FTH1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Ferritin is a predominantly cytoplasmic protein in mammalian cells. The IBA annotation based on phylogenetic inference is well-supported by the UniProt subcellular location annotation which states "Cytoplasm" with experimental evidence (PMID:26436293). Crystal structures and functional studies consistently show cytoplasmic localization of the ferritin complex. Reason: The cytoplasmic localization of FTH1 is a core functional characteristic. The 24-mer ferritin nanocage forms in the cytoplasm where it performs its iron storage function. This is supported by extensive structural and cell biological evidence. Supporting Evidence: PMID:26436293 NCOA4 is a selective cargo receptor for the autophagic turnover of ferritin, a process critical for regulation of intracellular iron bioavailability file:human/FTH1/FTH1-deep-research-falcon.md model: Edison Scientific Literature
GO:0008198 ferrous iron binding	IBA GO_REF:0000033	ACCEPT	Summary: Ferrous iron (Fe2+) binding is the initial step in ferritin's iron storage mechanism. The IBA annotation is strongly supported by direct experimental evidence from PMID:9003196 which used stopped-flow assays and site-directed mutagenesis to demonstrate Fe2+ binding at the ferroxidase center, showing that "the first 48 Fe(II) atoms/molecule added are bound and oxidized at the dinuclear centers." Reason: Fe2+ binding is essential to FTH1's core ferroxidase function. The ferritin H chain binds Fe2+ at its dinuclear ferroxidase center (sites A and B) prior to oxidation. This is experimentally validated and central to the protein's physiological role. Supporting Evidence: PMID:9003196 the first 48 Fe(II) atoms/molecule added are bound and oxidized at the dinuclear centers
GO:0006826 iron ion transport	IBA GO_REF:0000033	MODIFY	Summary: Iron ion transport describes the movement of iron ions. While FTH1 is involved in iron handling, its primary role is iron storage rather than active transport. The UniProt function annotation states FTH1 "Stores iron in a soluble, non-toxic, readily available form" and "Also plays a role in delivery of iron to cells" but this delivery function is attributed to the assembled ferritin complex being taken up by cells, not direct transport activity. Reason: FTH1's primary function is iron sequestration and storage, not active transport. The term "iron ion transport" implies movement across membranes or between compartments, whereas ferritin accumulates iron within its mineral core. Iron release occurs via ferritinophagy (lysosomal degradation), not a transport mechanism intrinsic to FTH1. Proposed replacements: intracellular iron ion homeostasis
GO:0008199 ferric iron binding	IBA GO_REF:0000033	ACCEPT	Summary: Ferric iron (Fe3+) is the oxidized form stored within the ferritin mineral core. The deep research confirms that FTH1 catalyzes "oxidation of Fe2+ to Fe3+, producing an Fe(III) mineral within the 24-mer lumen." The ferric iron is coordinated in a ferrihydrite-like mineral structure. Reason: Fe3+ binding/storage is the end product of FTH1's ferroxidase activity. The ferrihydrite mineral core contains coordinated Fe3+ ions. This is central to the iron storage function of ferritin. Supporting Evidence: PMID:9003196 The ferroxidase activity of human ferritin has previously been associated with a diiron site situated centrally within the four-helix bundle of H-type chains
GO:0004322 ferroxidase activity	IEA GO_REF:0000120	ACCEPT	Summary: The IEA annotation based on EC number mapping (EC 1.16.3.1) is appropriate. FTH1's ferroxidase activity is well-established experimentally, with the catalytic reaction: 4 Fe(2+) + O2 + 4 H(+) = 4 Fe(3+) + 2 H2O. This is validated by direct experimental evidence in PMID:9003196. Reason: Ferroxidase activity is the defining enzymatic function of the ferritin heavy chain. The dinuclear ferroxidase center in FTH1 oxidizes Fe2+ to Fe3+ coupled to oxygen reduction. This is the mechanistic basis for ferritin's iron storage capacity and distinguishes the H chain from the L chain. Supporting Evidence: PMID:9003196 The ferroxidase activity of human ferritin has previously been associated with a diiron site situated centrally within the four-helix bundle of H-type chains
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Duplicate annotation for cytoplasmic localization with IEA evidence based on UniProtKB subcellular location vocabulary mapping. Consistent with the IBA annotation above. Reason: Cytoplasmic localization is well-supported and a core characteristic. This annotation is redundant with the IBA annotation but correctly captures the primary subcellular location.
