, immunofluorescence, western blot, IRE-binding assay for TP53 3'UTR\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV overexpression with molecular pathway validation, single lab\",\n      \"pmids\": [\"38936518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IRP2 deficiency reduces expression of HIF2α and its transcriptional target EPO, compromising stress erythropoiesis. The HIF2α IRE has a bulge uridine in the upper stem that specifically impairs IRP2 binding but not IRP1 binding, resulting in IRP1-selective regulation of HIF2α and EPO. This explains the distinct erythropoietic phenotypes of IRP1- vs IRP2-deficient mice.\",\n      \"method\": \"IRP1-/- and IRP2-/- mouse models, in vitro IRE binding assays with wild-type and mutant IREs, EPO measurement, erythropoiesis phenotyping\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assays with mutant IREs plus in vivo genetic models demonstrating differential binding affinity mechanism\",\n      \"pmids\": [\"39316647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The deubiquitinase OTUD3 stabilizes IRP2 protein expression; OTUD3-mediated IRP2 stabilization reduces hippocampal neuron ferroptosis by inhibiting the p53/PTGS2 pathway.\",\n      \"method\": \"Lentiviral OTUD3 overexpression and IRP2 knockdown in cerebral ischemia-reperfusion mouse model and OGD/R neuronal model, co-immunoprecipitation, western blot\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, co-IP and overexpression/KD without direct deubiquitinase activity assay on IRP2\",\n      \"pmids\": [\"39415292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM28 functions as a novel E3 ubiquitin ligase that directly binds IRP2 and promotes K48-linked ubiquitination at the K877 site, leading to IRP2 degradation, reduced TfR1 expression, suppression of intracellular iron uptake, and attenuation of cardiomyocyte ferroptosis during ischemia/reperfusion injury.\",\n      \"method\": \"Co-immunoprecipitation coupled with mass spectrometry, ubiquitinome profiling, AAV9-mediated cardiomyocyte-specific TRIM28 overexpression, cardiomyocyte-specific TRIM28 knockout mice, K877 site mutagenesis\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct E3 ligase activity established by ubiquitinome profiling, site-specific mutagenesis, and in vivo genetic models\",\n      \"pmids\": [\"41797698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The p.Asp826Val (D826V) missense variant in IRP2 causes significant protein degradation leading to misregulation of intracellular iron homeostasis. In a CRISPR-Cas9 knock-in mouse model, this variant causes reduced IRP2 protein levels, dysregulated iron metabolism, synaptic dysfunction (impaired LTP, increased microglial activation, decreased dendritic spine density), and neurobehavioral deficits. Proteasome inhibitor treatment restores IRP2 expression.\",\n      \"method\": \"CRISPR-Cas9 D826V knock-in mice, behavioral testing (Morris water maze, open field, Y-maze), LTP electrophysiology, proteasome inhibitor rescue, immunoblot in patient-derived cells\",\n      \"journal\": \"Orphanet journal of rare diseases / Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — CRISPR knock-in animal model with functional rescue, multiple orthogonal phenotypic and molecular readouts, human patient variant confirmed\",\n      \"pmids\": [\"39587636\", \"41234066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FGFR1 stabilizes IRP2 protein through regulation of intracellular protein degradation pathways, leading to increased IRP2 binding to the IRE of TfR1 mRNA, upregulation of TfR1, and expansion of the labile iron pool in prostate cancer cells. Forced IRP2 expression in FGFR1-depleted cells rescues TfR1 expression and tumor growth.\",\n      \"method\": \"FGFR1 knockout (DU145 cells), IRP2 forced expression rescue, IRP2-IRE binding assay (RNA immunoprecipitation), labile iron pool measurement\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment plus IRE binding assay, single lab\",\n      \"pmids\": [\"39154074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Leishmania donovani increases IRP2 protein expression and decreases its stability regulator FBXL5 in macrophages/splenocytes, causing increased IRP2 binding to the 5'IRE of ferroportin mRNA and blocking ferroportin translation, thereby retaining iron in macrophages to support intracellular parasite growth.