TCF25

UniProt ID: Q9BQ70
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

TCF25 (Ribosome quality control complex subunit TCF25; also known as Nulp1/hnulp1, "nuclear localized protein 1") is the human ortholog of the yeast RQC factor Rqc1 and a component of the ribosome-associated quality control (RQC) complex together with the E3 ubiquitin ligase LTN1/Listerin and NEMF on the stalled 60S ribosomal subunit. Within this complex TCF25 acts as an accessory factor required to promote formation of Lys48-linked polyubiquitin chains during LTN1-mediated ubiquitination of incompletely synthesized nascent chains, thereby ensuring efficient targeting of stalled translation products for proteasomal degradation. Despite the legacy "Transcription Factor 25" name, TCF25 has no demonstrated sequence-specific transcription-factor activity in this role; earlier work described it as a mainly nuclear basic-helix-loop-helix protein (Nulp1/hnulp1) with a transcriptional repressive domain and a role in cell-death control and XIAP binding. It is widely expressed with high levels in heart and, in the embryo, brain, and is found in both the nucleus and the cytosol.

Existing Annotations Review

GO Term Evidence Action Reason
GO:1990112 RQC complex
IBA
GO_REF:0000033 		ACCEPT
Summary: TCF25 is a conserved subunit of the RQC complex (LTN1, TCF25, NEMF) on the 60S subunit, as inferred phylogenetically from the Rqc1/TCF25 family.
Reason: Directly demonstrated in human (PMID:30244831) and conserved across the family; TCF25 is a bona fide RQC complex component.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Component of the ribosome quality control complex (RQC), composed of the E3 ubiquitin ligase LTN1, TCF25 and NEMF associated with the 60S ribosomal subunit
GO:0005634 nucleus
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: TCF25/Nulp1 is reported as mainly nuclear in earlier studies. While experimentally real, the nuclear pool is peripheral to its characterized molecular role in cytoplasmic RQC.
Reason: Nuclear localization is experimentally supported (EXP PMID:16574069, PMID:18068114) and noted by UniProt as "Mainly nuclear", but the informative, mechanistically defined function (RQC K48 ubiquitination) occurs in the cytosol on the 60S subunit.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
SUBCELLULAR LOCATION: Nucleus
GO:0005829 cytosol
IEA
GO_REF:0000044 		ACCEPT
Summary: Cytosolic localization is consistent with TCF25's role in the 60S-associated RQC complex.
Reason: Correct compartment for the RQC function; UniProt also records Cytoplasm, cytosol experimentally (PMID:18068114).
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Cytoplasm, cytosol
GO:0005515 protein binding
IPI
PMID:16189514
Towards a proteome-scale map of the human protein-protein in... 		KEEP AS NON CORE
Summary: High-throughput interactome (CCSB) capturing a TCF25 interaction. Bare protein binding is uninformative.
Reason: Records a real interaction but the generic protein binding term is uninformative and the partners do not define TCF25's core RQC function; per guidelines not elevated to core.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Q9BQ70; P21673: SAT1
GO:0005515 protein binding
IPI
PMID:19060904
An empirical framework for binary interactome mapping. 		KEEP AS NON CORE
Summary: High-throughput binary interactome mapping capturing a TCF25 interaction. Bare protein binding is uninformative.
Reason: Real interaction but uninformative term; not part of the core RQC function.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Q9BQ70; P21673: SAT1
GO:0005515 protein binding
IPI
PMID:21516116
Next-generation sequencing to generate interactome datasets. 		KEEP AS NON CORE
Summary: Next-generation interactome dataset capturing a TCF25 interaction. Bare protein binding is uninformative.
Reason: Real interaction but uninformative term; not part of the core RQC function.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Q9BQ70; P21673: SAT1
GO:0005515 protein binding
IPI
PMID:24947832
Differential protein-protein interactions of LRRK1 and LRRK2... 		KEEP AS NON CORE
Summary: LRRK1/LRRK2 interaction study capturing a TCF25-LRRK2 interaction. Bare protein binding is uninformative.
Reason: Real interaction (LRRK2, Q5S007) but uninformative term; not part of the core RQC function.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Q9BQ70; Q5S007: LRRK2
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		KEEP AS NON CORE
Summary: Proteome-scale interactome map capturing TCF25 interactions. Bare protein binding is uninformative.
Reason: Real interactions but uninformative term; not part of the core RQC function.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Q9BQ70; P43364: MAGEA11
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		KEEP AS NON CORE
Summary: Interactome architecture study capturing a TCF25-GPRASP2 interaction. Bare protein binding is uninformative.
Reason: Real interaction (GPRASP2, Q96D09) but uninformative term; not core.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Q9BQ70; Q96D09: GPRASP2
GO:0005515 protein binding
IPI
PMID:31046837
Parkinson's disease-associated LRRK2-G2019S mutant acts thro... 		KEEP AS NON CORE
Summary: LRRK2-G2019S regulation study capturing a TCF25-LRRK2 interaction. Bare protein binding is uninformative.
Reason: Real interaction (LRRK2, Q5S007) but uninformative term; not core.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Q9BQ70; Q5S007: LRRK2
GO:0005515 protein binding
IPI
PMID:31515488
Extensive disruption of protein interactions by genetic vari... 		KEEP AS NON CORE
Summary: Variant-interactome perturbation study capturing TCF25 interactions. Bare protein binding is uninformative.
Reason: Real interactions but uninformative term; not core.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Q9BQ70; P43364: MAGEA11
