Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0009725 response to hormone	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation based on phylogenetic inference from PANTHER. NCOA4 was originally characterized as ARA70, a coactivator for the androgen receptor (PMID:8643607). However, the ferritinophagy function is now understood to be the primary role of NCOA4 (PMID:25327288). The hormone response function is secondary and relates to the legacy transcription coactivator activity. Reason: While NCOA4/ARA70 was originally identified as an androgen receptor coactivator that responds to hormones, this represents the historical/legacy function. The primary function of NCOA4 is now understood to be ferritinophagy cargo reception. The hormone response annotation is technically valid but represents a secondary, non-core function. Supporting Evidence: PMID:8643607 Using a yeast two-hybrid system, we were able to isolate a ligand-dependent AR-associated protein (ARA70), which functions as an activator to enhance AR transcriptional activity 10-fold in the presence of 10(-10) M dihydrotestosterone or 10(-9) M testosterone
GO:0003713 transcription coactivator activity	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: IEA annotation based on InterPro mapping. NCOA4 was originally characterized as ARA70, an androgen receptor coactivator (PMID:8643607). The N-terminal region mediates nuclear receptor interactions. This function is domain-separable from the ferritinophagy function. Reason: The transcription coactivator activity is a legitimate but secondary function of NCOA4. Modern literature (2023-2024 reviews) emphasizes ferritinophagy as the primary function, with coactivator function being domain-separable (N-terminal vs C-terminal). Supporting Evidence: PMID:8643607 Using a yeast two-hybrid system, we were able to isolate a ligand-dependent AR-associated protein (ARA70), which functions as an activator to enhance AR transcriptional activity file:human/NCOA4/NCOA4-deep-research-falcon.md N-terminal coiled-coil / nuclear-receptor-binding region (~1-237); C-terminal ferritin-binding domain (~238-614)
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: IEA annotation from UniProt subcellular location mapping. NCOA4 localizes to the nucleus in its coactivator role (PMID:8643607, PMID:24910095). However, the primary localization for its core ferritinophagy function is cytoplasm/autophagosome/autolysosome. Reason: Nuclear localization is valid but associated with the secondary transcription coactivator function. The primary functional localization of NCOA4 is in the cytoplasm, autophagosomes, and autolysosomes where ferritinophagy occurs. Supporting Evidence: file:human/NCOA4/NCOA4-deep-research-falcon.md NCOA4 also localizes to the nucleus when acting as a nuclear receptor coactivator
GO:0005694 chromosome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: IEA annotation from UniProt subcellular location mapping. NCOA4 binds to DNA replication origins and may inhibit activation of DNA replication origins (PMID:24910095). This is a tertiary function distinct from both ferritinophagy and coactivator roles. Reason: Chromosome localization is associated with the DNA replication origin binding function described in PMID:24910095. This is a minor function compared to the primary ferritinophagy role. The UniProt record confirms this localization.
GO:0005776 autophagosome	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation from UniProt subcellular location. NCOA4 localizes to autophagosomes during ferritinophagy, bridging ferritin to the autophagosomal membrane via interaction with LC3/GABARAP proteins (PMID:25327288). Reason: This is a CORE localization for NCOA4's primary function as a ferritinophagy cargo receptor. NCOA4 traffics with autophagosomes during ferritinophagy to deliver ferritin for degradation. 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
GO:0006351 DNA-templated transcription	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: IEA annotation inferred from UniProt keyword mapping (transcription). This is derived from NCOA4's coactivator function for nuclear receptors. Reason: Involvement in transcription is valid but secondary. This annotation reflects the legacy coactivator function, not the primary ferritinophagy role. The annotation is appropriately broad for the coactivator function.
GO:0006879 intracellular iron ion homeostasis	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro mapping. NCOA4-mediated ferritinophagy is central to intracellular iron homeostasis by degrading ferritin to release stored iron (PMID:25327288). Mouse knockout studies show NCOA4 is required for iron mobilization. Reason: This is a CORE biological process for NCOA4. By serving as the ferritinophagy cargo receptor, NCOA4 directly regulates intracellular iron availability. Ncoa4-/- mice show profound iron accumulation in splenic macrophages. Supporting Evidence: PMID:25327288 Ncoa4(-/-) mice exhibit a profound accumulation of iron in splenic macrophages, which are critical for the reutilization of iron from engulfed red blood cells file:human/NCOA4/NCOA4-deep-research-falcon.md By directing ferritin degradation, NCOA4 mobilizes stored iron for processes including heme synthesis and mitochondrial metabolism
GO:0031410 cytoplasmic vesicle	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation from UniProt keyword mapping. NCOA4 localizes to cytoplasmic vesicles, specifically autophagosomes and autolysosomes during ferritinophagy. Reason: This is a valid but general localization. NCOA4 is found in cytoplasmic vesicles as part of its ferritinophagy function. More specific terms (autophagosome, autolysosome) are also annotated.
GO:0044754 autolysosome	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation from UniProt subcellular location. NCOA4 delivers ferritin to autolysosomes for degradation during ferritinophagy (PMID:25327288). Reason: This is a CORE localization for NCOA4's primary function. NCOA4 co-localizes with autolysosomes during ferritinophagy where ferritin is degraded to release iron. 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
GO:0045893 positive regulation of DNA-templated transcription	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: IEA annotation inferred from transcription coactivator activity annotation. As a coactivator for nuclear receptors, NCOA4 positively regulates transcription. Reason: This is a valid inference from the coactivator function but represents a secondary function. The primary role of NCOA4 is ferritinophagy, not transcriptional regulation.
GO:0005515 protein binding	IPI PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro...	MODIFY	Summary: IPI annotation showing NCOA4 binds to ferritin (FTH1, FTL). This is the seminal paper identifying NCOA4 as the ferritinophagy cargo receptor. Reason: "Protein binding" is too vague and uninformative per GO guidelines. The actual function is more specific: NCOA4 functions as an autophagy cargo adaptor that binds ferritin and delivers it to autophagosomes. GO:0160247 "autophagy cargo adaptor activity" is the appropriate molecular function term. Proposed replacements: autophagy cargo adaptor activity 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:28514442 Architecture of the human interactome defines protein commun...	MODIFY	Summary: IPI annotation from high-throughput interactome study showing NCOA4-ferritin interaction. Reason: "Protein binding" is uninformative. The binding shown in interactome studies reflects NCOA4's role as an autophagy cargo adaptor for ferritin. Proposed replacements: autophagy cargo adaptor activity Supporting Evidence: PMID:28514442 Here we present BioPlex 2.0 (Biophysical Interactions of ORFeome-derived complexes), which uses robust affinity purification-mass spectrometry methodology to elucidate protein interaction networks
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MODIFY	Summary: IPI annotation from interactome remodeling study showing NCOA4-ferritin interaction. Reason: "Protein binding" is uninformative. Should be replaced with autophagy cargo adaptor activity to reflect the functional significance of the interaction. Proposed replacements: autophagy cargo adaptor activity Supporting Evidence: PMID:33961781 created two proteome-scale, cell-line-specific interaction networks. The first, BioPlex 3.0, results from affinity purification of 10,128 human proteins
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MODIFY	Summary: IPI annotation from multimodal cell maps study showing NCOA4-ferritin interaction. Reason: "Protein binding" is uninformative. The NCOA4-ferritin interaction reflects autophagy cargo adaptor activity for ferritinophagy. Proposed replacements: autophagy cargo adaptor activity Supporting Evidence: PMID:40205054 construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins
GO:0030520 estrogen receptor signaling pathway	NAS PMID:10428808 Isolation and characterization of ARA160 as the first androg...	UNDECIDED	Summary: NAS annotation citing PMID:10428808. However, this paper is about ARA160 (TMF), not NCOA4/ARA70. The paper mentions ARA70 can function cooperatively with ARA160 but does not directly demonstrate NCOA4 involvement in estrogen receptor signaling. Reason: PMID:10428808 is primarily about ARA160 (TMF), not NCOA4/ARA70. The paper states "this AR N-terminal coactivator can function cooperatively with AR C-terminal coactivator, ARA70" but does not directly implicate NCOA4 in estrogen receptor signaling. The evidence basis for this annotation is unclear. Supporting Evidence: PMID:10428808 Our data further suggest that this AR N-terminal coactivator can function cooperatively with AR C-terminal coactivator, ARA70, in PC-3 cells
GO:0071391 cellular response to estrogen stimulus	NAS PMID:10428808 Isolation and characterization of ARA160 as the first androg...	UNDECIDED	Summary: NAS annotation citing PMID:10428808. This paper is about ARA160 (TMF), not NCOA4/ARA70. The evidence for NCOA4's role in estrogen response is indirect. Reason: PMID:10428808 does not directly demonstrate NCOA4 involvement in cellular response to estrogen. The paper focuses on ARA160/TMF. Evidence for this annotation requires verification from other sources. Supporting Evidence: PMID:10428808 Isolation and characterization of ARA160 as the first androgen receptor N-terminal-associated coactivator in human prostate cells.
GO:0071394 cellular response to testosterone stimulus	NAS PMID:10428808 Isolation and characterization of ARA160 as the first androg...	KEEP AS NON CORE	Summary: NAS annotation citing PMID:10428808. While NCOA4/ARA70 is known to coactivate the androgen receptor (PMID:8643607), the cited paper (PMID:10428808) is primarily about ARA160 not NCOA4. Reason: NCOA4/ARA70 is a documented androgen receptor coactivator (PMID:8643607) and cellular response to testosterone is consistent with this function. However, this is a secondary function; ferritinophagy is the primary role. Supporting Evidence: PMID:8643607 Using a yeast two-hybrid system, we were able to isolate a ligand-dependent AR-associated protein (ARA70), which functions as an activator to enhance AR transcriptional activity 10-fold in the presence of 10(-10) M dihydrotestosterone or 10(-9) M testosterone PMID:10428808 Isolation and characterization of ARA160 as the first androgen receptor N-terminal-associated coactivator in human prostate cells.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9843120	KEEP AS NON CORE	Summary: TAS annotation from Reactome pathway "Coactivators are recruited to liganded PPARG:RXRA heterodimer". NCOA4 can coactivate PPAR-gamma (PMID:10347167). Reason: Nucleoplasm localization is associated with the secondary transcription coactivator function. Valid but not the primary functional localization.
GO:0006622 protein targeting to lysosome	IDA PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro...	ACCEPT	Summary: IDA annotation from the seminal ferritinophagy paper. NCOA4 targets ferritin to lysosomes (via autolysosomes) for degradation. Reason: This is a CORE biological process for NCOA4. The protein targeting function is the mechanistic essence of ferritinophagy - NCOA4 delivers ferritin to lysosomes for degradation to release iron. 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
GO:0044754 autolysosome	IDA PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro...	ACCEPT	Summary: IDA annotation showing NCOA4 localizes to autolysosomes. This is experimentally demonstrated in the seminal ferritinophagy paper. Reason: This is a CORE localization for NCOA4's primary function. Experimentally validated in PMID:25327288. Supporting Evidence: PMID:25327288 NCOA4, which accumulates in ATG7-deficient cells and co-localizes with autolysosomes
GO:0003713 transcription coactivator activity	TAS PMID:8643607 Cloning and characterization of a specific coactivator, ARA7...	KEEP AS NON CORE	Summary: TAS annotation from the original ARA70 characterization paper. NCOA4/ARA70 enhances androgen receptor transcriptional activity. Reason: This is the original function described for NCOA4/ARA70 in 1996. While valid, it is now understood to be a secondary function. The primary function (ferritinophagy) was discovered in 2014 (PMID:25327288). Supporting Evidence: PMID:8643607 Using a yeast two-hybrid system, we were able to isolate a ligand-dependent AR-associated protein (ARA70), which functions as an activator to enhance AR transcriptional activity 10-fold in the presence of 10(-10) M dihydrotestosterone
GO:0005634 nucleus	TAS PMID:8643607 Cloning and characterization of a specific coactivator, ARA7...	KEEP AS NON CORE	Summary: TAS annotation for nuclear localization from the original ARA70 paper. NCOA4 localizes to the nucleus in its coactivator role. Reason: Nuclear localization is associated with the secondary transcription coactivator function. The primary functional localization is cytoplasm/autophagosome/autolysosome. Supporting Evidence: PMID:8643607 Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells.
GO:0008584 male gonad development	TAS PMID:8643607 Cloning and characterization of a specific coactivator, ARA7...	KEEP AS NON CORE	Summary: TAS annotation from the original ARA70 paper. NCOA4/ARA70 coactivates androgen receptor, which plays a role in male sexual differentiation. Reason: This is an indirect inference from NCOA4's coactivation of the androgen receptor. The paper states AR "plays an important role in male sexual differentiation and prostate cell proliferation" but does not directly demonstrate NCOA4's role in gonad development. This is a secondary, pleiotropic function. Supporting Evidence: PMID:8643607 The androgen receptor (AR) is a member of the steroid receptor superfamily that plays an important role in male sexual differentiation and prostate cell proliferation
GO:0160247 autophagy cargo adaptor activity	IDA PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro...	NEW	Summary: NEW annotation for NCOA4's primary molecular function. NCOA4 is the selective autophagy cargo adaptor that binds ferritin and delivers it to autophagosomes for degradation (ferritinophagy). The 2024 cryo-EM structure (doi:10.1038/s41467-024-48151-1) resolved the 16-aa NCOA4 motif (484-499) that binds FTH1. Reason: This is the PRIMARY molecular function of NCOA4 that is currently missing from the annotation set. NCOA4 is the prototypical autophagy cargo adaptor for ferritinophagy. The term GO:0160247 "autophagy cargo adaptor activity" precisely describes this function. 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 file:human/NCOA4/NCOA4-deep-research-falcon.md Cryo-EM resolved a C-terminal NCOA4 fragment binding FTH1: 16-aa motif positions 484-499 (DSFQVIKNSPLSEWLI)
GO:0160020 positive regulation of ferroptosis	IMP PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a ro...	NEW	Summary: NEW annotation based on current literature. NCOA4-mediated ferritinophagy releases labile iron from ferritin stores, which increases susceptibility to ferroptosis by promoting lipid peroxidation via Fenton chemistry. Reason: NCOA4 is a positive regulator of ferroptosis through its ferritinophagy function. By degrading ferritin and releasing labile iron, NCOA4 sensitizes cells to ferroptotic cell death. This is well-documented in 2023-2024 reviews. Supporting Evidence: file:human/NCOA4/NCOA4-deep-research-falcon.md Excessive ferritinophagy increases labile Fe2+ and lipid peroxidation, sensitizing cells to ferroptosis PMID:25327288 Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo.