\",\n      \"method\": \"In vitro (J774 macrophages) and in vivo L. donovani infection models, supershift analysis identifying IRP2 involvement, 35S-methionine pulse-chase labeling, FBXL5/ferroportin siRNA knockdown\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — supershift assay identifying IRP2, siRNA functional knockdown, in vivo infection model, single lab\",\n      \"pmids\": [\"29470856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Diurnal oscillations in IRE-containing transcript regulation in mouse liver are mediated by feeding rhythms rather than the circadian clock. IRP2 protein levels show diurnal variation peaking at the light-dark transition, but ribosome profiling in IRP2-deficient mice reveals that maximum repression of target mRNAs at dark onset still occurs, indicating temporal redundancy with IRP1.\",\n      \"method\": \"IRP2-/- mice, ribosome profiling, liver transcript diurnal time-course analysis, circadian clock mutant mice with controlled feeding\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo ribosome profiling in IRP2 knockout with controlled feeding paradigm, single lab\",\n      \"pmids\": [\"38773499\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IRP2 (IREB2) is a cytosolic RNA-binding protein that post-transcriptionally regulates iron homeostasis by binding iron-responsive elements (IREs) in the 5'-UTR of target mRNAs (ferritin, HIF2α) to repress their translation, and in the 3'-UTR (TfR1, Mdm2, TP73) to stabilize them; its activity and protein stability are controlled by iron- and oxygen-dependent ubiquitin-proteasome degradation mediated primarily by the FBXL5 E3 ligase complex (whose [2Fe2S] cluster senses both iron and oxygen), with additional regulation by TRIM28 and HOIL-1 ubiquitin ligases, ISC availability, nitric oxide, heme-mediated oxidation of its heme regulatory motif (Cys201/His204), and transcriptional stimulation by c-MYC and Stat5; in vivo, IRP2 is the dominant regulator of erythroid TfR1 and systemic iron distribution, and its loss causes microcytic anemia, neurodegeneration, motor neuron dysfunction, and diabetes through functional iron starvation of erythroblasts, neurons, and beta cells respectively.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IREB2 (IRP2) is a cytosolic RNA-binding protein that serves as a central post-transcriptional regulator of cellular and systemic iron homeostasis by binding iron-responsive elements (IREs) in target mRNAs: occupancy of 5'-UTR IREs represses translation (ferritin) while binding of 3'-UTR IREs stabilizes transcripts such as TfR1 [#0, #8]. IRP2 binds ferritin IREs with molar efficacy equal to IRP1 but, unlike IRP1, retains RNA-binding activity after alkylation, marking it as a distinct iron sensor [#0]. Its RNA-binding output is governed chiefly by iron- and oxygen-dependent control of its own abundance: under iron- and oxygen-replete conditions IRP2 is targeted for ubiquitin-proteasome degradation, and the FBXL5 E3 ligase complex is the dominant route, with FBXL5 using a [2Fe2S] cluster (oxidized state stabilized by ambient oxygen) to recruit IRP2, sterically dislodge it from IRE RNA, and drive its ubiquitination — accounting for hypoxia-induced IRP2 stabilization [#16, #19]. Degradation requires the C-terminal domain 4, which is necessary and, when transferred, sufficient to confer iron sensitivity on IRP1 [#12], and is potentiated by heme binding through the heme regulatory motif (Cys201/His204) that licenses oxidative modification [#7]; degradation also depends on 2-oxoglutarate-dependent oxygenase activity [#5], while raising the labile iron pool is the proximal trigger [#10]. Additional E3 ligase input from TRIM28, which ubiquitinates IRP2 at K877, and deubiquitinase OTUD3 tune IRP2 levels [#29]. Beyond protein stability, suppression of iron-sulfur cluster synthesis activates IRP2 RNA binding independently of protein level, FBXL5, and IRP1 [#21], and IRP2 transcription is driven by c-MYC and by EpoR/Jak2/Stat5 signaling in erythroid cells [#2, #13]. In vivo, IRP2 is the dominant regulator of erythroid TfR1 and systemic iron distribution, and its loss causes microcytic anemia, motor neuron degeneration with mitochondrial dysfunction, and beta-cell dysfunction through functional iron starvation [#8, #17, #20]. Biallelic loss-of-function IREB2 variants in humans cause functional iron deficiency, mitochondrial dysfunction, and neurological disease, with phenotypes reversed by restoring IREB2 expression [#24, #30]. IRP2 additionally regulates an expanding set of 3'-UTR IRE-bearing transcripts (Mdm2, TP73, TP53) and HIF2\\u03b1/EPO, where an IRP2-impairing IRE bulge uridine renders HIF2\\u03b1 regulation IRP1-selective [#23, #22, #26, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that IRP2 is a bona fide IRE-binding regulator that represses translation via 5'-IREs and stabilizes mRNA via 3'-IREs, distinguishing it biochemically from IRP1.