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		KEEP AS NON CORE
Summary: HuRI reference binary interactome capturing TCF25 interactions. Bare protein binding is uninformative.
Reason: Real interactions but uninformative term; not core.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Q9BQ70; P21673: SAT1
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ... 		KEEP AS NON CORE
Summary: Neurodegeneration interactome capturing TCF25 interactions (KIF1B, WFS1). Bare protein binding is uninformative.
Reason: Real interactions but uninformative term; not core.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Q9BQ70; O76024: WFS1
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: BioPlex interactome capturing a TCF25-GPRASP2 interaction. Bare protein binding is uninformative.
Reason: Real interaction (GPRASP2, Q96D09) but uninformative term; not core.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Q9BQ70; Q96D09: GPRASP2
GO:0005515 protein binding
IPI
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human ce... 		KEEP AS NON CORE
Summary: OpenCell endogenous-tagging interactome capturing a TCF25-GPRASP2 interaction. Bare protein binding is uninformative.
Reason: Real interaction (GPRASP2, Q96D09) but uninformative term; not core.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Q9BQ70; Q96D09: GPRASP2
GO:0005829 cytosol
TAS
Reactome:R-HSA-9948318 		ACCEPT
Summary: Reactome curation of TCF25 cytosolic localization, consistent with its RQC role.
Reason: Correct compartment for the RQC function.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Cytoplasm, cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-9948362 		ACCEPT
Summary: Reactome curation of TCF25 cytosolic localization.
Reason: Correct compartment for the RQC function.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Cytoplasm, cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-9948427 		ACCEPT
Summary: Reactome curation of TCF25 cytosolic localization.
Reason: Correct compartment for the RQC function.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Cytoplasm, cytosol
GO:0005634 nucleus
EXP
PMID:16574069
hnulp1, a basic helix-loop-helix protein with a novel transc... 		KEEP AS NON CORE
Summary: Experimental evidence (hnulp1 characterization) for nuclear localization of TCF25. Real but peripheral to the characterized RQC molecular function.
Reason: Experimentally supported nuclear localization, but the mechanistically defined core function is cytoplasmic RQC; UniProt notes TCF25 is "Mainly nuclear", so this is retained as a genuine but non-core localization.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
SUBCELLULAR LOCATION: Nucleus
GO:0005634 nucleus
EXP
PMID:18068114
Nuclear localized protein-1 (Nulp1) increases cell death of ... 		KEEP AS NON CORE
Summary: Experimental evidence (Nulp1 osteosarcoma study) for nuclear localization of TCF25.
Reason: Experimentally supported nuclear localization; peripheral to the core cytoplasmic RQC function.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
SUBCELLULAR LOCATION: Nucleus
GO:0072344 rescue of stalled cytosolic ribosome
NAS
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria... 		ACCEPT
Summary: Review-based (ComplexPortal NAS) assertion of TCF25's RQC rescue role.
Reason: Consistent with the experimentally supported RQC function.
Supporting Evidence:
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria to humans
GO:1990112 RQC complex
NAS
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria... 		ACCEPT
Summary: Review-based (ComplexPortal NAS) assertion of TCF25 as an RQC complex subunit.
Reason: Consistent with experimentally demonstrated RQC complex membership.
Supporting Evidence:
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria to humans
GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process
NAS
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria... 		ACCEPT
Summary: Review-based (ComplexPortal NAS) assertion of TCF25's role in RQC ubiquitin- dependent catabolism.
Reason: Consistent with the experimentally supported process; TCF25 promotes the K48 chains that commit nascent chains to degradation.
Supporting Evidence:
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria to humans
GO:0061945 regulation of protein K48-linked ubiquitination
IDA
PMID:30244831
Release of Ubiquitinated and Non-ubiquitinated Nascent Chain... 		ACCEPT
Summary: TCF25 is required for preferential formation of K48-linked polyubiquitin chains on stalled nascent chains during RQC. This is its defining mechanistic contribution.
Reason: Directly demonstrated in mammalian RQC reconstitution; TCF25 ensures K48 linkage specificity of LTN1-mediated ubiquitination.
Supporting Evidence:
PMID:30244831
TCF25, a poorly characterized RQC component, ensures preferential formation of the K48-ubiquitin linkage
GO:0072344 rescue of stalled cytosolic ribosome
IDA
PMID:30244831
Release of Ubiquitinated and Non-ubiquitinated Nascent Chain... 		ACCEPT
Summary: TCF25 functions in the RQC pathway that resolves stalled ribosomes and degrades their nascent chains.
Reason: Directly demonstrated as part of the mammalian RQC pathway.
Supporting Evidence:
PMID:30244831
The ribosome-associated quality control (RQC) pathway degrades nascent chains (NCs) arising from interrupted translation
GO:1990112 RQC complex
IDA
PMID:30244831
Release of Ubiquitinated and Non-ubiquitinated Nascent Chain... 		ACCEPT
Summary: Direct evidence that TCF25 is a component of the mammalian RQC complex.
Reason: Core; experimentally demonstrated RQC complex membership.
Supporting Evidence:
file:human/TCF25/TCF25-uniprot.txt
Component of the ribosome quality control complex (RQC), composed of the E3 ubiquitin ligase LTN1, TCF25 and NEMF associated with the 60S ribosomal subunit