Core Functions

NCOA4 is the selective autophagy cargo adaptor that binds ferritin heavy chain (FTH1) via its C-terminal 16-aa motif (residues 484-499) and delivers ferritin complexes to autophagosomes/lysosomes for degradation, releasing stored iron. This is the primary function of NCOA4 discovered in 2014.

Molecular Function:

autophagy cargo adaptor activity

Directly Involved In:

intracellular iron ion homeostasis protein targeting to lysosome

Cellular Locations:

autophagosome autolysosome

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

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000108

Automatic assignment of GO terms using logical inference

PMID:8643607

Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells.

Original characterization of NCOA4 as ARA70, androgen receptor coactivator

"Using a yeast two-hybrid system, we were able to isolate a ligand-dependent AR-associated protein (ARA70), which functions as an activator to enhance AR transcriptional activity 10-fold in the presence of 10(-10) M dihydrotestosterone or 10(-9) M testosterone, but not 10(-6) M hydroxyflutamide in human prostate cancer DU145 cells"
Demonstrated ligand-dependent enhancement of AR transcriptional activity

"Using a yeast two-hybrid system, we were able to isolate a ligand-dependent AR-associated protein (ARA70), which functions as an activator to enhance AR transcriptional activity 10-fold in the presence of 10(-10) M dihydrotestosterone or 10(-9) M testosterone, but not 10(-6) M hydroxyflutamide in human prostate cancer DU145 cells"

PMID:10428808

Isolation and characterization of ARA160 as the first androgen receptor N-terminal-associated coactivator in human prostate cells.

Paper primarily about ARA160/TMF, not NCOA4

"we identified an androgen-enhanced AR N-terminal-associated protein ARA160, which consists of 1,093 amino acids with an apparent molecular mass of 160 kDa"
Mentions cooperative function between ARA160 and ARA70

"Our data further suggest that this AR N-terminal coactivator can function cooperatively with AR C-terminal coactivator, ARA70, in PC-3 cells"

PMID:25327288

Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo.

