Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0072344 rescue of stalled cytosolic ribosome	IBA GO_REF:0000033	ACCEPT	Summary: RNF25 acts on stalled/collided ribosomes in the RNF14-RNF25 quality control pathway. IBA inference is corroborated by direct experimental evidence. Reason: Core process; RNF25 ubiquitinates ribosomal proteins and translation factors on stalled ribosomes as part of ribosome-associated quality control. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
GO:0006511 ubiquitin-dependent protein catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: RNF25 ubiquitinates translation factors and ribosomal proteins on stalled ribosomes, targeting them for degradation. Core biological process. Reason: Directly supported; RNF25 promotes ubiquitin-dependent degradation of stalled translation factors (e.g. eEF1A, eRF1). Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt promotes ubiquitination and degradation of translation factors on stalled ribosomes
GO:0061630 ubiquitin protein ligase activity	IBA GO_REF:0000033	ACCEPT	Summary: RNF25 is a RING E3 ubiquitin ligase. This is its core molecular function. Reason: Defining molecular function, supported by phylogenetic inference and direct biochemistry. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
GO:0005634 nucleus	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: A nuclear pool of RNF25 is reported (from its AO7/NF-kB role), but its principal quality-control function is cytoplasmic/ribosome-associated. Reason: Nuclear localization is documented but peripheral to the core cytoplasmic RQC function. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt may also stimulate transcription mediated by NF-kappa-B via its interaction with RELA/p65
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Cytoplasmic localization, consistent with RNF25's ribosome-associated quality-control function. Reason: Correct compartment for the core RQC function. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm
GO:0061630 ubiquitin protein ligase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic transfer of ubiquitin ligase activity, consistent with direct evidence. Reason: Correct core molecular function. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
GO:0005515 protein binding	IPI PMID:18757723 EGF receptor-independent action of TGF-alpha protects Naked2...	KEEP AS NON CORE	Summary: High-throughput interaction. Bare protein binding is uninformative. Reason: Records a physical interaction but the generic term adds nothing to RNF25's E3 ligase function. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
GO:0005515 protein binding	IPI PMID:19549727 Analysis of the human E2 ubiquitin conjugating enzyme protei...	KEEP AS NON CORE	Summary: E2 ubiquitin-conjugating enzyme interaction network capturing RNF25-E2 (UbcH5/UBE2D) binding. Relevant to catalysis but recorded as bare protein binding. Reason: The E2 interaction underlies RNF25's ligase activity, but the generic protein binding term is uninformative; the catalytic role is captured by the ligase-activity term. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt Interacts with UBE2D2
GO:0005515 protein binding	IPI PMID:19690564 A comprehensive framework of E2-RING E3 interactions of the ...	KEEP AS NON CORE	Summary: E2-RING E3 interaction framework capturing RNF25-E2 binding. Bare protein binding. Reason: Reflects E2 engagement underlying catalysis; generic term is non-core. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt Interacts with UBE2D2
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: Interactome screen capturing RNF25 interactions. Bare protein binding. Reason: Generic term; uninformative for core function. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: Binary interactome (e.g. NKD2, a substrate; KCTD21). Bare protein binding. Reason: Records interactions including a substrate (NKD2), but the generic term is uninformative. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt Q969F2: NKD2
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	Summary: Neurodegeneration interactome screen. Bare protein binding with high-throughput partners unrelated to the core function. Reason: Isolated high-throughput interactions; generic term uninformative and not part of the core function. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: BioPlex affinity-purification interactome capturing RNF25 interactions. Bare protein binding. Reason: Generic term; uninformative for core function. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: Multimodal cell-maps interactome capturing RNF25 interactions. Bare protein binding. Reason: Generic term; uninformative for core function. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
GO:0004842 ubiquitin-protein transferase activity	IEA GO_REF:0000107	ACCEPT	Summary: Ubiquitin-protein transferase activity, equivalent to RNF25's E3 ligase function. Reason: Correct molecular function (the EC 2.3.2.27 ligase reaction). Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
GO:0016567 protein ubiquitination	IEA GO_REF:0000120	ACCEPT	Summary: RNF25 ubiquitinates substrate proteins; protein ubiquitination is the process it catalyzes. Reason: Directly supported core process. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt promotes ubiquitination and degradation of translation factors on stalled ribosomes
GO:0005737 cytoplasm	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of cytoplasmic localization, consistent with direct evidence. Reason: Correct compartment for the core function. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm
GO:0022626 cytosolic ribosome	IDA PMID:36638793 An E3 ligase network engages GCN1 to promote the degradation...	ACCEPT	Summary: RNF25 acts at the cytosolic ribosome, ubiquitinating ribosomal proteins on stalled/collided ribosomes. Reason: Directly supported site of action for the RQC function. Supporting Evidence: PMID:36638793 RNF25-dependent ubiquitination of the ribosomal protein
GO:0061630 ubiquitin protein ligase activity	IDA PMID:36638793 An E3 ligase network engages GCN1 to promote the degradation...	ACCEPT	Summary: Direct demonstration of RNF25 ubiquitin ligase activity in the RNF14-RNF25 pathway, ubiquitinating RPS27A and translation factors on stalled ribosomes. Reason: Directly demonstrated core molecular function in the GCN1-engaging E3 network. Supporting Evidence: PMID:36638793 RNF25-dependent ubiquitination of the ribosomal protein