Core Functions

Accessory subunit of the ribosome quality control (RQC) complex that, together with LTN1 and NEMF on the stalled 60S subunit, is required to promote formation of Lys48- linked polyubiquitin chains during ubiquitination of incompletely synthesized nascent chains, committing them to proteasomal degradation.

In Complex:
RQC complex
Supporting Evidence:
  • PMID:30244831
    TCF25, a poorly characterized RQC component, ensures preferential formation of the K48-ubiquitin linkage
  • file:human/TCF25/TCF25-uniprot.txt
    required to promote formation of 'Lys-48'-linked polyubiquitin chains during ubiquitination of incompletely synthesized proteins by LTN1

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:16189514
Towards a proteome-scale map of the human protein-protein interaction network.
PMID:16574069
hnulp1, a basic helix-loop-helix protein with a novel transcriptional repressive domain, inhibits transcriptional activity of serum response factor.
  • Characterizes TCF25/hnulp1 as a mainly nuclear bHLH protein with a transcriptional repressive domain (legacy, pre-RQC function).
PMID:18068114
Nuclear localized protein-1 (Nulp1) increases cell death of human osteosarcoma cells and binds the X-linked inhibitor of apoptosis protein.
  • Reports TCF25/Nulp1 nuclear localization, a pro-cell-death effect, and XIAP binding (legacy, pre-RQC function).
PMID:19060904
An empirical framework for binary interactome mapping.
PMID:21516116
Next-generation sequencing to generate interactome datasets.
PMID:24947832
Differential protein-protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:30244831
Release of Ubiquitinated and Non-ubiquitinated Nascent Chains from Stalled Mammalian Ribosomal Complexes by ANKZF1 and Ptrh1.
  • TCF25 ensures preferential formation of the K48-ubiquitin linkage during RQC ubiquitination of stalled nascent chains by LTN1.
  • Defines the mammalian RQC pathway in which 60S RNCs associate with NEMF, which recruits Listerin to ubiquitinate nascent chains.
PMID:31046837
Parkinson's disease-associated LRRK2-G2019S mutant acts through regulation of SERCA activity to control ER stress in astrocytes.
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
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:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:35452614
Ribosome-associated quality-control mechanisms from bacteria to humans.
  • Review summarizing RQC including TCF25/Rqc1 as an RQC complex component.
Reactome:R-HSA-9948318
Reactome: TCF25 cytosol localization
Reactome:R-HSA-9948362
Reactome: TCF25 cytosol localization
Reactome:R-HSA-9948427
Reactome: TCF25 cytosol localization
file:human/TCF25/TCF25-uniprot.txt
UniProt entry Q9BQ70 (TCF25_HUMAN), Ribosome quality control complex subunit TCF25
  • RQC complex subunit (with LTN1 and NEMF on the 60S subunit) required to promote formation of K48-linked polyubiquitin chains during LTN1-mediated ubiquitination of incompletely synthesized nascent chains; also reported as a mainly nuclear protein (Nulp1/hnulp1) with legacy roles in transcriptional repression and cell death.