Seminal paper identifying NCOA4 as ferritinophagy cargo receptor

"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"
NCOA4 directly binds FTH1 to target ferritin to autolysosomes

"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"
Ncoa4-/- mice show iron accumulation in splenic macrophages

"Ncoa4(-/-) mice exhibit a profound accumulation of iron in splenic macrophages, which are critical for the reutilization of iron from engulfed red blood cells"

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

Reactome:R-HSA-9843120

Coactivators are recruited to liganded PPARG:RXRA heterodimer

file:human/NCOA4/NCOA4-deep-research-falcon.md

Deep research synthesis on NCOA4 (2023-2024 reviews)

NCOA4 is the principal ferritin cargo receptor for ferritinophagy

"Serves as the selective cargo receptor that binds ferritin (FTH1) and delivers it to autophagic/lysosomal degradation"
N-terminal region mediates nuclear receptor coactivation (secondary function)

"N-terminal coiled-coil / nuclear-receptor-binding region (~1-237); C-terminal ferritin-binding domain (~238-614)"
Ferritinophagy positively regulates ferroptosis by increasing labile iron

"Excessive ferritinophagy increases labile Fe2+ and lipid peroxidation, sensitizing cells to ferroptosis"

Suggested Experiments

Experiment: Structure-function studies to confirm domain separation between ferritinophagy and coactivator functions

Experiment: In vivo studies to assess relative contributions of each function to physiological phenotypes

📚 Additional Documentation

Deep Research Falcon

(NCOA4-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2025-12-27T13:00:40.016550'
end_time: '2025-12-27T13:06:30.862646'
duration_seconds: 350.85
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: NCOA4
gene_symbol: NCOA4
uniprot_accession: Q13772
protein_description: 'RecName: Full=Nuclear receptor coactivator 4 {ECO:0000312|HGNC:HGNC:7671};
Short=NCoA-4 {ECO:0000305}; AltName: Full=Androgen receptor coactivator 70 kDa
protein {ECO:0000303|PubMed:8643607}; Short=70 kDa AR-activator {ECO:0000303|PubMed:8643607};
Short=70 kDa androgen receptor coactivator {ECO:0000303|PubMed:8643607}; AltName:
Full=Androgen receptor-associated protein of 70 kDa {ECO:0000305}; AltName: Full=Ferritin
cargo receptor NCOA4 {ECO:0000305}; AltName: Full=Ret-activating protein ELE1
{ECO:0000305};'
gene_info: Name=NCOA4; Synonyms=ARA70 {ECO:0000303|PubMed:8643607}, ELE1, RFG;
organism_full: Homo sapiens (Human).
protein_family: Not specified in UniProt
protein_domains: NCoA-4. (IPR039947); NCOA4_N. (IPR022174); ARA70 (PF12489)
provider_config:
timeout: 600
max_retries: 3
parameters:
allowed_domains: []
temperature: 0.1
citation_count: 18

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q13772
Protein Description: RecName: Full=Nuclear receptor coactivator 4 {ECO:0000312|HGNC:HGNC:7671}; Short=NCoA-4 {ECO:0000305}; AltName: Full=Androgen receptor coactivator 70 kDa protein {ECO:0000303|PubMed:8643607}; Short=70 kDa AR-activator {ECO:0000303|PubMed:8643607}; Short=70 kDa androgen receptor coactivator {ECO:0000303|PubMed:8643607}; AltName: Full=Androgen receptor-associated protein of 70 kDa {ECO:0000305}; AltName: Full=Ferritin cargo receptor NCOA4 {ECO:0000305}; AltName: Full=Ret-activating protein ELE1 {ECO:0000305};
Gene Information: Name=NCOA4; Synonyms=ARA70 {ECO:0000303|PubMed:8643607}, ELE1, RFG;
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: NCoA-4. (IPR039947); NCOA4_N. (IPR022174); ARA70 (PF12489)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "NCOA4" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'NCOA4' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene NCOA4 (gene ID: NCOA4, UniProt: Q13772) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q13772
Protein Description: RecName: Full=Nuclear receptor coactivator 4 {ECO:0000312|HGNC:HGNC:7671}; Short=NCoA-4 {ECO:0000305}; AltName: Full=Androgen receptor coactivator 70 kDa protein {ECO:0000303|PubMed:8643607}; Short=70 kDa AR-activator {ECO:0000303|PubMed:8643607}; Short=70 kDa androgen receptor coactivator {ECO:0000303|PubMed:8643607}; AltName: Full=Androgen receptor-associated protein of 70 kDa {ECO:0000305}; AltName: Full=Ferritin cargo receptor NCOA4 {ECO:0000305}; AltName: Full=Ret-activating protein ELE1 {ECO:0000305};
Gene Information: Name=NCOA4; Synonyms=ARA70 {ECO:0000303|PubMed:8643607}, ELE1, RFG;
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: NCoA-4. (IPR039947); NCOA4_N. (IPR022174); ARA70 (PF12489)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "NCOA4" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene NCOA4 (gene ID: NCOA4, UniProt: Q13772) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan and verification
- Identity verified: The target is human NCOA4, UniProt Q13772, historically known as ARA70/ELE1/RFG. NCOA4α is a 614-aa protein. Domain features match literature: an N-terminal coiled-coil/nuclear receptor–binding region (~1–237) and a C-terminal ferritin (FTH1)-binding region (~238–614) with substantial intrinsically disordered regions. Organism and synonymy are consistent with recent peer‑reviewed reviews and structural work (le2024theemergingrole pages 1-2, li2024ferritinophagyanovel pages 1-2, hoelzgen2024structuralbasisfor pages 1-2).

Key concepts and definitions
- NCOA4 (Nuclear receptor coactivator 4): a dual-function protein acting as the selective cargo receptor for ferritinophagy and as a nuclear receptor coactivator (originally ARA70). In ferritinophagy, NCOA4 binds ferritin heavy chain (FTH1) to deliver ferritin to autophagosomes/lysosomes for degradation, releasing iron to the labile Fe2+ pool and thereby influencing iron homeostasis and ferroptosis susceptibility (https://doi.org/10.1038/s41420-023-01753-y, 2023; https://doi.org/10.1111/cpr.13621, 2024) (wang2023ferritinophagyresearchadvance pages 1-2, li2024ferritinophagyanovel pages 5-7).
- Ferritinophagy: selective autophagy of ferritin mediated by NCOA4, coupling iron storage turnover to cellular iron needs; excessive activation can increase labile iron and drive ferroptotic lipid peroxidation (https://doi.org/10.1038/s41420-023-01753-y, 2023; https://doi.org/10.1111/cpr.13621, 2024) (wang2023ferritinophagyresearchadvance pages 1-2, li2024ferritinophagyanovel pages 5-7).
- Ferroptosis: iron-dependent, lipid peroxidation–driven regulated cell death; NCOA4-driven ferritinophagy can sensitize cells by elevating labile iron (https://doi.org/10.1111/cpr.13621, 2024) (li2024ferritinophagyanovel pages 12-13, li2024ferritinophagyanovel pages 5-7).
- Nuclear receptor coactivation: NCOA4/ARA70 can enhance nuclear receptor transcriptional activity; this function maps to the N-terminal region distinct from the ferritin-binding C-terminus (https://doi.org/10.1038/s41420-024-02075-3, 2024) (le2024theemergingrole pages 1-2).

Molecular architecture, localization, and mechanism
- Domains and disorder: Recent work and reviews describe an N-terminal coiled-coil/nuclear receptor–binding region (~1–237) and a C-terminal FTH1-binding region (~238–614); NCOA4 is largely intrinsically disordered apart from these functional regions (https://doi.org/10.1111/cpr.13621, 2024; https://doi.org/10.1038/s41467-024-48151-1, 2024) (li2024ferritinophagyanovel pages 1-2, hoelzgen2024structuralbasisfor pages 1-2).
- Cryo-EM binding interface: A 2024 Nature Communications study resolved the NCOA4–FTH1 interface, identifying a 16-aa NCOA4 motif (residues 484–499; sequence DSFQVIKNSPLSEWLI) that docks into a hydrophobic patch on FTH1; critical residues include NCOA4 I489/W497 and FTH1 R23; binding is specific for FTH1, not FTL. The work provides a structural basis for modulating ferritinophagy (https://doi.org/10.1038/s41467-024-48151-1, accepted April 19, 2024) (hoelzgen2024structuralbasisfor pages 1-2).
- Cellular localization: NCOA4 resides in the cytosol and traffics with autophagosomes/lysosomes during ferritinophagy; NCOA4 also localizes to the nucleus in its coactivator role (https://doi.org/10.1038/s41420-023-01753-y, 2023; https://doi.org/10.1038/s41420-024-02075-3, 2024) (wang2023ferritinophagyresearchadvance pages 1-2, le2024theemergingrole pages 1-2).
- Iron-dependent regulation via HERC2: Under iron-replete conditions, the E3 ligase HERC2 binds NCOA4 and mediates its ubiquitination and proteasomal degradation, restraining ferritinophagy; iron depletion stabilizes NCOA4 and promotes ferritin turnover (https://doi.org/10.1111/cpr.13621, 2024; https://doi.org/10.1038/s41420-024-02075-3, 2024) (li2024ferritinophagyanovel pages 4-5, le2024theemergingrole pages 2-3).
- ATM phosphorylation: ATM kinase promotes ferritinophagy by phosphorylating NCOA4, enhancing NCOA4–ferritin interaction; loss/inhibition of ATM reduces ferroptosis sensitivity, positioning ATM–NCOA4 as a regulatory axis for iron availability and death signaling (summarized 2024) (https://doi.org/10.1111/cpr.13621, 2024) (li2024ferritinophagyanovel pages 12-13).
- NRF2–HERC2–VAMP8 axis: Reviews in 2023–2024 synthesize evidence that NRF2 affects both HERC2 (controlling NCOA4/FBXL5 stability) and autophagosome–lysosome fusion (VAMP8), thereby adjusting ferritinophagy flux and the labile iron pool (https://doi.org/10.1038/s41420-023-01753-y, 2023; https://doi.org/10.1111/cpr.13621, 2024) (wang2023ferritinophagyresearchadvance pages 1-2, li2024ferritinophagyanovel pages 4-5).
- Condensates/LLPS and alternative routing: NCOA4’s IDRs can support formation of ~120 nm NCOA4 condensates under iron-replete conditions, sequestering NCOA4 away from ferritin; alternative CD63/endosomal routes for ferritin trafficking have been reported, indicating pathway plasticity (https://doi.org/10.1038/s41420-024-02075-3, 2024) (le2024theemergingrole pages 2-3).