\",\n      \"evidence\": \"in vitro translation assay and EMSA with purified recombinant IRP2\",\n      \"pmids\": [\"7890603\", \"7622457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro repression did not resolve which endogenous transcripts dominate in vivo\", \"Structural basis of IRE recognition not defined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed IRP2 is regulated through protein accumulation/degradation rather than the post-translational switch used by IRP1, predicting an independent stability regulator.\",\n      \"evidence\": \"cycloheximide/actinomycin D treatment with immunoblotting in Ltk- cells\",\n      \"pmids\": [\"7544791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The proposed protein controlling IRP2 stability was not identified\", \"Pharmacological inhibition is indirect\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Connected IRP2 to proliferative signaling by identifying it as a c-MYC transcriptional target that expands the intracellular iron pool.\",\n      \"evidence\": \"c-MYC gain/loss-of-function and transformation assays\",\n      \"pmids\": [\"9924025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding by c-MYC at IREB2 not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Proposed HOIL-1 as an E3 ligase recognizing heme-oxidized IRP2, offering a mechanism linking heme/iron status to IRP2 turnover.\",\n      \"evidence\": \"co-IP, ubiquitination and cell-based degradation assays\",\n      \"pmids\": [\"12629548\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Later contested as non-obligate for iron-mediated degradation\", \"Single lab\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Reframed the degradation mechanism by showing it depends on 2-oxoglutarate-dependent oxygenase activity and not the previously proposed cysteine-oxidation domain.\",\n      \"evidence\": \"deletion/cysteine-mutant analysis with DMOG inhibition in H1299 cells\",\n      \"pmids\": [\"14729944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The relevant oxygenase was not identified\", \"Direct hydroxylation of IRP2 not demonstrated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Proposed S-nitrosylation at C178 as a route for NO-induced IRP2 degradation.\",\n      \"evidence\": \"S-nitrosylation assay, C178S mutagenesis and ubiquitination assay in RAW 264.7 cells\",\n      \"pmids\": [\"14673166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Later contested by data showing NO-donor degradation is iron-mediated and C178-independent\", \"Single lab\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the heme regulatory motif (Cys201/His204) as the heme-sensing element whose oxidative modification triggers degradation and HOIL-1 recognition.\",\n      \"evidence\": \"spectroscopic heme-binding studies, site-directed mutagenesis, degradation assays\",\n      \"pmids\": [\"16039587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship of HRM-dependent degradation to FBXL5 pathway not resolved\", \"In vivo relevance of HRM not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated in vivo that IRP2 is the dominant stabilizer of erythroid TfR1 mRNA and governs systemic iron distribution.\",\n      \"evidence\": \"Irp2-/- knockout mice with hematology and TfR1 mRNA quantification\",\n      \"pmids\": [\"15956281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-autonomous vs systemic contributions not fully separated\", \"Degradation machinery in vivo not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed NO can stabilize IRP2 and act as a diffusible intercellular iron-signaling cue, complicating the earlier S-nitrosylation degradation model.\",\n      \"evidence\": \"NO-donor treatment and co-culture with NOS II-expressing cells, proteasome assays\",\n      \"pmids\": [\"15684386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic reconciliation of NO stabilizing vs degrading IRP2 unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved the NO controversy by showing SNP-induced IRP2 degradation acts by raising the labile iron pool, not via C178 S-nitrosylation.\",\n      \"evidence\": \"C178S/Delta73 mutants, calcein labile-iron measurement, inhibitor dissection in H1299 cells\",\n      \"pmids\": [\"16479012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the iron-sensing degradation machinery\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Challenged HOIL-1 as the obligate IRP2 E3 ligase by showing its knockdown does not affect endogenous iron-mediated IRP2 degradation.\",\n      \"evidence\": \"reciprocal co-IP and HOIL-1 siRNA knockdown in HEK293 cells\",\n      \"pmids\": [\"17822790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the true iron-dependent E3 ligase\", \"Cell-type-specific roles not excluded\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the C-terminal domain 4 as necessary and transferable for iron-dependent degradation, localizing the degron.