GO:0072344 rescue of stalled cytosolic ribosome	IDA PMID:36638793 An E3 ligase network engages GCN1 to promote the degradation...	ACCEPT	Summary: RNF25 acts on stalled/collided ribosomes, ubiquitinating RPS27A to activate RNF14 and promote degradation of stalled translation factors. Reason: Directly demonstrated involvement in the stalled-ribosome quality-control response. Supporting Evidence: PMID:36638793 RNF25-dependent ubiquitination of the ribosomal protein
GO:0061630 ubiquitin protein ligase activity	IDA PMID:37951215 K6-linked ubiquitylation marks formaldehyde-induced RNA-prot...	ACCEPT	Summary: Direct demonstration of RNF25 E3 ligase activity in marking RNA-protein crosslinks with ubiquitin. Reason: Directly demonstrated core molecular function. Supporting Evidence: PMID:37951215 K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks
GO:0160127 protein-RNA covalent cross-linking repair	IDA PMID:37951215 K6-linked ubiquitylation marks formaldehyde-induced RNA-prot...	ACCEPT	Summary: RNF25 (with RNF14) assembles K6-linked ubiquitin chains that flag RNA-protein crosslinks for translation-coupled resolution. Reason: Directly demonstrated role in resolving covalent RNA-protein crosslinks. Supporting Evidence: PMID:37951215 K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks
GO:0061630 ubiquitin protein ligase activity	IDA PMID:37651229 Drug-induced eRF1 degradation promotes readthrough and revea...	ACCEPT	Summary: Direct demonstration of RNF25 ligase activity in drug-induced eRF1 degradation that promotes readthrough. Reason: Directly demonstrated core molecular function. Supporting Evidence: PMID:37651229 E3 ubiquitin ligases RNF14 and RNF25
GO:0072344 rescue of stalled cytosolic ribosome	IDA PMID:37651229 Drug-induced eRF1 degradation promotes readthrough and revea...	ACCEPT	Summary: RNF25 (with RNF14) acts on stalled/collided ribosomes following eRF1 trapping to clear stalled translation factors. Reason: Directly demonstrated involvement in resolving stalled ribosomes. Supporting Evidence: PMID:37651229 E3 ubiquitin ligases RNF14 and RNF25
GO:0072344 rescue of stalled cytosolic ribosome	IDA PMID:37951216 RNF14-dependent atypical ubiquitylation promotes translation...	ACCEPT	Summary: RNF25 (with RNF14) acts in translation-coupled resolution of RNA-protein crosslinks at collided ribosomes. Reason: Directly demonstrated involvement in stalled-ribosome resolution. Supporting Evidence: PMID:37951216 RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution
GO:0061630 ubiquitin protein ligase activity	IDA PMID:26475854 Insights into Ubiquitination from the Unique Clamp-like Bind...	ACCEPT	Summary: Structural/biochemical study of the AO7 (RNF25) RING-E2 (UbcH5B) interaction demonstrating its ubiquitin ligase activity. Reason: Directly demonstrated RING E3 ligase activity with its E2 partner. Supporting Evidence: PMID:26475854 Insights into Ubiquitination from the Unique Clamp-like Binding of the RING E3 AO7 to the E2 UbcH5B
GO:0006511 ubiquitin-dependent protein catabolic process	IDA PMID:27863242 Decoding Mammalian Ribosome-mRNA States by Translational GTP...	ACCEPT	Summary: RNF25-dependent ubiquitination targets factors on stalled ribosomes for degradation. Reason: Directly supported core process. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt promotes ubiquitination and degradation of translation factors on stalled ribosomes
GO:0022626 cytosolic ribosome	IDA PMID:27863242 Decoding Mammalian Ribosome-mRNA States by Translational GTP...	ACCEPT	Summary: RNF25 acts at the cytosolic ribosome in ribosome-associated quality control. Reason: Directly supported site of action. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt Catalyzes ubiquitination of RPS27A in response to ribosome collisions
GO:0061630 ubiquitin protein ligase activity	IDA PMID:27863242 Decoding Mammalian Ribosome-mRNA States by Translational GTP...	ACCEPT	Summary: Direct demonstration of RNF25 ubiquitin ligase activity in the RQC context. Reason: Directly demonstrated core molecular function. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
GO:0072344 rescue of stalled cytosolic ribosome	IDA PMID:27863242 Decoding Mammalian Ribosome-mRNA States by Translational GTP...	ACCEPT	Summary: RNF25 acts on stalled/collided ribosomes in ribosome-associated quality control. Reason: Directly supported core process. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt Catalyzes ubiquitination of RPS27A in response to ribosome collisions
GO:0085020 protein K6-linked ubiquitination	IDA PMID:27863242 Decoding Mammalian Ribosome-mRNA States by Translational GTP...	ACCEPT	Summary: RNF25 assembles atypical K6-linked ubiquitin chains, a distinctive feature of its RQC signaling. Reason: Directly demonstrated; K6-linked ubiquitination marks RNA-protein crosslinks and stalled-ribosome substrates. Supporting Evidence: PMID:37951215 K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks
GO:0004842 ubiquitin-protein transferase activity	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of ubiquitin-protein transferase activity, consistent with direct evidence. Reason: Correct core molecular function. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
GO:0005634 nucleus	IDA PMID:12748188 RING finger protein AO7 supports NF-kappaB-mediated transcri...	KEEP AS NON CORE	Summary: Direct nuclear localization reported in the original AO7/NF-kB study. Reason: Genuine nuclear pool linked to the NF-kB role; peripheral to the core cytoplasmic RQC function. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt may also stimulate transcription mediated by NF-kappa-B via its interaction with RELA/p65
GO:0005829 cytosol	IDA PMID:12748188 RING finger protein AO7 supports NF-kappaB-mediated transcri...	ACCEPT	Summary: Direct cytosolic localization, consistent with the core ribosome-associated function. Reason: Correct localization for the cytoplasmic RQC function. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm
GO:0016567 protein ubiquitination	ISS GO_REF:0000024	ACCEPT	Summary: RNF25 catalyzes protein ubiquitination. Reason: Correct core process. Supporting Evidence: file:human/RNF25/RNF25-uniprot.txt promotes ubiquitination and degradation of translation factors on stalled ribosomes
GO:0051059 NF-kappaB binding	IPI PMID:12748188 RING finger protein AO7 supports NF-kappaB-mediated transcri...	KEEP AS NON CORE	Summary: RNF25 (AO7) binds RELA/p65 and supports NF-kappaB-mediated transcription, a function distinct from its ribosome-associated quality-control role. Reason: Documented physical interaction underlying the NF-kB moonlighting role; retained as non-core relative to the E3-ligase RQC function. Supporting Evidence: PMID:12748188 RING finger protein AO7 supports NF-kappaB-mediated transcription