Primary biological roles and pathways
- Iron homeostasis: By directing ferritin degradation, NCOA4 mobilizes stored iron for processes including heme synthesis and mitochondrial metabolism, maintaining iron balance during fluctuating supply (https://doi.org/10.1038/s41420-023-01753-y, 2023; https://doi.org/10.1111/cpr.13621, 2024) (wang2023ferritinophagyresearchadvance pages 1-2, li2024ferritinophagyanovel pages 4-5).
- Erythropoiesis and systemic iron: NCOA4 is upregulated in erythroblasts; mouse studies show Ncoa4 deficiency impairs ferritin turnover, producing hypochromic microcytic anemia and altered iron mobilization after blood loss, indicating a role in hepatic iron release and red cell iron supply (https://doi.org/10.1111/cpr.13621, 2024) (li2024ferritinophagyanovel pages 5-7).
- Ferroptosis regulation: Excessive ferritinophagy increases labile Fe2+ and lipid peroxidation, sensitizing cells to ferroptosis; conversely, downregulating NCOA4 limits iron release and can reduce ferroptotic death (https://doi.org/10.1111/cpr.13621, 2024) (li2024ferritinophagyanovel pages 5-7).
- Nuclear receptor signaling: As ARA70, NCOA4 can coactivate androgen and other nuclear receptors, providing an iron‑independent functional facet that is domain‑separable from ferritin recognition (https://doi.org/10.1038/s41420-024-02075-3, 2024) (le2024theemergingrole pages 1-2).

Recent developments and latest research (priority 2023–2024)
- Structural breakthrough: The 2024 cryo-EM structure of the NCOA4–FTH1 interface defines a 16‑aa NCOA4 motif (484–499) and critical residues (NCOA4 I489/W497; FTH1 R23), providing a detailed, druggable surface for ferritinophagy modulators (https://doi.org/10.1038/s41467-024-48151-1, 2024) (hoelzgen2024structuralbasisfor pages 1-2).
- Post-translational control: Updated reviews consolidate that iron status gates NCOA4 stability via HERC2-mediated ubiquitination, while ATM-dependent phosphorylation positively tunes NCOA4–ferritin coupling, integrating DNA damage sensing with iron mobilization (https://doi.org/10.1111/cpr.13621, 2024) (li2024ferritinophagyanovel pages 12-13, li2024ferritinophagyanovel pages 4-5).
- Systems-level regulation: NRF2’s influence on HERC2 and VAMP8 connects antioxidant signaling to ferritinophagy flux and ferroptosis resistance, linking stress responses to iron handling (https://doi.org/10.1038/s41420-023-01753-y, 2023; https://doi.org/10.1111/cpr.13621, 2024) (wang2023ferritinophagyresearchadvance pages 1-2, li2024ferritinophagyanovel pages 4-5).
- Pathway plasticity/condensates: NCOA4 forms condensates and can route ferritin via endosomal/CD63 pathways depending on iron and lysosomal status, suggesting multiple modulatable checkpoints for iron turnover (https://doi.org/10.1038/s41420-024-02075-3, 2024) (le2024theemergingrole pages 2-3).

Current applications and real-world implementations
- Therapeutic targeting concepts: Reviews emphasize NCOA4–ferritin as a targetable axis to modulate the labile iron pool—either to promote ferroptosis in cancer or to limit ferroptosis in degenerative/injury settings. The 2024 structure enables rational design of small molecules or peptides to tune the NCOA4–FTH1 interaction (https://doi.org/10.1038/s41467-024-48151-1, 2024; https://doi.org/10.1038/s41420-023-01753-y, 2023; https://doi.org/10.1111/cpr.13621, 2024) (hoelzgen2024structuralbasisfor pages 1-2, wang2023ferritinophagyresearchadvance pages 1-2, li2024ferritinophagyanovel pages 4-5).
- Biomarker and disease associations: Dysregulated NCOA4/ferritinophagy is implicated in cancers and neurodegeneration; pathway state (e.g., low NCOA4 or high ferritin) associates with disease phenotypes and ferroptosis sensitivity/resistance in models, supporting translational biomarker exploration (https://doi.org/10.1038/s41420-023-01753-y, 2023; https://doi.org/10.1111/cpr.13621, 2024) (wang2023ferritinophagyresearchadvance pages 1-2, li2024ferritinophagyanovel pages 5-7).

Expert opinions and analyses from authoritative sources
- Comprehensive reviews (2023–2024) concur that NCOA4 is the principal ferritin cargo receptor and a hub integrating iron homeostasis with ferroptotic vulnerability. They argue for targeted ferritinophagy modulation and highlight outstanding questions on lysosomal delivery signals and condensate control (https://doi.org/10.1038/s41420-023-01753-y, 2023; https://doi.org/10.1111/cpr.13621, 2024; https://doi.org/10.1038/s41420-024-02075-3, 2024) (wang2023ferritinophagyresearchadvance pages 1-2, li2024ferritinophagyanovel pages 4-5, le2024theemergingrole pages 2-3, le2024theemergingrole pages 1-2).

Relevant statistics and quantitative data
- Structural determinants: 16-aa NCOA4 motif (484–499; DSFQVIKNSPLSEWLI) binds an FTH1 hydrophobic patch; alanine scanning and interface hydrogen bonds (e.g., FTH1 N22–NCOA4 W497; FTH1 R23–NCOA4 S492; FTH1 D90–NCOA4 S485) support residue-level contributions, with specificity for FTH1 over FTL (https://doi.org/10.1038/s41467-024-48151-1, 2024) (hoelzgen2024structuralbasisfor pages 1-2).
- Isoforms and size: Human NCOA4 encodes at least two transcript variants; NCOA4α is 614 aa (~70 kDa), and literature notes additional isoforms from alternative splicing (https://doi.org/10.1111/cpr.13621, 2024; https://doi.org/10.1038/s41420-024-02075-3, 2024) (li2024ferritinophagyanovel pages 1-2, le2024theemergingrole pages 1-2).
- Phenotypic outcomes: Mouse deficiency studies link NCOA4 loss to impaired ferritin turnover, hypochromic microcytic anemia, and defective iron mobilization upon blood loss (https://doi.org/10.1111/cpr.13621, 2024) (li2024ferritinophagyanovel pages 5-7).