\",\n      \"evidence\": \"truncation and IRP1/IRP2 domain-swap chimeras in H1299 cells\",\n      \"pmids\": [\"18226225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The recognizing ligase was still unknown\", \"Structural detail of domain 4 not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked erythropoietin signaling to iron metabolism by identifying IRP2 as a direct Stat5 transcriptional target whose loss causes microcytic anemia.\",\n      \"evidence\": \"Stat5-/- mice, ChIP, reporter assays, TfR1 surface flow cytometry\",\n      \"pmids\": [\"18694996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution relative to c-MYC-driven transcription unclear\", \"Direct vs indirect effects on TfR1 not fully separated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided proof-of-principle rescue showing IRP1 activation by Tempol can compensate for IRP2 loss in brain, restoring iron homeostasis and neuromuscular function.\",\n      \"evidence\": \"dietary Tempol in Irp2-/- mice, IRP1 IRE-binding and brain TfR1/ferritin assays\",\n      \"pmids\": [\"18685102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term and disease-stage efficacy not established\", \"Mechanism of Tempol on IRP1 cluster not fully defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Implicated IRP2 in tumor growth in a manner dependent on its unique 73-aa insert, linking iron handling to proliferation.\",\n      \"evidence\": \"tetracycline-inducible IRP2 and Delta73 in nude mouse xenografts\",\n      \"pmids\": [\"20405006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic role of the 73-aa insert in tumorigenesis unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established FBXL5 as the physiologically dominant IRP2 degradation pathway through genetic epistasis, since Irp2 ablation rescues Fbxl5-/- iron-overload lethality.\",\n      \"evidence\": \"Fbxl5-/- and Fbxl5-/-;Irp2-/- mice with iron-diet challenge\",\n      \"pmids\": [\"21907140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of FBXL5 iron/oxygen sensing not yet structural\", \"Tissue-specific contributions only partially mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the neurodegenerative consequences of IRP2 loss as functional iron starvation with mitochondrial complex dysfunction, partially rescuable by IRP reactivation or ferritin reduction.\",\n      \"evidence\": \"Irp2-/- mice, mitochondrial complex assays, genetic ferritin reduction, Tempol\",\n      \"pmids\": [\"22003390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selective neuronal vulnerability not fully explained\", \"Link to human disease still pending at this point\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified YB-1 as a direct iron-dependent IRP2 partner that modulates IRE-dependent translational control.\",\n      \"evidence\": \"yeast two-hybrid, co-IP, EMSA and in vitro translation reporter\",\n      \"pmids\": [\"12192037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo significance of YB-1 modulation unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the structural and biophysical basis for iron/oxygen sensing, showing FBXL5's oxidized [2Fe2S] cluster organizes IRP2 recruitment and sterically displaces it from IRE RNA.\",\n      \"evidence\": \"cryo-EM of IRP2-FBXL5-SKP1, EPR spectroscopy, ubiquitination and RNA competition assays\",\n      \"pmids\": [\"32126207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics of cluster oxidation in cells not measured\", \"Non-FBXL5 ligase contributions not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended IRP2's physiological reach to beta-cell function by linking iron starvation to defective Fe-S enzyme Cdkal1 and proinsulin misreading.\",\n      \"evidence\": \"Irp2-/- mice, tRNA modification mass spectrometry, iron-repletion rescue\",\n      \"pmids\": [\"31941883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human diabetes relevance not established\", \"Other Fe-S enzymes affected not catalogued\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed IRP2 RNA-binding can be activated by ISC synthesis suppression independently of protein level, FBXL5, and IRP1, expanding sensing beyond degradation control.\",\n      \"evidence\": \"ISC inhibition, IRP1/IRP2 double-deletion cells, direct RNA-binding assays\",\n      \"pmids\": [\"34039609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular switch converting ISC status to IRP2 binding undefined\", \"In vivo significance at tissue O2 not fully tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed IRP2 within a tumor-suppressor/aging axis by showing it destabilizes TP73 mRNA via a 3'-UTR IRE downstream of FDXR/FDX2.