Core Functions

RING-type E3 ubiquitin ligase that, in the RNF14-RNF25 translation quality control pathway, ubiquitinates the ribosomal protein RPS27A/eS31 on collided ribosomes (activating RNF14) and ubiquitinates other ribosomal proteins and stalled ETF1/eRF1, targeting translation factors on stalled ribosomes for degradation.

Molecular Function:

ubiquitin protein ligase activity

Cellular Locations:

cytosolic ribosome

Supporting Evidence:

file:human/RNF25/RNF25-uniprot.txt
Catalyzes ubiquitination of RPS27A in response to ribosome collisions, promoting activation of RNF14
PMID:36638793
RNF25-dependent ubiquitination of the ribosomal protein

Assembles atypical K6-linked ubiquitin chains (with RNF14) that flag formaldehyde-induced RNA-protein crosslinks for translation-coupled resolution.

Molecular Function:

ubiquitin protein ligase activity

Cellular Locations:

cytosolic ribosome

Supporting Evidence:

PMID:37951215
K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks

References

GO_REF:0000024

Manual transfer of annotations from one model organism to another based on sequence orthology

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

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

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:12748188

RING finger protein AO7 supports NF-kappaB-mediated transcription by interacting with the transactivation domain of the p65 subunit.

AO7 (RNF25) interacts with RELA/p65 and supports NF-kappaB-mediated transcription; localizes to nucleus and cytosol.

PMID:18757723

EGF receptor-independent action of TGF-alpha protects Naked2 from AO7-mediated ubiquitylation and proteasomal degradation.

PMID:19549727

Analysis of the human E2 ubiquitin conjugating enzyme protein interaction network.

PMID:19690564

A comprehensive framework of E2-RING E3 interactions of the human ubiquitin-proteasome system.

PMID:26475854

Insights into Ubiquitination from the Unique Clamp-like Binding of the RING E3 AO7 to the E2 UbcH5B.

Structural and biochemical characterization of the RING E3 AO7 (RNF25) binding to the E2 UbcH5B (UBE2D2), establishing its ubiquitin ligase activity.

PMID:27863242

Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes.

RNF25 acts at the cytosolic ribosome and forms K6-linked ubiquitin chains in ribosome-associated quality control.

PMID:28514442

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

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

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

PMID:36638793

An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes.

RNF14 and RNF25 are required for eEF1A degradation on stalled ribosomes; RNF25 ubiquitinates RPS27A/eS31 as an essential signaling input that activates RNF14.

PMID:37651229

Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control.

Readthrough drugs trap eRF1, causing ribosome stalls/collisions and eRF1 degradation by the E3 ubiquitin ligases RNF14 and RNF25.

PMID:37951215

K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution.

RNF25 assembles K6-linked ubiquitin chains that mark formaldehyde-induced RNA-protein crosslinks for resolution.

PMID:37951216

RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution of RNA-protein crosslinks.

RNF14-dependent atypical ubiquitylation (with RNF25) promotes translation-coupled resolution of RNA-protein crosslinks at collided ribosomes.

PMID:40205054

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

Suggested Experiments

Experiment: Site-specific ubiquitin-proteomics (diGly) in RNF25-knockout versus wild-type cells under collision-inducing stress to define the endogenous RNF25 substrate set and ubiquitin-chain linkage types.

Experiment: Reconstituted ubiquitination assays with RNF25, RNF14, UBE2D2 and collided ribosomes to dissect the order of RPS27A ubiquitination and RNF14 activation.

📚 Additional Documentation

Notes

(RNF25-notes.md)

RNF25 (AO7) — research notes

UniProt: Q96BH1. RING-H2 E3 ubiquitin ligase (RING-H2_RNF25, RWD domain + RING). Cytoplasmic.