GO:0005764 lysosome	IEA GO_REF:0000044	ACCEPT	Summary: Lysosomal localization of ferritin occurs during ferritinophagy. PMID:26436293 demonstrates that ferritin is delivered to lysosomes via NCOA4-mediated autophagy. UniProt subcellular location annotation confirms "Lysosome" with experimental evidence. Reason: Lysosomal targeting is integral to ferritin's physiological turnover and iron release mechanism. NCOA4-mediated ferritinophagy delivers FTH1-containing complexes to lysosomes for degradation, which is essential for iron recycling. Supporting Evidence: PMID:26436293 direct association via a key surface arginine in FTH1 and a C-terminal element in NCOA4 is required for delivery of ferritin to the lysosome via autophagosomes
GO:0005776 autophagosome	IEA GO_REF:0000044	ACCEPT	Summary: Autophagosome localization reflects ferritinophagy, where NCOA4 delivers ferritin to autophagosomes for eventual lysosomal degradation. This is supported by UniProt annotation "Cytoplasmic vesicle, autophagosome" with experimental evidence from PMID:24695223. Reason: Autophagosome localization is part of the ferritinophagy pathway. NCOA4 binds ferritin and traffics the complex to autophagosomes prior to lysosomal fusion. This is physiologically important for regulated iron release. Supporting Evidence: PMID:24695223 delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin led to decreased bioavailable intracellular iron
GO:0006826 iron ion transport	IEA GO_REF:0000002	MODIFY	Summary: Duplicate annotation for iron ion transport from InterPro domain mapping. Same considerations apply as for the IBA annotation. Reason: FTH1's primary function is iron sequestration/storage within the ferritin shell, not active membrane transport. While iron enters and exits the ferritin cage, this is not a transport function in the GO sense. Proposed replacements: intracellular iron ion homeostasis
GO:0006879 intracellular iron ion homeostasis	IEA GO_REF:0000002	ACCEPT	Summary: FTH1 is central to intracellular iron homeostasis through its iron storage function. By sequestering excess iron as inert ferric mineral, FTH1 buffers the labile iron pool and prevents iron-mediated toxicity. This is supported by the deep research review and TAS annotation from PMID:6589621. Reason: Intracellular iron ion homeostasis accurately describes FTH1's physiological role. The ferritin system maintains iron balance by storing excess iron and releasing it when needed through ferritinophagy. Supporting Evidence: PMID:6589621 Ferritin, the main iron-storage protein, is composed of two partially homologous subunits, heavy (H) and light (L)
GO:0008199 ferric iron binding	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate annotation for ferric iron binding from InterPro domain mapping. Same considerations apply as for the IBA annotation. Reason: Fe3+ binding/storage is central to ferritin function. The IEA annotation is consistent with the IBA annotation and well-supported by experimental evidence.
GO:0016491 oxidoreductase activity	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: The oxidoreductase activity annotation is accurate but too general. FTH1 has the more specific ferroxidase activity (GO:0004322) which is already annotated. The general oxidoreductase term does not add informative value. Reason: While technically correct (ferroxidase is an oxidoreductase), this term is too broad to be informative. The specific ferroxidase activity annotation (GO:0004322) provides the functionally relevant information.
GO:0031410 cytoplasmic vesicle	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Cytoplasmic vesicle is a broad term that encompasses autophagosomes. The more specific autophagosome annotation (GO:0005776) is already present. This general annotation is less informative. Reason: The specific autophagosome localization is already captured. "Cytoplasmic vesicle" is too general to be maximally informative when more specific terms are annotated.