Embedded summary table of verified facts
| Topic | Key finding | Evidence (citation id) | Source URL | Year |
|---|---|---:|---|---:|
| Identity & synonyms (ARA70) | Human NCOA4 (UniProt Q13772) encodes the ~614 aa NCOA4α isoform; historical alias ARA70 (and other synonyms: ELE1, RFG). | (le2024theemergingrole pages 1-2, li2024ferritinophagyanovel pages 1-2) | https://doi.org/10.1038/s41420-024-02075-3; https://doi.org/10.1111/cpr.13621 | 2024 |
| Domain architecture | N-terminal coiled-coil / nuclear-receptor-binding region (~1–237); C-terminal ferritin‑binding domain (~238–614); multiple intrinsically disordered regions (IDRs). | (li2024ferritinophagyanovel pages 1-2, hoelzgen2024structuralbasisfor pages 1-2) | https://doi.org/10.1111/cpr.13621; https://doi.org/10.1038/s41467-024-48151-1 | 2024 |
| Cellular localization | Localizes to cytosol and autophagosomes/lysosomes during ferritinophagy; also observed in nucleus when acting as a nuclear receptor coactivator. | (wang2023ferritinophagyresearchadvance pages 1-2, le2024theemergingrole pages 1-2) | https://doi.org/10.1038/s41420-023-01753-y; https://doi.org/10.1038/s41420-024-02075-3 | 2023–2024 |
| Primary function: ferritinophagy receptor | Serves as the selective cargo receptor that binds ferritin (FTH1) and delivers it to autophagic/lysosomal degradation, releasing iron and modulating the labile Fe2+ pool and ferroptosis sensitivity. | (wang2023ferritinophagyresearchadvance pages 1-2, li2024ferritinophagyanovel pages 5-7) | https://doi.org/10.1038/s41420-023-01753-y; https://doi.org/10.1111/cpr.13621 | 2023–2024 |
| Nuclear receptor coactivator role | Originally identified as AR coactivator ARA70; N-terminal region mediates nuclear receptor interactions and transcriptional coactivation roles separate from ferritinophagy. | (le2024theemergingrole pages 1-2) | https://doi.org/10.1038/s41420-024-02075-3 | 2024 |
| Cryo-EM NCOA4–FTH1 interface | Cryo-EM resolved a C-terminal NCOA4 fragment binding FTH1: 16‑aa motif positions 484–499 (DSFQVIKNSPLSEWLI); critical residues include NCOA4 I489/W497 and FTH1 R23; binding is specific for FTH1. | (hoelzgen2024structuralbasisfor pages 1-2) | https://doi.org/10.1038/s41467-024-48151-1 | 2024 |
| Iron-dependent regulation (HERC2) | HERC2 E3 ligase binds NCOA4 under iron-replete conditions to ubiquitinate and promote proteasomal degradation of NCOA4, limiting ferritinophagy. | (li2024ferritinophagyanovel pages 4-5, le2024theemergingrole pages 2-3) | https://doi.org/10.1111/cpr.13621; https://doi.org/10.1038/s41420-024-02075-3 | 2024 |
| ATM phosphorylation → ferritinophagy/ferroptosis | ATM kinase phosphorylates NCOA4, promoting NCOA4–ferritin interaction and sustaining ferritinophagy, thereby increasing ferroptosis sensitivity (reported in reviews citing Wu et al.). | (li2024ferritinophagyanovel pages 12-13) | https://doi.org/10.1111/cpr.13621 | 2023–2024 |
| NRF2–HERC2–VAMP8 regulatory axis | NRF2-linked pathways influence HERC2 expression and autophagy/lysosomal flux (VAMP8), thereby modulating NCOA4 stability and ferritinophagy flux (summarized in recent reviews). | (wang2023ferritinophagyresearchadvance pages 1-2, li2024ferritinophagyanovel pages 4-5) | https://doi.org/10.1038/s41420-023-01753-y; https://doi.org/10.1111/cpr.13621 | 2023–2024 |
| Roles in iron homeostasis & ferroptosis | NCOA4-mediated ferritinophagy mobilizes stored iron for heme synthesis/erythropoiesis but excessive activity raises labile iron and sensitizes cells to ferroptotic lipid peroxidation. | (wang2023ferritinophagyresearchadvance pages 1-2, li2024ferritinophagyanovel pages 5-7) | https://doi.org/10.1038/s41420-023-01753-y; https://doi.org/10.1111/cpr.13621 | 2023–2024 |
| Physiological role in erythropoiesis & iron mobilization | Required for mobilizing hepatic iron after blood loss and for effective erythropoiesis; NCOA4 deficiency in mice causes impaired ferritin turnover and hypochromic microcytic anemia. | (li2024ferritinophagyanovel pages 5-7, li2024ferritinophagyanovel pages 4-5) | https://doi.org/10.1111/cpr.13621; https://doi.org/10.1111/cpr.13621 | 2024 |
| Condensates / LLPS & alternative trafficking | C-terminal region plus IDRs can form NCOA4 condensates (~120 nm) that sequester NCOA4 under iron‑replete conditions; alternative endosomal/CD63-mediated ferritin trafficking routes have been reported. | (le2024theemergingrole pages 2-3, hoelzgen2024structuralbasisfor pages 1-2) | https://doi.org/10.1038/s41420-024-02075-3; https://doi.org/10.1038/s41467-024-48151-1 | 2024 |

Table: Concise, citable summary of verified molecular, structural, regulatory, cellular-localization, and physiological facts about human NCOA4 (UniProt Q13772), with source IDs and URLs to the supporting literature.

Conclusions
Human NCOA4 (Q13772) is a bifunctional protein central to selective autophagic ferritin turnover and to nuclear receptor coactivation. Mechanistically, its C-terminal 16-aa motif binds FTH1 with defined residue specificity, while HERC2-mediated ubiquitination limits NCOA4 under iron repletion and ATM phosphorylation promotes ferritinophagy during stress. NCOA4 thereby tunes iron homeostasis and ferroptosis sensitivity and is essential for erythroid iron mobilization. Recent structural advances now enable rational ferritinophagy modulators, offering translational routes to either induce ferroptosis in cancer or curb iron-driven damage in degenerative and injury contexts (hoelzgen2024structuralbasisfor pages 1-2, li2024ferritinophagyanovel pages 4-5, li2024ferritinophagyanovel pages 12-13, wang2023ferritinophagyresearchadvance pages 1-2, li2024ferritinophagyanovel pages 5-7, le2024theemergingrole pages 2-3, le2024theemergingrole pages 1-2).

References

(le2024theemergingrole pages 1-2): Yue Le, Qinjie Liu, Yi Yang, and Jie Wu. The emerging role of nuclear receptor coactivator 4 in health and disease: a novel bridge between iron metabolism and immunity. Cell Death Discovery, Jul 2024. URL: https://doi.org/10.1038/s41420-024-02075-3, doi:10.1038/s41420-024-02075-3. This article has 29 citations and is from a peer-reviewed journal.
(li2024ferritinophagyanovel pages 1-2): Jing‐Yan Li, Yan‐Hua Feng, Yu‐Xuan Li, Peng‐Yi He, Qi‐Yuan Zhou, Ying‐Ping Tian, Ren‐Qi Yao, and Yong‐Ming Yao. Ferritinophagy: a novel insight into the double‐edged sword in ferritinophagy–ferroptosis axis and human diseases. Cell Proliferation, Feb 2024. URL: https://doi.org/10.1111/cpr.13621, doi:10.1111/cpr.13621. This article has 53 citations and is from a peer-reviewed journal.
(hoelzgen2024structuralbasisfor pages 1-2): Fabian Hoelzgen, Thuy T. P. Nguyen, Elina Klukin, Mohamed Boumaiza, Ayush K. Srivastava, Elizabeth Y. Kim, Ran Zalk, Anat Shahar, Sagit Cohen-Schwartz, Esther G. Meyron-Holtz, Fadi Bou-Abdallah, Joseph D. Mancias, and Gabriel A. Frank. Structural basis for the intracellular regulation of ferritin degradation. Nature Communications, May 2024. URL: https://doi.org/10.1038/s41467-024-48151-1, doi:10.1038/s41467-024-48151-1. This article has 39 citations and is from a highest quality peer-reviewed journal.
(wang2023ferritinophagyresearchadvance pages 1-2): Jiewen Wang, Nayiyuan Wu, Mingjing Peng, Linda Oyang, Xianjie Jiang, Qiu Peng, Yujuan Zhou, Zuping He, and Qianjin Liao. Ferritinophagy: research advance and clinical significance in cancers. Cell Death Discovery, Dec 2023. URL: https://doi.org/10.1038/s41420-023-01753-y, doi:10.1038/s41420-023-01753-y. This article has 83 citations and is from a peer-reviewed journal.
(li2024ferritinophagyanovel pages 5-7): Jing‐Yan Li, Yan‐Hua Feng, Yu‐Xuan Li, Peng‐Yi He, Qi‐Yuan Zhou, Ying‐Ping Tian, Ren‐Qi Yao, and Yong‐Ming Yao. Ferritinophagy: a novel insight into the double‐edged sword in ferritinophagy–ferroptosis axis and human diseases. Cell Proliferation, Feb 2024. URL: https://doi.org/10.1111/cpr.13621, doi:10.1111/cpr.13621. This article has 53 citations and is from a peer-reviewed journal.
(li2024ferritinophagyanovel pages 12-13): Jing‐Yan Li, Yan‐Hua Feng, Yu‐Xuan Li, Peng‐Yi He, Qi‐Yuan Zhou, Ying‐Ping Tian, Ren‐Qi Yao, and Yong‐Ming Yao. Ferritinophagy: a novel insight into the double‐edged sword in ferritinophagy–ferroptosis axis and human diseases. Cell Proliferation, Feb 2024. URL: https://doi.org/10.1111/cpr.13621, doi:10.1111/cpr.13621. This article has 53 citations and is from a peer-reviewed journal.
(li2024ferritinophagyanovel pages 4-5): Jing‐Yan Li, Yan‐Hua Feng, Yu‐Xuan Li, Peng‐Yi He, Qi‐Yuan Zhou, Ying‐Ping Tian, Ren‐Qi Yao, and Yong‐Ming Yao. Ferritinophagy: a novel insight into the double‐edged sword in ferritinophagy–ferroptosis axis and human diseases. Cell Proliferation, Feb 2024. URL: https://doi.org/10.1111/cpr.13621, doi:10.1111/cpr.13621. This article has 53 citations and is from a peer-reviewed journal.
(le2024theemergingrole pages 2-3): Yue Le, Qinjie Liu, Yi Yang, and Jie Wu. The emerging role of nuclear receptor coactivator 4 in health and disease: a novel bridge between iron metabolism and immunity. Cell Death Discovery, Jul 2024. URL: https://doi.org/10.1038/s41420-024-02075-3, doi:10.1038/s41420-024-02075-3. This article has 29 citations and is from a peer-reviewed journal.