Core function — RQC / translation quality control

RNF25 is a RING E3 ubiquitin ligase acting in the RNF14-RNF25 translation quality control pathway
on stalled/collided ribosomes.
- Catalyzes ubiquitination of RPS27A/eS31 in response to ribosome collisions, promoting activation of RNF14.
- Ubiquitinates other ribosomal proteins (uL... eS...) and stalled ETF1/eRF1 for degradation.
[file:human/RNF25/RNF25-uniprot.txt "E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway"]
[file:human/RNF25/RNF25-uniprot.txt "Catalyzes ubiquitination of RPS27A in response to ribosome collisions, promoting activation of RNF14"]
- PMID:36638793 — RNF14 + RNF25 required for eEF1A degradation; RNF25 ubiquitinates RPS27A/eS31 as a second signal.
- PMID:37651229 — drug (eRF1-trapping)-induced readthrough via RNF14/RNF25 degradation of eRF1.
- PMID:37951216 — RNF25 acts with RNF14 in resolving RNA-protein crosslinks (collision-coupled).
- PMID:37951215 — atypical K6-linked ubiquitination (GO:0085020); RNF25 IDA.
- PMID:27863242 cryo-EM/RQC study: RNF25 K6-linked ubiquitination, cytosolic ribosome, ubiquitin protein ligase activity.

E2 interaction / catalysis

Interacts with UBE2D2 (UbcH5B), may interact with UBE2E1/E3. RWD domain binds E2.
PMID:26475854

Moonlighting / older

Originally cloned as AO7, supports NF-kB (RELA/p65)-mediated transcription PMID:12748188; nuclear+cytosol IDA, NF-kB binding IPI. Keep non-core.
Mediates ubiquitination/degradation of NKD2 (by similarity).

Action plan

Core MF: GO:0061630 ubiquitin protein ligase activity. Core BP: GO:0072344 rescue of stalled cytosolic ribosome; GO:0006511 ubiquitin-dependent protein catabolic process; GO:0085020 K6-linked ubiquitination; GO:0160127 protein-RNA covalent cross-linking repair.
protein binding IPI (HT screens, E2s): keep non-core / over-annotated.
NF-kB binding, nucleus: keep non-core (older AO7 role).

Pn Notes

(RNF25-pn-notes.md)

RNF25 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q96BH1
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07c
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/RNF25/RNF25-ai-review.yaml
AIGR review HTML: present - genes/human/RNF25/RNF25-ai-review.html
Gene notes: present - genes/human/RNF25/RNF25-notes.md
GOA TSV: present - genes/human/RNF25/RNF25-goa.tsv
UniProt record: present - genes/human/RNF25/RNF25-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/RNF25.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/RNF25.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: RNF25 (RING finger protein 25, originally identified as AO7) is a cytoplasmic RING-H2 E3 ubiquitin-protein ligase that, with an N-terminal RWD domain for E2 recognition, functions in ribosome-associated quality control. It is a core component of the RNF14-RNF25 translation quality control pathway that operates when ribosomes stall and collide during translation. RNF25 catalyzes ubiquitination of the ribosomal protein RPS27A/eS31 in response to ribosome collisions, providing a signal that activates the partner ligase RNF14, and it ubiquitinates additional ribosomal proteins and stalled release factor ETF1/eRF1, marking translation factors on stalled ribosomes for degradation. RNF25 also assembles atypical K6-linked ubiquitin chains that flag formaldehyde-induced RNA-protein crosslinks for translation-coupled resolution. It works with the E2 enzyme UBE2D2 (UbcH5B). Independently of the stalled-ribosome response, RNF25 was originally characterized as a regulator that supports NF-kappaB (RELA/p65)-mediated transcription and can target substrates such as NKD2 for degradation.
Existing/core annotation action counts: ACCEPT: 25; KEEP_AS_NON_CORE: 11

PN Consistency Summary

Consistency: Excellent. Deep research, review and PN concur: RING-H2 E3 (RWD for E2 recognition; works with UBE2D2/UbcH5B), the partner ligase of RNF14 in the RNF14-RNF25 pathway — ubiquitinates RPS27A/eS31 on collided ribosomes to activate RNF14, ubiquitinates eRF1/ribosomal proteins, and assembles K6 chains on formaldehyde RNA-protein crosslinks (GO:0160127); legacy AO7/NF-kB(RELA) role kept non-core. PN correctly tags the catalytic ligase MF. No contradictions.
PN story / NEW pressure: GO:0061630 (verified real) and GO:0016567 already in GOA + review (IDA PMID:36638793, 26475854, 37651229, 37951215). GO:0006515 (verified real) is new_to_goa; RNF25 genuinely drives stalled-ribosome QC so it is a defensible higher-level ADD, but broader than the review's precise set (GO:0072344, GO:0085020 K6, GO:0160127, GO:0006511). Conclude: ligase MF + ubiquitination already captured; GO:0006515 defensible-but-broader ADD.
Evidence alignment: PN RING row cites "PMID 19489725 / rev" — NOT in the review references. Review RQC/ligase evidence (PMID:36638793, 26475854, 37651229, 37951215/16, 27863242, 12748188) is HIGH/VERIFIED and far richer. Divergence: the single PN-cited RING PMID is uncited in the review (likely an older RING/E3 review; low impact, ligase MF independently well-supported).
Verdict: Fully consistent; PN ligase MF (GO:0061630) and ubiquitination already captured, GO:0006515 a defensible-but-broader ADD. No YAML change needed.