GO:0046872 metal ion binding	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Metal ion binding is extremely general. FTH1 has specific annotations for ferrous and ferric iron binding which are much more informative. This general term does not add value. Reason: FTH1 is specifically an iron-binding protein, not a general metal binder. The specific ferrous iron binding (GO:0008198) and ferric iron binding (GO:0008199) annotations provide the relevant functional information.
GO:0005515 protein binding	IPI PMID:16169070 A human protein-protein interaction network: a resource for ...	MARK AS OVER ANNOTATED	Summary: High-throughput protein-protein interaction data showing interaction with FTL (P02792). The FTH1-FTL interaction is biologically meaningful for ferritin heteropolymer assembly. Reason: While the FTH1-FTL interaction is functionally important for ferritin assembly, "protein binding" is uninformative. The identical protein binding annotation captures homo-oligomerization, but a more specific term for hetero-oligomerization with FTL would be more valuable. Supporting Evidence: PMID:16169070 A human protein-protein interaction network: a resource for annotating the proteome.
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: High-throughput PPI data showing interactions with FTL (P02792) and FXR2 (P51116). The FTL interaction is functionally relevant. Reason: Generic protein binding annotation provides minimal functional insight. The FTL interaction reflects ferritin heteropolymer assembly; other interactions require validation for functional relevance. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network.
GO:0005515 protein binding	IPI PMID:17355907 The TSC1 gene product hamartin interacts with NADE.	MARK AS OVER ANNOTATED	Summary: Interaction with TSC1 (Q92574) hamartin reported. The functional significance of this interaction is unclear from available literature. Reason: Generic protein binding annotation. The biological relevance of the FTH1-TSC1 interaction is not well established in the context of ferritin's iron storage function. Supporting Evidence: PMID:17355907 2007 Feb 12. The TSC1 gene product hamartin interacts with NADE.
GO:0005515 protein binding	IPI PMID:20133674 Binding and uptake of H-ferritin are mediated by human trans...	KEEP AS NON CORE	Summary: Interaction with TFRC (P02786, transferrin receptor 1). This interaction is functionally meaningful as TfR1 mediates cellular uptake of extracellular H-ferritin. Reason: The FTH1-TFRC interaction is biologically significant for H-ferritin uptake, but this represents an extracellular signaling/uptake function rather than the core intracellular iron storage function. A more specific MF term would be preferable. Supporting Evidence: PMID:20133674 Binding and uptake of H-ferritin are mediated by human transferrin receptor-1.
GO:0005515 protein binding	IPI PMID:20195357 A comprehensive resource of interacting protein regions for ...	MARK AS OVER ANNOTATED	Summary: Interaction with MAX (P61244) transcription factor. The functional significance of this interaction is unclear. Reason: Generic protein binding annotation from high-throughput study. The biological relevance of the FTH1-MAX interaction is not established. Supporting Evidence: PMID:20195357 A comprehensive resource of interacting protein regions for refining human transcription factor networks.
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	MARK AS OVER ANNOTATED	Summary: Next-generation sequencing interactome study showing FTL interaction. Reason: Redundant with other FTH1-FTL interaction annotations. Generic protein binding is uninformative. Supporting Evidence: PMID:21516116 Next-generation sequencing to generate interactome datasets.
GO:0005515 protein binding	IPI PMID:21573799 FTH1 binds to Daxx and inhibits Daxx-mediated cell apoptosis...	KEEP AS NON CORE	Summary: FTH1 binds DAXX (Q9UER7) and inhibits DAXX-mediated cell apoptosis. This represents a specific functional interaction. Reason: The FTH1-DAXX interaction appears to have functional consequences for apoptosis regulation. However, this represents a secondary/non-core function rather than the primary iron storage role. The generic "protein binding" term is still uninformative - a more specific term would be preferable. Supporting Evidence: PMID:21573799 May 15. FTH1 binds to Daxx and inhibits Daxx-mediated cell apoptosis.