Suggested Questions for Experts

Q: How does TCF25 mechanistically enforce K48-linkage specificity of LTN1 during RQC - by positioning the E2, the substrate lysine, or the growing chain?

Q: Is the nuclear pool of TCF25/Nulp1 functionally distinct from its RQC role, and does it retain any genuine transcriptional or cell-death-regulatory activity in human cells?

Suggested Experiments

Experiment: Reconstitute LTN1-mediated nascent-chain ubiquitination with and without TCF25 and measure ubiquitin chain linkage composition (K48 vs other) by mass spectrometry to define TCF25's effect on chain specificity.

Experiment: Map the TCF25 region(s) required for RQC versus nuclear localization by domain deletion, and test whether RQC-defective TCF25 retains the legacy transcriptional/XIAP- binding activities.

📚 Additional Documentation

Notes

(TCF25-notes.md)

TCF25 (Ribosome quality control complex subunit TCF25; Nulp1/hnulp1) notes

UniProt: Q9BQ70 (TCF25_HUMAN). Despite the legacy name "Transcription Factor 25", TCF25 is
the human Rqc1-like subunit of the RQC complex. Also called Nulp1 (nuclear localized protein 1)
/ hnulp1. TCF25 family.

Core function

Component of the RQC complex (LTN1 + TCF25 + NEMF on the 60S subunit). TCF25 is required to
promote formation of K48-linked polyubiquitin chains during LTN1-mediated ubiquitination of
stalled nascent chains.

  • UniProt FUNCTION: "Component of the ribosome quality control complex (RQC) ... In the RQC
    complex, required to promote formation of 'Lys-48'-linked polyubiquitin chains during
    ubiquitination of incompletely synthesized proteins by LTN1 (PubMed:30244831)."
  • PMID:30244831
  • UniProt SUBUNIT: "Component of the ribosome quality control complex (RQC), composed of the
    E3 ubiquitin ligase LTN1, TCF25 and NEMF associated with the 60S ribosomal subunit
    (PubMed:30244831)."

RQC context (PMID:30244831)

"60S RNCs associate with NEMF, which recruits the E3 ubiquitin ligase Listerin that
ubiquitinates NCs ... TCF25 ... ensures preferential formation of the K48-ubiquitin linkage."
GO terms (IDA, PMID:30244831): GO:0061945 regulation of protein K48-linked ubiquitination;
GO:0072344 rescue of stalled cytosolic ribosome; GO:1990112 RQC complex.

Legacy nuclear / transcription / apoptosis roles

  • Named "hnulp1" / "Nulp1" - reported as a bHLH protein with a transcriptional repressive
    domain (PMID:16574069) and as a nuclear protein that increases cell death and binds XIAP
    (PMID:18068114). UniProt: "Mainly nuclear."
  • UniProt FUNCTION (By similarity): "May negatively regulate the calcineurin-NFAT signaling
    cascade by suppressing the activity of transcription factor NFATC4" and "May play a role in
    cell death control" - both By similarity, not human-experimentally established here.
  • Nucleus localization (EXP PMID:16574069, PMID:18068114; IEA) - well-supported localization
    but the functional core relevant to GO MF/BP is the RQC role. Keep nucleus as NON_CORE given
    the predominant characterized molecular role is cytoplasmic RQC; however nuclear localization
    is experimentally real (mainly nuclear per UniProt).

protein binding (IPI) annotations

All 14 IPI GO:0005515 annotations come from high-throughput interactome maps (Rual 2005, Venkatesan
2009, Yu 2011, Rolland 2014/HI-II-14, Luck 2020/HuRI, Huttlin BioPlex, OpenCell, neurodegeneration
interactome, LRRK1/2 interactome). WITH partners include SAT1 (P21673), MAGEA11 (P43364),
GPRASP2 (Q96D09), LRRK2 (Q5S007), DERL1 (Q9BUN8), GPX7, KASH5, KIF1B, WFS1, APPBP2. None of these
inform the core RQC function; bare "protein binding" is uninformative -> KEEP_AS_NON_CORE.

Localization caveat

UniProt: Nucleus (mainly nuclear) AND Cytoplasm, cytosol. The RQC role is cytosolic/60S-associated.
Cytosol IEA/TAS -> ACCEPT (site of RQC action). Nucleus -> KEEP_AS_NON_CORE.