Full Consistency Review

UniProt: Q96BH1 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE (thorough; core RING ligase + RQC, AO7/NF-kB as non-core)
PN placement: 3 rows — Translation|Cytosolic translation|Ribosome-associated QC|ubiquitination of eEF1A on stalled ribosomes; UPS|E3 ubiquitin and UBL ligases|RING|ubiquitin binding domain|RWD; UPS|Ubiquitin and UBL binding|E3 ligase|RING / with UBD|RWD. PN-node mapping: RQC-type→mapped GO:0016567 protein ubiquitination (already_in_goa); RQC-group→GO:0006515 (new); RING-group→mapped GO:0061630 ubiquitin protein ligase activity (already_in_goa); UBL-binding E3-group→GO:0061630 (already_in_goa); RING subtype/type no_mapping. Projected: GO:0006515 (new), GO:0016567, GO:0061630×2 (all in GOA).
Consistency: Excellent. Deep research, review and PN concur: RING-H2 E3 (RWD for E2 recognition; works with UBE2D2/UbcH5B), the partner ligase of RNF14 in the RNF14-RNF25 pathway — ubiquitinates RPS27A/eS31 on collided ribosomes to activate RNF14, ubiquitinates eRF1/ribosomal proteins, and assembles K6 chains on formaldehyde RNA-protein crosslinks (GO:0160127); legacy AO7/NF-kB(RELA) role kept non-core. PN correctly tags the catalytic ligase MF. No contradictions.
PN story / NEW pressure: GO:0061630 (verified real) and GO:0016567 already in GOA + review (IDA PMID:36638793, 26475854, 37651229, 37951215). GO:0006515 (verified real) is new_to_goa; RNF25 genuinely drives stalled-ribosome QC so it is a defensible higher-level ADD, but broader than the review's precise set (GO:0072344, GO:0085020 K6, GO:0160127, GO:0006511). Conclude: ligase MF + ubiquitination already captured; GO:0006515 defensible-but-broader ADD.
Mapping strategy: Correctly resolves RNF25 as catalytic RING ligase (GO:0061630), distinct from a UBD reader; group-level mapping appropriate, subtype/type no_mapping avoids double-counting. RQC-group→GO:0006515 broader than terms already present. No node change warranted.
Evidence alignment: PN RING row cites "PMID 19489725 / rev" — NOT in the review references. Review RQC/ligase evidence (PMID:36638793, 26475854, 37651229, 37951215/16, 27863242, 12748188) is HIGH/VERIFIED and far richer. Divergence: the single PN-cited RING PMID is uncited in the review (likely an older RING/E3 review; low impact, ligase MF independently well-supported).
Verdict: Fully consistent; PN ligase MF (GO:0061630) and ubiquitination already captured, GO:0006515 a defensible-but-broader ADD. No YAML change needed.
Recommended edits: none required. [REF] (optional) check PN-cited PMID:19489725 (RING row) — absent from review; verify whether it adds RNF25-specific support or is a family review. [MAP] GO:0006515 broader than the exact RQC terms already annotated.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07c
review_yaml: genes/human/RNF25/RNF25-ai-review.yaml
PN workbook rows: 3

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | ubiquitination of eEF1A on stalled ribosomes

UniProt: Q96BH1
In branches: TR, UPS
PN-node mapping records (path + ancestors):
- [type] Translation|Cytosolic translation|Ribosome-associated QC|ubiquitination of eEF1A on stalled ribosomes
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0016567 protein ubiquitination]
  rationale: This PN RQC type is a specific ubiquitination bucket for eEF1A on stalled ribosomes. Protein ubiquitination is the shared process target.
- [group] Translation|Cytosolic translation|Ribosome-associated QC
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0006515 protein quality control for misfolded or incompletely synthesized proteins]
  rationale: The PN ribosome-associated quality-control group covers surveillance and disposal of stalled or defective nascent-chain translation products. GO lacks a dedicated ribosome-associated QC term in the local cache, so the broader protein-quality-control process is the best supported target.
- [class] Translation|Cytosolic translation
  status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
  rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
- [branch] Translation
  status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
  rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING | ubiquitin binding domain | RWD

UniProt: Q96BH1
In branches: TR, UPS
Signature domains: IPR001841
Auxiliary domains: IPR006575
PN references (titles):
- 19489725 / rev
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|ubiquitin binding domain|RWD
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|ubiquitin binding domain
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This PN group is a catalytic ubiquitin E3 ligase bucket. The shared GO molecular-function target is ubiquitin protein ligase activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL binding | E3 ligase | RING / with UBD | RWD

UniProt: Q96BH1
In branches: TR, UPS
Signature domains: IPR006575
Auxiliary domains: IPR001841
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase|RING / with UBD|RWD
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower enzyme-family, domain, or architecture subdivision already covered by a curated parent enzyme mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase|RING / with UBD
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower enzyme-family, domain, or architecture subdivision already covered by a curated parent enzyme mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This PN group captures ubiquitin/UBL-binding factors that are E3 ligases. The shared molecular-function target is ubiquitin protein ligase activity.
- [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
  status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
  rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (4)

GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Ribosome-associated QC
GO:0016567 protein ubiquitination | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Translation|Cytosolic translation|Ribosome-associated QC|ubiquitination of eEF1A on stalled ribosomes
GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING
GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q96BH1
gene_symbol: RNF25
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: RNF25 (RING finger protein 25, originally identified as AO7) is a cytoplasmic RING-H2 E3 ubiquitin-protein ligase that, with an N-terminal RWD domain for E2 recognition, functions in ribosome-associated quality control. It is a core component of the RNF14-RNF25 translation quality control pathway that operates when ribosomes stall and collide during translation. RNF25 catalyzes ubiquitination of the ribosomal protein RPS27A/eS31 in response to ribosome collisions, providing a signal that activates the partner ligase RNF14, and it ubiquitinates additional ribosomal proteins and stalled release factor ETF1/eRF1, marking translation factors on stalled ribosomes for degradation. RNF25 also assembles atypical K6-linked ubiquitin chains that flag formaldehyde-induced RNA-protein crosslinks for translation-coupled resolution. It works with the E2 enzyme UBE2D2 (UbcH5B). Independently of the stalled-ribosome response, RNF25 was originally characterized as a regulator that supports NF-kappaB (RELA/p65)-mediated transcription and can target substrates such as NKD2 for degradation.
existing_annotations:
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: RNF25 acts on stalled/collided ribosomes in the RNF14-RNF25 quality control pathway. IBA inference is corroborated by direct experimental evidence.
    action: ACCEPT
    reason: Core process; RNF25 ubiquitinates ribosomal proteins and translation factors on stalled ribosomes as part of ribosome-associated quality control.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: RNF25 ubiquitinates translation factors and ribosomal proteins on stalled ribosomes, targeting them for degradation. Core biological process.
    action: ACCEPT
    reason: Directly supported; RNF25 promotes ubiquitin-dependent degradation of stalled translation factors (e.g. eEF1A, eRF1).
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: promotes ubiquitination and degradation of translation factors on stalled ribosomes
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: RNF25 is a RING E3 ubiquitin ligase. This is its core molecular function.
    action: ACCEPT
    reason: Defining molecular function, supported by phylogenetic inference and direct biochemistry.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: A nuclear pool of RNF25 is reported (from its AO7/NF-kB role), but its principal quality-control function is cytoplasmic/ribosome-associated.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is documented but peripheral to the core cytoplasmic RQC function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: may also stimulate transcription mediated by NF-kappa-B via its interaction with RELA/p65
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasmic localization, consistent with RNF25's ribosome-associated quality-control function.
    action: ACCEPT
    reason: Correct compartment for the core RQC function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic transfer of ubiquitin ligase activity, consistent with direct evidence.
    action: ACCEPT
    reason: Correct core molecular function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18757723
  qualifier: enables
  review:
    summary: High-throughput interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a physical interaction but the generic term adds nothing to RNF25's E3 ligase function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19549727
  qualifier: enables
  review:
    summary: E2 ubiquitin-conjugating enzyme interaction network capturing RNF25-E2 (UbcH5/UBE2D) binding. Relevant to catalysis but recorded as bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: The E2 interaction underlies RNF25's ligase activity, but the generic protein binding term is uninformative; the catalytic role is captured by the ligase-activity term.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: Interacts with UBE2D2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19690564
  qualifier: enables
  review:
    summary: E2-RING E3 interaction framework capturing RNF25-E2 binding. Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: Reflects E2 engagement underlying catalysis; generic term is non-core.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: Interacts with UBE2D2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Interactome screen capturing RNF25 interactions. Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: Generic term; uninformative for core function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome (e.g. NKD2, a substrate; KCTD21). Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: Records interactions including a substrate (NKD2), but the generic term is uninformative.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: 'Q969F2: NKD2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegeneration interactome screen. Bare protein binding with high-throughput partners unrelated to the core function.
    action: KEEP_AS_NON_CORE
    reason: Isolated high-throughput interactions; generic term uninformative and not part of the core function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interactome capturing RNF25 interactions. Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: Generic term; uninformative for core function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-maps interactome capturing RNF25 interactions. Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: Generic term; uninformative for core function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ubiquitin-protein transferase activity, equivalent to RNF25's E3 ligase function.
    action: ACCEPT
    reason: Correct molecular function (the EC 2.3.2.27 ligase reaction).
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: RNF25 ubiquitinates substrate proteins; protein ubiquitination is the process it catalyzes.
    action: ACCEPT
    reason: Directly supported core process.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: promotes ubiquitination and degradation of translation factors on stalled ribosomes
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity transfer of cytoplasmic localization, consistent with direct evidence.