GO:0005515 protein binding	IPI PMID:21653829 Protein interactome reveals converging molecular pathways am...	MARK AS OVER ANNOTATED	Summary: High-throughput study on autism-related protein interactome showing FXR2 and TSC1 interactions. Reason: Generic protein binding from high-throughput study. The biological relevance of these interactions to ferritin function is unclear. Supporting Evidence: PMID:21653829 Protein interactome reveals converging molecular pathways among autism disorders.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MARK AS OVER ANNOTATED	Summary: Liver protein interactome study showing DAXX interaction. Reason: Redundant with other DAXX interaction annotation. Generic protein binding is uninformative. Supporting Evidence: PMID:21988832 Toward an understanding of the protein interaction network of the human liver.
GO:0005515 protein binding	IPI PMID:22458338 Host-pathogen interactome mapping for HTLV-1 and -2 retrovir...	MARK AS OVER ANNOTATED	Summary: Host-pathogen interactome study showing interaction with HTLV HBZ protein (Q2Q067). Reason: Viral protein interaction from host-pathogen study. The biological significance for normal ferritin function is unclear. Generic protein binding is uninformative. Supporting Evidence: PMID:22458338 Host-pathogen interactome mapping for HTLV-1 and -2 retroviruses.
GO:0005515 protein binding	IPI PMID:25277244 The functional landscape of Hsp27 reveals new cellular proce...	MARK AS OVER ANNOTATED	Summary: Interaction with HSPB1/Hsp27 (P04792) from functional landscape study. Reason: The biological significance of the FTH1-HSPB1 interaction is unclear. Generic protein binding annotation is uninformative. Supporting Evidence: PMID:25277244 Epub 2014 Oct 2. The functional landscape of Hsp27 reveals new cellular processes such as DNA repair and alternative splicing and proposes novel anticancer targets.
GO:0005515 protein binding	IPI PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro...	ACCEPT	Summary: Interaction with NCOA4 (Q13772), the cargo receptor that mediates ferritinophagy. This is a critical functional interaction for ferritin turnover. Reason: The FTH1-NCOA4 interaction is functionally essential for ferritinophagy and iron homeostasis. NCOA4 binds FTH1 at Arg-23 to target ferritin to autolysosomes. While "protein binding" is generic, this specific interaction is core to ferritin biology. Supporting Evidence: PMID:25327288 NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Proteome-scale interactome map showing FTL interaction. Reason: Redundant with other FTH1-FTL interaction annotations. Generic protein binding is uninformative. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	MARK AS OVER ANNOTATED	Summary: Study on genetic variant effects on protein interactions, showing FTL interaction. Reason: Redundant FTL interaction annotation. Generic protein binding is uninformative. Supporting Evidence: PMID:25910212 Widespread macromolecular interaction perturbations in human genetic disorders.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Human interactome architecture study showing FTL and NCOA4 interactions. Reason: Redundant with existing annotations. The NCOA4 interaction is accepted elsewhere. Generic protein binding is uninformative. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: Study on genetic variant disruption of protein interactions, showing FTL and FXR2 interactions. Reason: Redundant FTL interaction annotation. Generic protein binding is uninformative. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Reference interactome map showing BAG4 (O95429) interaction. Reason: The biological significance of FTH1-BAG4 interaction is unclear. Generic protein binding annotation is uninformative. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Dual proteome interactome study showing FTL and NCOA4 interactions. Reason: Redundant with existing annotations. Generic protein binding is uninformative. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: Multimodal cell maps study showing FTL and NCOA4 interactions. Reason: Redundant with existing annotations. Generic protein binding is uninformative. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
GO:0042802 identical protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	ACCEPT	Summary: FTH1 self-interaction detected in proteome-scale interactome study. This is consistent with the 24-mer homo/heteropolymer assembly of ferritin. Reason: Identical protein binding accurately reflects FTH1 homo-oligomerization within the 24-subunit ferritin shell. While H-ferritin typically forms heteropolymers with L-ferritin, homo-oligomerization of H chains also occurs. Supporting Evidence: PMID:6589621 Ferritin, the main iron-storage protein, is composed of two partially homologous subunits, heavy (H) and light (L) PMID:25416956 A proteome-scale map of the human interactome network.