Actions summary

  • Core: GO:1990112 RQC complex (part_of, IDA); GO:0061945 regulation of K48 ubiquitination (IDA);
    GO:0072344 rescue of stalled ribosome (IDA); GO:1990116 RQC catabolism (NAS).
  • Core MF: there is no specific MF annotation; TCF25's molecular role is as a RQC scaffold/cofactor
    promoting K48 chains. Best captured by the BP GO:0061945 + complex membership. Use core_functions
    with molecular_function = the most informative available term.
  • protein binding IPI x14 -> KEEP_AS_NON_CORE.
  • nucleus -> KEEP_AS_NON_CORE; cytosol -> ACCEPT.

Pn Notes

(TCF25-pn-notes.md)

TCF25 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9BQ70
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07c
  • Batch change status: added

Source Files Checked

Deep Research Files

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

AIGR Review Snapshot

  • Description: TCF25 (Ribosome quality control complex subunit TCF25; also known as Nulp1/hnulp1, "nuclear localized protein 1") is the human ortholog of the yeast RQC factor Rqc1 and a component of the ribosome-associated quality control (RQC) complex together with the E3 ubiquitin ligase LTN1/Listerin and NEMF on the stalled 60S ribosomal subunit. Within this complex TCF25 acts as an accessory factor required to promote formation of Lys48-linked polyubiquitin chains during LTN1-mediated ubiquitination of incompletely synthesized nascent chains, thereby ensuring efficient targeting of stalled translation products for proteasomal degradation. Despite the legacy "Transcription Factor 25" name, TCF25 has no demonstrated sequence-specific transcription-factor activity in this role; earlier work described it as a mainly nuclear basic-helix-loop-helix protein (Nulp1/hnulp1) with a transcriptional repressive domain and a role in cell-death control and XIAP binding. It is widely expressed with high levels in heart and, in the embryo, brain, and is found in both the nucleus and the cytosol.
  • Existing/core annotation action counts: ACCEPT: 11; KEEP_AS_NON_CORE: 15

PN Consistency Summary

  • Consistency: Excellent. Deep research/notes, review and PN concur: TCF25 (= yeast Rqc1 ortholog; legacy Nulp1/hnulp1) is an accessory subunit of the 60S RQC complex (LTN1 + NEMF + TCF25), required to promote K48-linked polyubiquitin chains during LTN1-mediated nascent-chain ubiquitination (PMID:30244831). The legacy bHLH "transcription factor"/XIAP/cell-death role is correctly demoted to non-core. PN's "other RQC processes" no_mapping is consistent with the review treating TCF25 as a cofactor/scaffold without a clean own-MF. No contradictions.
  • PN story / NEW pressure: GO:0006515 (verified real) is new_to_goa and absent from the review. The review instead uses GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process (NAS), GO:0061945 regulation of protein K48-linked ubiquitination (IDA), GO:0072344 (NAS/IDA) and GO:1990112 RQC complex (IDA/IBA/NAS). Verified via OLS: GO:1990116 sits in the catabolic-process branch (under GO:0006511), NOT under GO:0006515 — so GO:0006515 is a related but distinct higher-level QC-process term, a defensible ADD that better matches the canonical RQC framing. Conclude: function captured (via GO:0061945/GO:1990116/GO:1990112); GO:0006515 a reasonable additional/parent QC-process ADD.
  • Evidence alignment: PN row cites no PMIDs. Review's key evidence PMID:30244831 (K48 linkage role) + PMID:35452614 (RQC review, ComplexPortal NAS) is HIGH/VERIFIED. The 14 IPI protein-binding partners are all high-throughput, correctly non-core. No divergence.
  • Verdict: Fully consistent; function captured via GO:1990112/GO:0061945/GO:1990116; PN's GO:0006515 is a defensible additional QC-process ADD (distinct from the catabolic-branch GO:1990116). No YAML change needed.