Citations

le2024theemergingrole pages 1-2
hoelzgen2024structuralbasisfor pages 1-2
li2024ferritinophagyanovel pages 12-13
le2024theemergingrole pages 2-3
li2024ferritinophagyanovel pages 5-7
li2024ferritinophagyanovel pages 1-2
wang2023ferritinophagyresearchadvance pages 1-2
li2024ferritinophagyanovel pages 4-5
https://doi.org/10.1038/s41420-023-01753-y,
https://doi.org/10.1111/cpr.13621,
https://doi.org/10.1038/s41420-024-02075-3,
https://doi.org/10.1038/s41467-024-48151-1,
https://doi.org/10.1038/s41420-024-02075-3;
https://doi.org/10.1111/cpr.13621
https://doi.org/10.1111/cpr.13621;
https://doi.org/10.1038/s41467-024-48151-1
https://doi.org/10.1038/s41420-023-01753-y;
https://doi.org/10.1038/s41420-024-02075-3

📄 View Raw YAML

id: Q13772
gene_symbol: NCOA4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: NCOA4 (Nuclear Receptor Coactivator 4) is primarily the selective 
  cargo receptor for ferritinophagy, the autophagic degradation of ferritin to 
  release stored iron. NCOA4 directly binds ferritin heavy chain (FTH1) via a 
  C-terminal 16-aa motif (residues 484-499) and delivers the ferritin complex to
  autophagosomes/lysosomes for degradation. This function is central to 
  intracellular iron homeostasis and erythropoiesis. By mobilizing stored iron, 
  NCOA4-mediated ferritinophagy also positively regulates ferroptosis 
  susceptibility by increasing the labile iron pool. The legacy function as a 
  transcription coactivator for androgen receptor (AR) and other nuclear 
  receptors is domain-separable (N-terminal region) and now considered secondary
  to its ferritinophagy role.
existing_annotations:
  - term:
      id: GO:0009725
      label: response to hormone
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation based on phylogenetic inference from PANTHER. 
        NCOA4 was originally characterized as ARA70, a coactivator for the 
        androgen receptor (PMID:8643607). However, the ferritinophagy function 
        is now understood to be the primary role of NCOA4 (PMID:25327288). The 
        hormone response function is secondary and relates to the legacy 
        transcription coactivator activity.
      action: KEEP_AS_NON_CORE
      reason: While NCOA4/ARA70 was originally identified as an androgen 
        receptor coactivator that responds to hormones, this represents the 
        historical/legacy function. The primary function of NCOA4 is now 
        understood to be ferritinophagy cargo reception. The hormone response 
        annotation is technically valid but represents a secondary, non-core 
        function.
      supported_by:
        - reference_id: PMID:8643607
          supporting_text: Using a yeast two-hybrid system, we were able to 
            isolate a ligand-dependent AR-associated protein (ARA70), which 
            functions as an activator to enhance AR transcriptional activity 
            10-fold in the presence of 10(-10) M dihydrotestosterone or 10(-9) M
            testosterone
  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA annotation based on InterPro mapping. NCOA4 was originally 
        characterized as ARA70, an androgen receptor coactivator (PMID:8643607).
        The N-terminal region mediates nuclear receptor interactions. This 
        function is domain-separable from the ferritinophagy function.
      action: KEEP_AS_NON_CORE
      reason: The transcription coactivator activity is a legitimate but 
        secondary function of NCOA4. Modern literature (2023-2024 reviews) 
        emphasizes ferritinophagy as the primary function, with coactivator 
        function being domain-separable (N-terminal vs C-terminal).
      supported_by:
        - reference_id: PMID:8643607
          supporting_text: Using a yeast two-hybrid system, we were able to 
            isolate a ligand-dependent AR-associated protein (ARA70), which 
            functions as an activator to enhance AR transcriptional activity
        - reference_id: file:human/NCOA4/NCOA4-deep-research-falcon.md
          supporting_text: N-terminal coiled-coil / nuclear-receptor-binding 
            region (~1-237); C-terminal ferritin-binding domain (~238-614)
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation from UniProt subcellular location mapping. NCOA4 
        localizes to the nucleus in its coactivator role (PMID:8643607, 
        PMID:24910095). However, the primary localization for its core 
        ferritinophagy function is cytoplasm/autophagosome/autolysosome.
      action: KEEP_AS_NON_CORE
      reason: Nuclear localization is valid but associated with the secondary 
        transcription coactivator function. The primary functional localization 
        of NCOA4 is in the cytoplasm, autophagosomes, and autolysosomes where 
        ferritinophagy occurs.
      supported_by:
        - reference_id: file:human/NCOA4/NCOA4-deep-research-falcon.md
          supporting_text: NCOA4 also localizes to the nucleus when acting as a 
            nuclear receptor coactivator
  - term:
      id: GO:0005694
      label: chromosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation from UniProt subcellular location mapping. NCOA4 
        binds to DNA replication origins and may inhibit activation of DNA 
        replication origins (PMID:24910095). This is a tertiary function 
        distinct from both ferritinophagy and coactivator roles.
      action: KEEP_AS_NON_CORE
      reason: Chromosome localization is associated with the DNA replication 
        origin binding function described in PMID:24910095. This is a minor 
        function compared to the primary ferritinophagy role. The UniProt record
        confirms this localization.
  - term:
      id: GO:0005776
      label: autophagosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation from UniProt subcellular location. NCOA4 localizes
        to autophagosomes during ferritinophagy, bridging ferritin to the 
        autophagosomal membrane via interaction with LC3/GABARAP proteins 
        (PMID:25327288).
      action: ACCEPT
      reason: This is a CORE localization for NCOA4's primary function as a 
        ferritinophagy cargo receptor. NCOA4 traffics with autophagosomes during
        ferritinophagy to deliver ferritin for degradation.
      supported_by:
        - reference_id: PMID:25327288
          supporting_text: 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
  - term:
      id: GO:0006351
      label: DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA annotation inferred from UniProt keyword mapping 
        (transcription). This is derived from NCOA4's coactivator function for 
        nuclear receptors.
      action: KEEP_AS_NON_CORE
      reason: Involvement in transcription is valid but secondary. This 
        annotation reflects the legacy coactivator function, not the primary 
        ferritinophagy role. The annotation is appropriately broad for the 
        coactivator function.
  - term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA annotation from InterPro mapping. NCOA4-mediated 
        ferritinophagy is central to intracellular iron homeostasis by degrading
        ferritin to release stored iron (PMID:25327288). Mouse knockout studies 
        show NCOA4 is required for iron mobilization.
      action: ACCEPT
      reason: This is a CORE biological process for NCOA4. By serving as the 
        ferritinophagy cargo receptor, NCOA4 directly regulates intracellular 
        iron availability. Ncoa4-/- mice show profound iron accumulation in 
        splenic macrophages.
      supported_by:
        - reference_id: PMID:25327288
          supporting_text: Ncoa4(-/-) mice exhibit a profound accumulation of 
            iron in splenic macrophages, which are critical for the 
            reutilization of iron from engulfed red blood cells
        - reference_id: file:human/NCOA4/NCOA4-deep-research-falcon.md
          supporting_text: By directing ferritin degradation, NCOA4 mobilizes 
            stored iron for processes including heme synthesis and mitochondrial
            metabolism
  - term:
      id: GO:0031410
      label: cytoplasmic vesicle
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA annotation from UniProt keyword mapping. NCOA4 localizes to 
        cytoplasmic vesicles, specifically autophagosomes and autolysosomes 
        during ferritinophagy.
      action: ACCEPT
      reason: This is a valid but general localization. NCOA4 is found in 
        cytoplasmic vesicles as part of its ferritinophagy function. More 
        specific terms (autophagosome, autolysosome) are also annotated.
  - term:
      id: GO:0044754
      label: autolysosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation from UniProt subcellular location. NCOA4 delivers 
        ferritin to autolysosomes for degradation during ferritinophagy 
        (PMID:25327288).
      action: ACCEPT
      reason: This is a CORE localization for NCOA4's primary function. NCOA4 
        co-localizes with autolysosomes during ferritinophagy where ferritin is 
        degraded to release iron.
      supported_by:
        - reference_id: PMID:25327288
          supporting_text: 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
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: IEA annotation inferred from transcription coactivator activity 
        annotation. As a coactivator for nuclear receptors, NCOA4 positively 
        regulates transcription.
      action: KEEP_AS_NON_CORE
      reason: This is a valid inference from the coactivator function but 