GO:0042802 identical protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	ACCEPT	Summary: FTH1 self-interaction from genetic variant study. Reason: Consistent with homo-oligomerization in ferritin assembly. Supports the accepted identical protein binding annotation. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
GO:0042802 identical protein binding	IPI PMID:33087927 Atomic-resolution protein structure determination by cryo-EM...	ACCEPT	Summary: High-resolution cryo-EM structure demonstrating FTH1 self-assembly in the 24-mer cage. Reason: Structural evidence for FTH1 homo-oligomerization. This is well-established from the extensive crystal and cryo-EM structural data for human ferritin. Supporting Evidence: PMID:33087927 Oct 21. Atomic-resolution protein structure determination by cryo-EM.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation based on immunofluorescence data from the Human Protein Atlas. Cytosolic localization is consistent with ferritin's primary site of function. Reason: Cytosolic localization is a core characteristic of ferritin. The annotation is based on direct imaging evidence and is consistent with ferritin biology.
GO:0110076 negative regulation of ferroptosis	IMP PMID:26403645 Activation of the p62-Keap1-NRF2 pathway protects against fe...	ACCEPT	Summary: This IMP annotation is based on knockdown experiments in hepatocellular carcinoma cells. PMID:26403645 shows that "Knockdown of p62, quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1 by RNA interference in HCC cells promoted ferroptosis in response to erastin and sorafenib." FTH1 is transcriptionally activated by NRF2 as part of the antioxidant response. Reason: Negative regulation of ferroptosis is a core function of FTH1. By sequestering labile iron, FTH1 limits iron-mediated lipid peroxidation, the hallmark of ferroptosis. This is experimentally validated and physiologically significant. Supporting Evidence: PMID:26403645 Knockdown of p62, quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1 by RNA interference in HCC cells promoted ferroptosis in response to erastin and sorafenib
GO:0004322 ferroxidase activity	IMP PMID:9003196 Dinuclear center of ferritin: studies of iron binding and ox...	ACCEPT	Summary: Direct experimental evidence for ferroxidase activity using stopped-flow assays and site-directed mutagenesis. The study demonstrates that "The ferroxidase activity of human ferritin has previously been associated with a diiron site situated centrally within the four-helix bundle of H-type chains (HuHF)." Reason: Ferroxidase activity is the defining enzymatic function of FTH1. This IMP annotation is based on rigorous biochemical characterization including kinetic analysis and mutagenesis of the ferroxidase center residues (Glu-28, Lys-87, Glu-108). Supporting Evidence: PMID:9003196 The ferroxidase activity of human ferritin has previously been associated with a diiron site situated centrally within the four-helix bundle of H-type chains (HuHF)
GO:0008198 ferrous iron binding	IMP PMID:9003196 Dinuclear center of ferritin: studies of iron binding and ox...	ACCEPT	Summary: Direct experimental evidence for Fe2+ binding at the ferroxidase center using stopped-flow assays and phenanthroline competition. The study dissected binding and oxidation steps, showing sequential binding at sites A and B. Reason: Fe2+ binding is the first step in ferroxidase catalysis and is core to FTH1 function. The IMP evidence from detailed biochemical analysis strongly supports this annotation. Supporting Evidence: PMID:9003196 the first 48 Fe(II) atoms/molecule added are bound and oxidized at the dinuclear centers
GO:0140315 iron ion sequestering activity	IDA PMID:9924025 Coordinated regulation of iron-controlling genes, H-ferritin...	ACCEPT	Summary: PMID:9924025 demonstrates that FTH1 sequesters intracellular iron, and that c-MYC represses FTH1 expression to increase the labile iron pool. The study states that H-ferritin "sequesters intracellular iron." Reason: Iron ion sequestering activity is the primary molecular function of FTH1. The ferritin nanocage physically sequesters iron atoms within its mineral core, removing them from the reactive labile iron pool. This is the functional essence of ferritin. Supporting Evidence: PMID:9924025 the heavy subunit of the protein ferritin (H-ferritin), which sequesters intracellular iron
GO:0044754 autolysosome	IDA PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro...	ACCEPT	Summary: PMID:25327288 demonstrates that NCOA4 delivers ferritin to autolysosomes for degradation. The study shows that "NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex... to autolysosomes following starvation or iron depletion." Reason: Autolysosomal localization is integral to ferritinophagy and ferritin turnover. This represents a physiologically important trafficking step in iron release. Supporting Evidence: PMID:25327288 NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion
GO:1904724 tertiary granule lumen	TAS Reactome:R-HSA-6798745	KEEP AS NON CORE	Summary: Reactome pathway annotation for neutrophil degranulation. Ferritin is found in neutrophil tertiary granules and can be released during degranulation. Reason: Tertiary granule localization in neutrophils represents a cell-type specific localization related to immune function rather than the core iron storage role. This is a valid annotation but peripheral to the main function.