Full Consistency Review

  • UniProt: Q9BQ70 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE (clean; core = RQC complex K48-chain cofactor, Nulp1 legacy non-core)
  • PN placement: 1 row — Translation|Cytosolic translation|Ribosome-associated QC|other RQC processes. PN-node mapping: RQC-type ("other RQC processes")→no_mapping (heterogeneous bucket); RQC-group→mapped GO:0006515 protein QC (new_to_goa); class/branch context_only. Projected: GO:0006515 (new) only.
  • Consistency: Excellent. Deep research/notes, review and PN concur: TCF25 (= yeast Rqc1 ortholog; legacy Nulp1/hnulp1) is an accessory subunit of the 60S RQC complex (LTN1 + NEMF + TCF25), required to promote K48-linked polyubiquitin chains during LTN1-mediated nascent-chain ubiquitination (PMID:30244831). The legacy bHLH "transcription factor"/XIAP/cell-death role is correctly demoted to non-core. PN's "other RQC processes" no_mapping is consistent with the review treating TCF25 as a cofactor/scaffold without a clean own-MF. No contradictions.
  • PN story / NEW pressure: GO:0006515 (verified real) is new_to_goa and absent from the review. The review instead uses GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process (NAS), GO:0061945 regulation of protein K48-linked ubiquitination (IDA), GO:0072344 (NAS/IDA) and GO:1990112 RQC complex (IDA/IBA/NAS). Verified via OLS: GO:1990116 sits in the catabolic-process branch (under GO:0006511), NOT under GO:0006515 — so GO:0006515 is a related but distinct higher-level QC-process term, a defensible ADD that better matches the canonical RQC framing. Conclude: function captured (via GO:0061945/GO:1990116/GO:1990112); GO:0006515 a reasonable additional/parent QC-process ADD.
  • Mapping strategy: Sound. The leaf "other RQC processes"→no_mapping (heterogeneous) is the right call; the only projection comes from the RQC-group→GO:0006515. TCF25 genuinely participates in protein QC of incompletely synthesized proteins, so GO:0006515 is appropriately scoped (not over-broad here, since TCF25 has no competing finer own-process term beyond the complex/regulation annotations). No node change.
  • Evidence alignment: PN row cites no PMIDs. Review's key evidence PMID:30244831 (K48 linkage role) + PMID:35452614 (RQC review, ComplexPortal NAS) is HIGH/VERIFIED. The 14 IPI protein-binding partners are all high-throughput, correctly non-core. No divergence.
  • Verdict: Fully consistent; function captured via GO:1990112/GO:0061945/GO:1990116; PN's GO:0006515 is a defensible additional QC-process ADD (distinct from the catabolic-branch GO:1990116). No YAML change needed.
  • Recommended edits: none required. [YAML] (optional) GO:0006515 protein quality control for misfolded or incompletely synthesized proteins could be added as an involved_in process term to better surface TCF25's RQC role (currently only catabolic/regulation/complex terms present); supported by PMID:30244831.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/TCF25/TCF25-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | other RQC processes

  • UniProt: Q9BQ70
  • In branches: TR
  • PN-node mapping records (path + ancestors):
    • [type] Translation|Cytosolic translation|Ribosome-associated QC|other RQC processes
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [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.

Projected GO annotations (1)