\",\n      \"evidence\": \"MEFs, FDXR/IRP2 siRNA, 3'UTR IRE reporter assays\",\n      \"pmids\": [\"32304229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological setting where this axis dominates unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified Mdm2 mRNA as a 3'-UTR IRE target stabilized by IRP2, coupling iron regulation to proliferation control.\",\n      \"evidence\": \"ectopic IRP2, siRNA/CRISPR KO, IRE-3'UTR stability and reporter assays\",\n      \"pmids\": [\"31907996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of IRP2-Mdm2 axis untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added TP53 as an IRP2-upregulated IRE target and implicated IRP2-driven iron deposition in dopaminergic neuron ferroptosis via SLC7A11-ALOX12.\",\n      \"evidence\": \"AAV IRP2 overexpression in substantia nigra, MPTP PD model, TP53 3'UTR IRE assay\",\n      \"pmids\": [\"38936518\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent opposing effects on p73 vs p53 not reconciled\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Explained divergent IRP1 vs IRP2 erythropoietic phenotypes by an HIF2\\u03b1 IRE bulge uridine that selectively impairs IRP2 binding.\",\n      \"evidence\": \"IRP1-/-/IRP2-/- mice and in vitro binding with wild-type/mutant IREs, EPO measurement\",\n      \"pmids\": [\"39316647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability of IRE sequence selectivity across targets not mapped\", \"Structural basis of bulge discrimination not solved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated human disease causality of biallelic IREB2 loss-of-function through patient cells and lentiviral rescue of iron metabolism defects.\",\n      \"evidence\": \"patient-derived lymphoblasts, ferritin/TfR1 immunoblot, mitochondrial assays, lentiviral rescue\",\n      \"pmids\": [\"35602653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype spectrum across patients not fully defined\", \"Tissue-specific vulnerability mechanisms incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Modeled a specific IREB2 missense variant (D826V) causing destabilization, synaptic dysfunction, and behavioral deficits rescuable by proteasome inhibition.\",\n      \"evidence\": \"CRISPR knock-in mice, behavioral and LTP testing, proteasome-inhibitor rescue, patient cells\",\n      \"pmids\": [\"39587636\", \"41234066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why D826V destabilizes IRP2 mechanistically not fully defined\", \"Translation to patient therapy untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified additional inputs to IRP2 stability and binding via upstream regulators G3BP1 (suppressing FBXL5 translation) and FGFR1 (stabilizing IRP2), tying IRP2 to ferroptosis and cancer iron expansion.\",\n      \"evidence\": \"co-IP, siRNA, ubiquitination, labile iron and IRE-binding assays in multiple cell lines\",\n      \"pmids\": [\"38118197\", \"39154074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect effects on IRP2 stability not fully separated\", \"Single lab per axis\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined TRIM28 as a direct K48-linked E3 ligase ubiquitinating IRP2 at K877, controlling cardiomyocyte iron uptake and ferroptosis.\",\n      \"evidence\": \"co-IP/MS, ubiquitinome profiling, K877 mutagenesis, cardiomyocyte-specific TRIM28 mouse models\",\n      \"pmids\": [\"41797698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship of TRIM28 to FBXL5 pathway hierarchy unresolved\", \"Iron/oxygen dependence of TRIM28 targeting not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple, partly conflicting IRP2 stability inputs (FBXL5, TRIM28, OTUD3, heme/HRM oxidation, ISC sensing, NO) are hierarchically integrated across tissues and oxygen tensions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model ranks the relative contribution of each ligase/DUB in a given tissue\", \"Crosstalk between protein-level control and ISC-driven RNA-binding activation undefined\", \"Full IRE-target repertoire and sequence determinants of IRP2 vs IRP1 selectivity incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 8, 19, 21, 23, 27]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 18, 33]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [19, 21, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 8, 23, 27]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [8, 16, 32]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [25, 26, 29]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [16, 19, 29]}\n    ],\n    \"complexes\": [\n      \"FBXL5-SKP1 (CRL2) E3 ubiquitin ligase complex (as substrate)\"\n    ],\n    \"partners\": [\n      \"FBXL5\",\n      \"TRIM28\",\n      \"HOIL-1\",\n      \"OTUD3\",\n      \"YB-1\",\n      \"G3BP1\",\n      \"SKP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}