        represents a secondary function. The primary role of NCOA4 is 
        ferritinophagy, not transcriptional regulation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25327288
    review:
      summary: IPI annotation showing NCOA4 binds to ferritin (FTH1, FTL). This 
        is the seminal paper identifying NCOA4 as the ferritinophagy cargo 
        receptor.
      action: MODIFY
      reason: '"Protein binding" is too vague and uninformative per GO guidelines.
        The actual function is more specific: NCOA4 functions as an autophagy cargo
        adaptor that binds ferritin and delivers it to autophagosomes. GO:0160247
        "autophagy cargo adaptor activity" is the appropriate molecular function term.'
      proposed_replacement_terms:
        - id: GO:0160247
          label: autophagy cargo adaptor activity
      supported_by:
        - reference_id: PMID:25327288
          supporting_text: 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
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: IPI annotation from high-throughput interactome study showing 
        NCOA4-ferritin interaction.
      action: MODIFY
      reason: '"Protein binding" is uninformative. The binding shown in interactome
        studies reflects NCOA4''s role as an autophagy cargo adaptor for ferritin.'
      proposed_replacement_terms:
        - id: GO:0160247
          label: autophagy cargo adaptor activity
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: Here we present BioPlex 2.0 (Biophysical Interactions
            of ORFeome-derived complexes), which uses robust affinity 
            purification-mass spectrometry methodology to elucidate protein 
            interaction networks
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: IPI annotation from interactome remodeling study showing 
        NCOA4-ferritin interaction.
      action: MODIFY
      reason: '"Protein binding" is uninformative. Should be replaced with autophagy
        cargo adaptor activity to reflect the functional significance of the interaction.'
      proposed_replacement_terms:
        - id: GO:0160247
          label: autophagy cargo adaptor activity
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: created two proteome-scale, cell-line-specific 
            interaction networks. The first, BioPlex 3.0, results from affinity 
            purification of 10,128 human proteins
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    review:
      summary: IPI annotation from multimodal cell maps study showing 
        NCOA4-ferritin interaction.
      action: MODIFY
      reason: '"Protein binding" is uninformative. The NCOA4-ferritin interaction
        reflects autophagy cargo adaptor activity for ferritinophagy.'
      proposed_replacement_terms:
        - id: GO:0160247
          label: autophagy cargo adaptor activity
      supported_by:
        - reference_id: PMID:40205054
          supporting_text: construct a global map of human subcellular 
            architecture through joint measurement of biophysical interactions 
            and immunofluorescence images for over 5,100 proteins
  - term:
      id: GO:0030520
      label: estrogen receptor signaling pathway
    evidence_type: NAS
    original_reference_id: PMID:10428808
    review:
      summary: NAS annotation citing PMID:10428808. However, this paper is about
        ARA160 (TMF), not NCOA4/ARA70. The paper mentions ARA70 can function 
        cooperatively with ARA160 but does not directly demonstrate NCOA4 
        involvement in estrogen receptor signaling.
      action: UNDECIDED
      reason: PMID:10428808 is primarily about ARA160 (TMF), not NCOA4/ARA70. 
        The paper states "this AR N-terminal coactivator can function 
        cooperatively with AR C-terminal coactivator, ARA70" but does not 
        directly implicate NCOA4 in estrogen receptor signaling. The evidence 
        basis for this annotation is unclear.
      additional_reference_ids:
        - PMID:10428808
      supported_by:
        - reference_id: PMID:10428808
          supporting_text: Our data further suggest that this AR N-terminal 
            coactivator can function cooperatively with AR C-terminal 
            coactivator, ARA70, in PC-3 cells
  - term:
      id: GO:0071391
      label: cellular response to estrogen stimulus
    evidence_type: NAS
    original_reference_id: PMID:10428808
    review:
      summary: NAS annotation citing PMID:10428808. This paper is about ARA160 
        (TMF), not NCOA4/ARA70. The evidence for NCOA4's role in estrogen 
        response is indirect.
      action: UNDECIDED
      reason: PMID:10428808 does not directly demonstrate NCOA4 involvement in 
        cellular response to estrogen. The paper focuses on ARA160/TMF. Evidence
        for this annotation requires verification from other sources.
      additional_reference_ids:
        - PMID:10428808
      supported_by:
        - reference_id: PMID:10428808
          supporting_text: Isolation and characterization of ARA160 as the first
            androgen receptor N-terminal-associated coactivator in human 
            prostate cells.
  - term:
      id: GO:0071394
      label: cellular response to testosterone stimulus
    evidence_type: NAS
    original_reference_id: PMID:10428808
    review:
      summary: NAS annotation citing PMID:10428808. While NCOA4/ARA70 is known 
        to coactivate the androgen receptor (PMID:8643607), the cited paper 
        (PMID:10428808) is primarily about ARA160 not NCOA4.
      action: KEEP_AS_NON_CORE
      reason: NCOA4/ARA70 is a documented androgen receptor coactivator 
        (PMID:8643607) and cellular response to testosterone is consistent with 
        this function. However, this is a secondary function; ferritinophagy is 
        the primary role.
      supported_by:
        - reference_id: PMID:8643607
          supporting_text: Using a yeast two-hybrid system, we were able to 
            isolate a ligand-dependent AR-associated protein (ARA70), which 
            functions as an activator to enhance AR transcriptional activity 
            10-fold in the presence of 10(-10) M dihydrotestosterone or 10(-9) M
            testosterone
        - reference_id: PMID:10428808
          supporting_text: Isolation and characterization of ARA160 as the first
            androgen receptor N-terminal-associated coactivator in human 
            prostate cells.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9843120
    review:
      summary: TAS annotation from Reactome pathway "Coactivators are recruited 
        to liganded PPARG:RXRA heterodimer". NCOA4 can coactivate PPAR-gamma 
        (PMID:10347167).
      action: KEEP_AS_NON_CORE
      reason: Nucleoplasm localization is associated with the secondary 
        transcription coactivator function. Valid but not the primary functional
        localization.
  - term:
      id: GO:0006622
      label: protein targeting to lysosome
    evidence_type: IDA
    original_reference_id: PMID:25327288
    review:
      summary: IDA annotation from the seminal ferritinophagy paper. NCOA4 
        targets ferritin to lysosomes (via autolysosomes) for degradation.
      action: ACCEPT
      reason: This is a CORE biological process for NCOA4. The protein targeting
        function is the mechanistic essence of ferritinophagy - NCOA4 delivers 
        ferritin to lysosomes for degradation to release iron.
      supported_by:
        - reference_id: PMID:25327288
          supporting_text: 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
  - term:
      id: GO:0044754
      label: autolysosome
    evidence_type: IDA
    original_reference_id: PMID:25327288
    review:
      summary: IDA annotation showing NCOA4 localizes to autolysosomes. This is 
        experimentally demonstrated in the seminal ferritinophagy paper.
      action: ACCEPT
      reason: This is a CORE localization for NCOA4's primary function. 
        Experimentally validated in PMID:25327288.
      supported_by:
        - reference_id: PMID:25327288
          supporting_text: NCOA4, which accumulates in ATG7-deficient cells and 
            co-localizes with autolysosomes
  - term:
      id: GO:0003713
      label: transcription coactivator activity
    evidence_type: TAS
    original_reference_id: PMID:8643607
    review:
      summary: TAS annotation from the original ARA70 characterization paper. 
        NCOA4/ARA70 enhances androgen receptor transcriptional activity.
      action: KEEP_AS_NON_CORE
      reason: This is the original function described for NCOA4/ARA70 in 1996. 
        While valid, it is now understood to be a secondary function. The 
        primary function (ferritinophagy) was discovered in 2014 
        (PMID:25327288).
      supported_by:
        - reference_id: PMID:8643607
          supporting_text: Using a yeast two-hybrid system, we were able to 
            isolate a ligand-dependent AR-associated protein (ARA70), which 
            functions as an activator to enhance AR transcriptional activity 
            10-fold in the presence of 10(-10) M dihydrotestosterone
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: TAS
    original_reference_id: PMID:8643607
    review:
      summary: TAS annotation for nuclear localization from the original ARA70 
        paper. NCOA4 localizes to the nucleus in its coactivator role.
      action: KEEP_AS_NON_CORE
      reason: Nuclear localization is associated with the secondary 
        transcription coactivator function. The primary functional localization 