  • 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

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: Q9BQ70
gene_symbol: TCF25
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: TCF25 (Ribosome quality control complex subunit TCF25; also known as Nulp1/hnulp1, "nuclear localized protein 1") is the human ortholog of the yeast RQC factor Rqc1 and a component of the ribosome-associated quality control (RQC) complex together with the E3 ubiquitin ligase LTN1/Listerin and NEMF on the stalled 60S ribosomal subunit. Within this complex TCF25 acts as an accessory factor required to promote formation of Lys48-linked polyubiquitin chains during LTN1-mediated ubiquitination of incompletely synthesized nascent chains, thereby ensuring efficient targeting of stalled translation products for proteasomal degradation. Despite the legacy "Transcription Factor 25" name, TCF25 has no demonstrated sequence-specific transcription-factor activity in this role; earlier work described it as a mainly nuclear basic-helix-loop-helix protein (Nulp1/hnulp1) with a transcriptional repressive domain and a role in cell-death control and XIAP binding. It is widely expressed with high levels in heart and, in the embryo, brain, and is found in both the nucleus and the cytosol.
existing_annotations:
- term:
    id: GO:1990112
    label: RQC complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: TCF25 is a conserved subunit of the RQC complex (LTN1, TCF25, NEMF) on the 60S subunit, as inferred phylogenetically from the Rqc1/TCF25 family.
    action: ACCEPT
    reason: Directly demonstrated in human (PMID:30244831) and conserved across the family; TCF25 is a bona fide RQC complex component.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: Component of the ribosome quality control complex (RQC), composed of the E3 ubiquitin ligase LTN1, TCF25 and NEMF associated with the 60S ribosomal subunit
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: TCF25/Nulp1 is reported as mainly nuclear in earlier studies. While experimentally real, the nuclear pool is peripheral to its characterized molecular role in cytoplasmic RQC.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is experimentally supported (EXP PMID:16574069, PMID:18068114) and noted by UniProt as "Mainly nuclear", but the informative, mechanistically defined function (RQC K48 ubiquitination) occurs in the cytosol on the 60S subunit.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytosolic localization is consistent with TCF25's role in the 60S-associated RQC complex.
    action: ACCEPT
    reason: Correct compartment for the RQC function; UniProt also records Cytoplasm, cytosol experimentally (PMID:18068114).
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: High-throughput interactome (CCSB) capturing a TCF25 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction but the generic protein binding term is uninformative and the partners do not define TCF25's core RQC function; per guidelines not elevated to core.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'Q9BQ70; P21673: SAT1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19060904
  qualifier: enables
  review:
    summary: High-throughput binary interactome mapping capturing a TCF25 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction but uninformative term; not part of the core RQC function.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'Q9BQ70; P21673: SAT1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: Next-generation interactome dataset capturing a TCF25 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction but uninformative term; not part of the core RQC function.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'Q9BQ70; P21673: SAT1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24947832
  qualifier: enables
  review:
    summary: LRRK1/LRRK2 interaction study capturing a TCF25-LRRK2 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (LRRK2, Q5S007) but uninformative term; not part of the core RQC function.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'Q9BQ70; Q5S007: LRRK2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale interactome map capturing TCF25 interactions. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interactions but uninformative term; not part of the core RQC function.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'Q9BQ70; P43364: MAGEA11'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Interactome architecture study capturing a TCF25-GPRASP2 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (GPRASP2, Q96D09) but uninformative term; not core.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'Q9BQ70; Q96D09: GPRASP2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31046837
  qualifier: enables
  review:
    summary: LRRK2-G2019S regulation study capturing a TCF25-LRRK2 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (LRRK2, Q5S007) but uninformative term; not core.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'Q9BQ70; Q5S007: LRRK2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: Variant-interactome perturbation study capturing TCF25 interactions. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interactions but uninformative term; not core.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'Q9BQ70; P43364: MAGEA11'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: HuRI reference binary interactome capturing TCF25 interactions. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interactions but uninformative term; not core.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'Q9BQ70; P21673: SAT1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegeneration interactome capturing TCF25 interactions (KIF1B, WFS1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interactions but uninformative term; not core.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'Q9BQ70; O76024: WFS1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex interactome capturing a TCF25-GPRASP2 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (GPRASP2, Q96D09) but uninformative term; not core.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'Q9BQ70; Q96D09: GPRASP2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: OpenCell endogenous-tagging interactome capturing a TCF25-GPRASP2 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (GPRASP2, Q96D09) but uninformative term; not core.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'Q9BQ70; Q96D09: GPRASP2'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948318
  qualifier: located_in
  review:
    summary: Reactome curation of TCF25 cytosolic localization, consistent with its RQC role.
    action: ACCEPT
    reason: Correct compartment for the RQC function.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948362
  qualifier: located_in
  review:
    summary: Reactome curation of TCF25 cytosolic localization.
    action: ACCEPT
    reason: Correct compartment for the RQC function.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9948427
  qualifier: located_in
  review:
    summary: Reactome curation of TCF25 cytosolic localization.
    action: ACCEPT