GO:1904813 ficolin-1-rich granule lumen	TAS Reactome:R-HSA-6800434	KEEP AS NON CORE	Summary: Reactome pathway annotation for neutrophil granule content. Similar to tertiary granule annotation. Reason: Cell-type specific localization in neutrophil granules. Valid but peripheral to the core iron storage function.
GO:0005515 protein binding	IPI PMID:15607035 Systematic identification of hepatocellular proteins interac...	MARK AS OVER ANNOTATED	Summary: Interaction with hepatitis C virus NS5A protein identified in systematic hepatocellular protein interaction study. Reason: Viral protein interaction from host-pathogen study. The significance for normal ferritin function is unclear. Generic protein binding is uninformative. Supporting Evidence: PMID:15607035 Systematic identification of hepatocellular proteins interacting with NS5A of the hepatitis C virus.
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: High-throughput direct assay (HDA) evidence for exosomal localization from proteomics of urinary exosomes in prostatic secretions. Reason: Exosomal secretion of ferritin has been documented and may contribute to serum ferritin levels and intercellular iron transfer. This is peripheral to the core intracellular iron storage function. Supporting Evidence: PMID:23533145 2013 Apr 23. In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	KEEP AS NON CORE	Summary: Nuclear localization detected in sperm nucleus proteomics. The deep research review notes that nuclear FTH1 (nFTH1) in BRCA1/2-mutant breast cancer predicts shorter survival, suggesting nuclear localization has biological significance. Reason: Nuclear localization of FTH1 has been observed in specific contexts and may have prognostic significance in cancer. However, this is not the primary site of ferritin function. Supporting Evidence: PMID:21630459 Jun 1. Proteomic characterization of the human sperm nucleus.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: Urinary exosome proteomics showing ferritin presence. Reason: Redundant with other exosome annotation. Exosomal secretion is peripheral to core function. Supporting Evidence: PMID:19056867 2008 Dec 3. Large-scale proteomics and phosphoproteomics of urinary exosomes.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6798745	KEEP AS NON CORE	Summary: Reactome pathway annotation related to neutrophil degranulation and secretion. Reason: Extracellular ferritin (serum ferritin) is well-documented and clinically important as a biomarker. Secretion occurs via non-classical pathways. This is peripheral to the core intracellular function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6800434	KEEP AS NON CORE	Summary: Duplicate annotation for extracellular region from Reactome. Reason: Same as above - extracellular presence is documented but peripheral to core function.
GO:0005829 cytosol	TAS Reactome:R-HSA-1562626	ACCEPT	Summary: Reactome pathway annotation for ferritin complex oxidizing Fe2+ to Fe3+. Cytosolic localization is consistent with ferritin's primary function site. Reason: Cytosolic localization is the primary site of ferritin's iron storage function.
GO:0005829 cytosol	TAS Reactome:R-HSA-434362	ACCEPT	Summary: Reactome pathway annotation for recruitment of cytoplasmic proteins to vesicles. Reason: Cytosolic localization is core to ferritin function.