        is cytoplasm/autophagosome/autolysosome.
      supported_by:
        - reference_id: PMID:8643607
          supporting_text: Cloning and characterization of a specific 
            coactivator, ARA70, for the androgen receptor in human prostate 
            cells.
  - term:
      id: GO:0008584
      label: male gonad development
    evidence_type: TAS
    original_reference_id: PMID:8643607
    review:
      summary: TAS annotation from the original ARA70 paper. NCOA4/ARA70 
        coactivates androgen receptor, which plays a role in male sexual 
        differentiation.
      action: KEEP_AS_NON_CORE
      reason: This is an indirect inference from NCOA4's coactivation of the 
        androgen receptor. The paper states AR "plays an important role in male 
        sexual differentiation and prostate cell proliferation" but does not 
        directly demonstrate NCOA4's role in gonad development. This is a 
        secondary, pleiotropic function.
      supported_by:
        - reference_id: PMID:8643607
          supporting_text: The androgen receptor (AR) is a member of the steroid
            receptor superfamily that plays an important role in male sexual 
            differentiation and prostate cell proliferation
  - term:
      id: GO:0160247
      label: autophagy cargo adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:25327288
    review:
      summary: NEW annotation for NCOA4's primary molecular function. NCOA4 is 
        the selective autophagy cargo adaptor that binds ferritin and delivers 
        it to autophagosomes for degradation (ferritinophagy). The 2024 cryo-EM 
        structure (doi:10.1038/s41467-024-48151-1) resolved the 16-aa NCOA4 
        motif (484-499) that binds FTH1.
      action: NEW
      reason: This is the PRIMARY molecular function of NCOA4 that is currently 
        missing from the annotation set. NCOA4 is the prototypical autophagy 
        cargo adaptor for ferritinophagy. The term GO:0160247 "autophagy cargo 
        adaptor activity" precisely describes this function.
      supported_by:
        - reference_id: PMID:25327288
          supporting_text: 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
        - reference_id: file:human/NCOA4/NCOA4-deep-research-falcon.md
          supporting_text: 'Cryo-EM resolved a C-terminal NCOA4 fragment binding FTH1:
            16-aa motif positions 484-499 (DSFQVIKNSPLSEWLI)'
  - term:
      id: GO:0160020
      label: positive regulation of ferroptosis
    evidence_type: IMP
    original_reference_id: PMID:25327288
    review:
      summary: NEW annotation based on current literature. NCOA4-mediated 
        ferritinophagy releases labile iron from ferritin stores, which 
        increases susceptibility to ferroptosis by promoting lipid peroxidation 
        via Fenton chemistry.
      action: NEW
      reason: NCOA4 is a positive regulator of ferroptosis through its 
        ferritinophagy function. By degrading ferritin and releasing labile 
        iron, NCOA4 sensitizes cells to ferroptotic cell death. This is 
        well-documented in 2023-2024 reviews.
      supported_by:
        - reference_id: file:human/NCOA4/NCOA4-deep-research-falcon.md
          supporting_text: Excessive ferritinophagy increases labile Fe2+ and 
            lipid peroxidation, sensitizing cells to ferroptosis
        - reference_id: PMID:25327288
          supporting_text: Selective VPS34 inhibitor blocks autophagy and 
            uncovers a role for NCOA4 in ferritin degradation and iron 
            homeostasis in vivo.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference
    findings: []
  - id: PMID:8643607
    title: Cloning and characterization of a specific coactivator, ARA70, for 
      the androgen receptor in human prostate cells.
    findings:
      - statement: Original characterization of NCOA4 as ARA70, androgen 
          receptor coactivator
        supporting_text: Using a yeast two-hybrid system, we were able to 
          isolate a ligand-dependent AR-associated protein (ARA70), which 
          functions as an activator to enhance AR transcriptional activity 
          10-fold in the presence of 10(-10) M dihydrotestosterone or 10(-9) M 
          testosterone, but not 10(-6) M hydroxyflutamide in human prostate 
          cancer DU145 cells
      - statement: Demonstrated ligand-dependent enhancement of AR 
          transcriptional activity
        supporting_text: Using a yeast two-hybrid system, we were able to 
          isolate a ligand-dependent AR-associated protein (ARA70), which 
          functions as an activator to enhance AR transcriptional activity 
          10-fold in the presence of 10(-10) M dihydrotestosterone or 10(-9) M 
          testosterone, but not 10(-6) M hydroxyflutamide in human prostate 
          cancer DU145 cells
  - id: PMID:10428808
    title: Isolation and characterization of ARA160 as the first androgen 
      receptor N-terminal-associated coactivator in human prostate cells.
    findings:
      - statement: Paper primarily about ARA160/TMF, not NCOA4
        supporting_text: we identified an androgen-enhanced AR 
          N-terminal-associated protein ARA160, which consists of 1,093 amino 
          acids with an apparent molecular mass of 160 kDa
      - statement: Mentions cooperative function between ARA160 and ARA70
        supporting_text: Our data further suggest that this AR N-terminal 
          coactivator can function cooperatively with AR C-terminal coactivator,
          ARA70, in PC-3 cells
  - id: PMID:25327288
    title: Selective VPS34 inhibitor blocks autophagy and uncovers a role for 
      NCOA4 in ferritin degradation and iron homeostasis in vivo.
    findings:
      - statement: Seminal paper identifying NCOA4 as ferritinophagy cargo 
          receptor
        supporting_text: 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
      - statement: NCOA4 directly binds FTH1 to target ferritin to autolysosomes
        supporting_text: 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
      - statement: Ncoa4-/- mice show iron accumulation in splenic macrophages
        supporting_text: Ncoa4(-/-) mice exhibit a profound accumulation of iron
          in splenic macrophages, which are critical for the reutilization of 
          iron from engulfed red blood cells
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and
      disease networks.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:40205054
    title: Multimodal cell maps as a foundation for structural and functional 
      genomics.
    findings: []
  - id: Reactome:R-HSA-9843120
    title: Coactivators are recruited to liganded PPARG:RXRA heterodimer
    findings: []
  - id: file:human/NCOA4/NCOA4-deep-research-falcon.md
    title: Deep research synthesis on NCOA4 (2023-2024 reviews)
    findings:
      - statement: NCOA4 is the principal ferritin cargo receptor for 
          ferritinophagy
        supporting_text: Serves as the selective cargo receptor that binds 
          ferritin (FTH1) and delivers it to autophagic/lysosomal degradation
      - statement: N-terminal region mediates nuclear receptor coactivation 
          (secondary function)
        supporting_text: N-terminal coiled-coil / nuclear-receptor-binding 
          region (~1-237); C-terminal ferritin-binding domain (~238-614)
      - statement: Ferritinophagy positively regulates ferroptosis by increasing
          labile iron
        supporting_text: Excessive ferritinophagy increases labile Fe2+ and 
          lipid peroxidation, sensitizing cells to ferroptosis
core_functions:
  - description: NCOA4 is the selective autophagy cargo adaptor that binds 
      ferritin heavy chain (FTH1) via its C-terminal 16-aa motif (residues 
      484-499) and delivers ferritin complexes to autophagosomes/lysosomes for 
      degradation, releasing stored iron. This is the primary function of NCOA4 
      discovered in 2014.
    molecular_function:
      id: GO:0160247
      label: autophagy cargo adaptor activity
    directly_involved_in:
      - id: GO:0006879
        label: intracellular iron ion homeostasis
      - id: GO:0006622
        label: protein targeting to lysosome
    locations:
      - id: GO:0005776
        label: autophagosome
      - id: GO:0044754
        label: autolysosome
    supported_by:
      - reference_id: PMID:25327288
        supporting_text: 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
proposed_new_terms: []
suggested_questions:
  - question: Is there a ferritinophagy-specific GO term that should be created?
  - question: Should there be a term for "ferritin binding" as a specific 
      molecular function?
  - question: How should the dual-function nature of NCOA4 be represented in GO 
      annotations?
suggested_experiments:
  - description: Structure-function studies to confirm domain separation between
      ferritinophagy and coactivator functions
  - description: In vivo studies to assess relative contributions of each 
      function to physiological phenotypes
tags:
  - ferroptosis

NCOA4

Gene Description

Existing Annotations Review

Core Functions

NCOA4 is the selective autophagy cargo adaptor that binds ferritin heavy chain (FTH1) via its C-terminal 16-aa motif (residues 484-499) and delivers ferritin complexes to autophagosomes/lysosomes for degradation, releasing stored iron. This is the primary function of NCOA4 discovered in 2014.

References

Suggested Questions for Experts

Suggested Experiments

Tags

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

📄 View Raw YAML