    action: ACCEPT
    reason: Correct compartment for the core function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0022626
    label: cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: is_active_in
  review:
    summary: RNF25 acts at the cytosolic ribosome, ubiquitinating ribosomal proteins on stalled/collided ribosomes.
    action: ACCEPT
    reason: Directly supported site of action for the RQC function.
    supported_by:
    - reference_id: PMID:36638793
      supporting_text: RNF25-dependent ubiquitination of the ribosomal protein
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: enables
  review:
    summary: Direct demonstration of RNF25 ubiquitin ligase activity in the RNF14-RNF25 pathway, ubiquitinating RPS27A and translation factors on stalled ribosomes.
    action: ACCEPT
    reason: Directly demonstrated core molecular function in the GCN1-engaging E3 network.
    supported_by:
    - reference_id: PMID:36638793
      supporting_text: RNF25-dependent ubiquitination of the ribosomal protein
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: involved_in
  review:
    summary: RNF25 acts on stalled/collided ribosomes, ubiquitinating RPS27A to activate RNF14 and promote degradation of stalled translation factors.
    action: ACCEPT
    reason: Directly demonstrated involvement in the stalled-ribosome quality-control response.
    supported_by:
    - reference_id: PMID:36638793
      supporting_text: RNF25-dependent ubiquitination of the ribosomal protein
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:37951215
  qualifier: enables
  review:
    summary: Direct demonstration of RNF25 E3 ligase activity in marking RNA-protein crosslinks with ubiquitin.
    action: ACCEPT
    reason: Directly demonstrated core molecular function.
    supported_by:
    - reference_id: PMID:37951215
      supporting_text: K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks
- term:
    id: GO:0160127
    label: protein-RNA covalent cross-linking repair
  evidence_type: IDA
  original_reference_id: PMID:37951215
  qualifier: involved_in
  review:
    summary: RNF25 (with RNF14) assembles K6-linked ubiquitin chains that flag RNA-protein crosslinks for translation-coupled resolution.
    action: ACCEPT
    reason: Directly demonstrated role in resolving covalent RNA-protein crosslinks.
    supported_by:
    - reference_id: PMID:37951215
      supporting_text: K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:37651229
  qualifier: enables
  review:
    summary: Direct demonstration of RNF25 ligase activity in drug-induced eRF1 degradation that promotes readthrough.
    action: ACCEPT
    reason: Directly demonstrated core molecular function.
    supported_by:
    - reference_id: PMID:37651229
      supporting_text: E3 ubiquitin ligases RNF14 and RNF25
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:37651229
  qualifier: involved_in
  review:
    summary: RNF25 (with RNF14) acts on stalled/collided ribosomes following eRF1 trapping to clear stalled translation factors.
    action: ACCEPT
    reason: Directly demonstrated involvement in resolving stalled ribosomes.
    supported_by:
    - reference_id: PMID:37651229
      supporting_text: E3 ubiquitin ligases RNF14 and RNF25
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:37951216
  qualifier: involved_in
  review:
    summary: RNF25 (with RNF14) acts in translation-coupled resolution of RNA-protein crosslinks at collided ribosomes.
    action: ACCEPT
    reason: Directly demonstrated involvement in stalled-ribosome resolution.
    supported_by:
    - reference_id: PMID:37951216
      supporting_text: RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:26475854
  qualifier: enables
  review:
    summary: Structural/biochemical study of the AO7 (RNF25) RING-E2 (UbcH5B) interaction demonstrating its ubiquitin ligase activity.
    action: ACCEPT
    reason: Directly demonstrated RING E3 ligase activity with its E2 partner.
    supported_by:
    - reference_id: PMID:26475854
      supporting_text: Insights into Ubiquitination from the Unique Clamp-like Binding of the RING E3 AO7 to the E2 UbcH5B
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: involved_in
  review:
    summary: RNF25-dependent ubiquitination targets factors on stalled ribosomes for degradation.
    action: ACCEPT
    reason: Directly supported core process.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: promotes ubiquitination and degradation of translation factors on stalled ribosomes
- term:
    id: GO:0022626
    label: cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: is_active_in
  review:
    summary: RNF25 acts at the cytosolic ribosome in ribosome-associated quality control.
    action: ACCEPT
    reason: Directly supported site of action.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: Catalyzes ubiquitination of RPS27A in response to ribosome collisions
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: enables
  review:
    summary: Direct demonstration of RNF25 ubiquitin ligase activity in the RQC context.
    action: ACCEPT
    reason: Directly demonstrated core molecular function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: involved_in
  review:
    summary: RNF25 acts on stalled/collided ribosomes in ribosome-associated quality control.
    action: ACCEPT
    reason: Directly supported core process.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: Catalyzes ubiquitination of RPS27A in response to ribosome collisions
- term:
    id: GO:0085020
    label: protein K6-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: involved_in
  review:
    summary: RNF25 assembles atypical K6-linked ubiquitin chains, a distinctive feature of its RQC signaling.
    action: ACCEPT
    reason: Directly demonstrated; K6-linked ubiquitination marks RNA-protein crosslinks and stalled-ribosome substrates.
    supported_by:
    - reference_id: PMID:37951215
      supporting_text: K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity transfer of ubiquitin-protein transferase activity, consistent with direct evidence.
    action: ACCEPT
    reason: Correct core molecular function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:12748188
  qualifier: located_in
  review:
    summary: Direct nuclear localization reported in the original AO7/NF-kB study.
    action: KEEP_AS_NON_CORE
    reason: Genuine nuclear pool linked to the NF-kB role; peripheral to the core cytoplasmic RQC function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: may also stimulate transcription mediated by NF-kappa-B via its interaction with RELA/p65