GO:0048147 negative regulation of fibroblast proliferation	IDA PMID:9924025 Coordinated regulation of iron-controlling genes, H-ferritin...	KEEP AS NON CORE	Summary: PMID:9924025 shows that FTH1 expression is repressed by c-MYC, and that "Down-regulation of the expression of H-ferritin gene was required for cell transformation by c-MYC." This indicates FTH1 negatively regulates proliferation. Reason: The anti-proliferative effect of FTH1 is indirect, mediated through iron sequestration reducing the labile iron pool needed for proliferation. This is a downstream consequence rather than a direct molecular function. Supporting Evidence: PMID:9924025 Down-regulation of the expression of H-ferritin gene was required for cell transformation by c-MYC
GO:0006955 immune response	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation based on similarity to UniProtKB:Q8TD27 (FAM81A). The functional relevance of this annotation to FTH1 is unclear. The deep research mentions FTH1's role in Treg lineage stability and immune function through iron provision to TET dioxygenases. Reason: FTH1 does have roles in immune function, particularly in supporting Treg cell stability and iron metabolism in immune cells. However, "immune response" is very broad and the ISS evidence is weak. This is peripheral to core function.
GO:0008285 negative regulation of cell population proliferation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation similar to the fibroblast proliferation annotation. FTH1's iron sequestration function can limit proliferation by reducing labile iron. Reason: Anti-proliferative effects are indirect consequences of iron sequestration rather than a direct molecular function of FTH1. The ISS evidence is weak.
GO:0005506 iron ion binding	TAS PMID:3020541 Cloning, characterization, expression, and chromosomal local...	MODIFY	Summary: TAS annotation from the 1986 paper cloning and characterizing the FTH1 gene. Iron binding is fundamental to ferritin function. Reason: "Iron ion binding" is accurate but less specific than "ferrous iron binding" and "ferric iron binding" which are already annotated. The specific annotations are more informative about the mechanistic role. Proposed replacements: ferrous iron binding ferric iron binding Supporting Evidence: PMID:3020541 Cloning, characterization, expression, and chromosomal localization of a human ferritin heavy-chain gene.
GO:0006879 intracellular iron ion homeostasis	TAS PMID:6589621 Isolation and characterization of a cDNA clone for human fer...	ACCEPT	Summary: The 1984 paper establishing human ferritin H chain cDNA. States that "Ferritin, the main iron-storage protein" highlighting its central role in iron homeostasis. Reason: Intracellular iron ion homeostasis is a core biological process for FTH1. The ferritin system is the primary mechanism for buffering intracellular iron levels. Supporting Evidence: PMID:6589621 Ferritin, the main iron-storage protein, is composed of two partially homologous subunits, heavy (H) and light (L)
GO:0070288 ferritin complex	TAS PMID:6589621 Isolation and characterization of a cDNA clone for human fer...	ACCEPT	Summary: FTH1 is a component of the 24-subunit ferritin complex along with FTL. The heteropolymer assembly is well-characterized structurally. Reason: Membership in the ferritin complex is essential to FTH1's function. The H and L chains assemble into the iron storage nanocage. Supporting Evidence: PMID:6589621 Ferritin, the main iron-storage protein, is composed of two partially homologous subunits, heavy (H) and light (L)

Gene Description

Existing Annotations Review

Core Functions

The ferroxidase activity of FTH1 catalyzes oxidation of Fe2+ to Fe3+ at the dinuclear center within the four-helix bundle (EC 1.16.3.1). This is the defining enzymatic function of the ferritin heavy chain that enables safe iron storage within the ferritin mineral core.

FTH1 sequesters intracellular iron by storing it within the ferritin nanocage as an inert ferrihydrite mineral, buffering the labile iron pool and preventing iron-mediated oxidative damage.

FTH1 binds ferrous iron (Fe2+) at the dinuclear ferroxidase center as the first step in the ferroxidase catalytic cycle, with sequential binding at sites A then B.

References

Tags

Deep Research

Falcon

📄 View Raw YAML