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:12748188
  qualifier: located_in
  review:
    summary: Direct cytosolic localization, consistent with the core ribosome-associated function.
    action: ACCEPT
    reason: Correct localization for the cytoplasmic RQC function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: RNF25 catalyzes protein ubiquitination.
    action: ACCEPT
    reason: Correct core process.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: promotes ubiquitination and degradation of translation factors on stalled ribosomes
- term:
    id: GO:0051059
    label: NF-kappaB binding
  evidence_type: IPI
  original_reference_id: PMID:12748188
  qualifier: enables
  review:
    summary: RNF25 (AO7) binds RELA/p65 and supports NF-kappaB-mediated transcription, a function distinct from its ribosome-associated quality-control role.
    action: KEEP_AS_NON_CORE
    reason: Documented physical interaction underlying the NF-kB moonlighting role; retained as non-core relative to the E3-ligase RQC function.
    supported_by:
    - reference_id: PMID:12748188
      supporting_text: RING finger protein AO7 supports NF-kappaB-mediated transcription
references:
- id: GO_REF:0000024
  title: Manual transfer of annotations from one model organism to another based on sequence orthology
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12748188
  title: RING finger protein AO7 supports NF-kappaB-mediated transcription by interacting with the transactivation domain of the p65 subunit.
  findings:
  - statement: AO7 (RNF25) interacts with RELA/p65 and supports NF-kappaB-mediated transcription; localizes to nucleus and cytosol.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; original characterization of AO7/RNF25 as a RING E3 interacting with the E2 UbcH5B/UBE2D2 (supports ubiquitin ligase identity), though the NF-kappaB transcription role is now considered secondary to the ribosome-quality-control function.
- id: PMID:18757723
  title: "EGF receptor-independent action of TGF-alpha protects Naked2 from AO7-mediated ubiquitylation and proteasomal degradation."
  findings: []
- id: PMID:19549727
  title: Analysis of the human E2 ubiquitin conjugating enzyme protein interaction network.
  findings: []
- id: PMID:19690564
  title: A comprehensive framework of E2-RING E3 interactions of the human ubiquitin-proteasome system.
  findings: []
- id: PMID:26475854
  title: Insights into Ubiquitination from the Unique Clamp-like Binding of the RING E3 AO7 to the E2 UbcH5B.
  findings:
  - statement: Structural and biochemical characterization of the RING E3 AO7 (RNF25) binding to the E2 UbcH5B (UBE2D2), establishing its ubiquitin ligase activity.
    reference_section_type: RESULTS
- id: PMID:27863242
  title: Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes.
  findings:
  - statement: RNF25 acts at the cytosolic ribosome and forms K6-linked ubiquitin chains in ribosome-associated quality control.
    reference_section_type: RESULTS
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:36638793
  title: An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes.
  findings:
  - statement: RNF14 and RNF25 are required for eEF1A degradation on stalled ribosomes; RNF25 ubiquitinates RPS27A/eS31 as an essential signaling input that activates RNF14.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; Results establish the RNF14-RNF25 pathway in which RNF25 ubiquitinates RPS27A/eS31 on collided ribosomes to activate RNF14 and drive degradation of stalled translation factors - RNF25's core E3 ligase function (GO:0061630).
- id: PMID:37651229
  title: Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control.
  findings:
  - statement: Readthrough drugs trap eRF1, causing ribosome stalls/collisions and eRF1 degradation by the E3 ubiquitin ligases RNF14 and RNF25.
    reference_section_type: RESULTS
- id: PMID:37951215
  title: K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution.
  findings:
  - statement: RNF25 assembles K6-linked ubiquitin chains that mark formaldehyde-induced RNA-protein crosslinks for resolution.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; supports RNF25's assembly of atypical K6-linked ubiquitin chains (with RNF14) flagging formaldehyde-induced RNA-protein crosslinks for translation-coupled resolution.
- id: PMID:37951216
  title: RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution of RNA-protein crosslinks.
  findings:
  - statement: RNF14-dependent atypical ubiquitylation (with RNF25) promotes translation-coupled resolution of RNA-protein crosslinks at collided ribosomes.
    reference_section_type: RESULTS
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
core_functions:
- description: RING-type E3 ubiquitin ligase that, in the RNF14-RNF25 translation quality control pathway, ubiquitinates the ribosomal protein RPS27A/eS31 on collided ribosomes (activating RNF14) and ubiquitinates other ribosomal proteins and stalled ETF1/eRF1, targeting translation factors on stalled ribosomes for degradation.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0022626
    label: cytosolic ribosome
  supported_by:
  - reference_id: file:human/RNF25/RNF25-uniprot.txt
    supporting_text: Catalyzes ubiquitination of RPS27A in response to ribosome collisions, promoting activation of RNF14
  - reference_id: PMID:36638793
    supporting_text: RNF25-dependent ubiquitination of the ribosomal protein
- description: Assembles atypical K6-linked ubiquitin chains (with RNF14) that flag formaldehyde-induced RNA-protein crosslinks for translation-coupled resolution.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0022626
    label: cytosolic ribosome
  supported_by:
  - reference_id: PMID:37951215
    supporting_text: K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks
proposed_new_terms: []
suggested_questions:
- question: What determines the substrate hierarchy in RNF25-mediated ubiquitination (RPS27A vs eRF1 vs other ribosomal proteins) and how does RPS27A ubiquitination activate RNF14?
- question: How is RNF25's RQC E3-ligase role partitioned from its older AO7/NF-kappaB transcriptional role, and are these mediated by distinct pools or stimuli?
suggested_experiments:
- description: Site-specific ubiquitin-proteomics (diGly) in RNF25-knockout versus wild-type cells under collision-inducing stress to define the endogenous RNF25 substrate set and ubiquitin-chain linkage types.
- description: Reconstituted ubiquitination assays with RNF25, RNF14, UBE2D2 and collided ribosomes to dissect the order of RPS27A ubiquitination and RNF14 activation.

RNF25

Gene Description