    reason: Correct compartment for the RQC function.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:16574069
  qualifier: located_in
  review:
    summary: Experimental evidence (hnulp1 characterization) for nuclear localization of TCF25. Real but peripheral to the characterized RQC molecular function.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported nuclear localization, but the mechanistically defined core function is cytoplasmic RQC; UniProt notes TCF25 is "Mainly nuclear", so this is retained as a genuine but non-core localization.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:18068114
  qualifier: located_in
  review:
    summary: Experimental evidence (Nulp1 osteosarcoma study) for nuclear localization of TCF25.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported nuclear localization; peripheral to the core cytoplasmic RQC function.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: NAS
  original_reference_id: PMID:35452614
  qualifier: involved_in
  review:
    summary: Review-based (ComplexPortal NAS) assertion of TCF25's RQC rescue role.
    action: ACCEPT
    reason: Consistent with the experimentally supported RQC function.
    supported_by:
    - reference_id: PMID:35452614
      supporting_text: Ribosome-associated quality-control mechanisms from bacteria to humans
- term:
    id: GO:1990112
    label: RQC complex
  evidence_type: NAS
  original_reference_id: PMID:35452614
  qualifier: part_of
  review:
    summary: Review-based (ComplexPortal NAS) assertion of TCF25 as an RQC complex subunit.
    action: ACCEPT
    reason: Consistent with experimentally demonstrated RQC complex membership.
    supported_by:
    - reference_id: PMID:35452614
      supporting_text: Ribosome-associated quality-control mechanisms from bacteria to humans
- term:
    id: GO:1990116
    label: ribosome-associated ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:35452614
  qualifier: involved_in
  review:
    summary: Review-based (ComplexPortal NAS) assertion of TCF25's role in RQC ubiquitin- dependent catabolism.
    action: ACCEPT
    reason: Consistent with the experimentally supported process; TCF25 promotes the K48 chains that commit nascent chains to degradation.
    supported_by:
    - reference_id: PMID:35452614
      supporting_text: Ribosome-associated quality-control mechanisms from bacteria to humans
- term:
    id: GO:0061945
    label: regulation of protein K48-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:30244831
  qualifier: involved_in
  review:
    summary: TCF25 is required for preferential formation of K48-linked polyubiquitin chains on stalled nascent chains during RQC. This is its defining mechanistic contribution.
    action: ACCEPT
    reason: Directly demonstrated in mammalian RQC reconstitution; TCF25 ensures K48 linkage specificity of LTN1-mediated ubiquitination.
    supported_by:
    - reference_id: PMID:30244831
      supporting_text: TCF25, a poorly characterized RQC component, ensures preferential formation of the K48-ubiquitin linkage
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:30244831
  qualifier: involved_in
  review:
    summary: TCF25 functions in the RQC pathway that resolves stalled ribosomes and degrades their nascent chains.
    action: ACCEPT
    reason: Directly demonstrated as part of the mammalian RQC pathway.
    supported_by:
    - reference_id: PMID:30244831
      supporting_text: The ribosome-associated quality control (RQC) pathway degrades nascent chains (NCs) arising from interrupted translation
- term:
    id: GO:1990112
    label: RQC complex
  evidence_type: IDA
  original_reference_id: PMID:30244831
  qualifier: part_of
  review:
    summary: Direct evidence that TCF25 is a component of the mammalian RQC complex.
    action: ACCEPT
    reason: Core; experimentally demonstrated RQC complex membership.
    supported_by:
    - reference_id: file:human/TCF25/TCF25-uniprot.txt
      supporting_text: Component of the ribosome quality control complex (RQC), composed of the E3 ubiquitin ligase LTN1, TCF25 and NEMF associated with the 60S ribosomal subunit
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of an IPI protein binding annotation. Not informative for TCF25's core RQC function.
- id: PMID:16574069
  title: hnulp1, a basic helix-loop-helix protein with a novel transcriptional repressive domain, inhibits transcriptional activity of serum response factor.
  full_text_unavailable: true
  findings:
  - statement: Characterizes TCF25/hnulp1 as a mainly nuclear bHLH protein with a transcriptional repressive domain (legacy, pre-RQC function).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Legacy "transcription factor" characterization; supports nuclear localization but not the core RQC molecular function.
- id: PMID:18068114
  title: Nuclear localized protein-1 (Nulp1) increases cell death of human osteosarcoma cells and binds the X-linked inhibitor of apoptosis protein.
  full_text_unavailable: true
  findings:
  - statement: Reports TCF25/Nulp1 nuclear localization, a pro-cell-death effect, and XIAP binding (legacy, pre-RQC function).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Legacy characterization supporting nuclear localization; peripheral to the core RQC function.
- id: PMID:19060904
  title: An empirical framework for binary interactome mapping.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; uninformative protein binding annotation.
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; uninformative protein binding annotation.
- id: PMID:24947832
  title: Differential protein-protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: LRRK1/2 interactome; TCF25-LRRK2 interaction not informative for the core RQC function.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; uninformative protein binding annotation.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; uninformative protein binding annotation.
- id: PMID:30244831
  title: Release of Ubiquitinated and Non-ubiquitinated Nascent Chains from Stalled Mammalian Ribosomal Complexes by ANKZF1 and Ptrh1.
  findings:
  - statement: TCF25 ensures preferential formation of the K48-ubiquitin linkage during RQC ubiquitination of stalled nascent chains by LTN1.
    reference_section_type: ABSTRACT
  - statement: Defines the mammalian RQC pathway in which 60S RNCs associate with NEMF, which recruits Listerin to ubiquitinate nascent chains.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Key paper establishing TCF25's mechanistic role (K48 linkage) in mammalian RQC.
- id: PMID:31046837
  title: Parkinson's disease-associated LRRK2-G2019S mutant acts through regulation of SERCA activity to control ER stress in astrocytes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: LRRK2-focused interactome; TCF25-LRRK2 interaction not informative for the core RQC function.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput variant-interactome; uninformative protein binding annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI interactome; uninformative protein binding annotation.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Neurodegeneration interactome; uninformative protein binding annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex interactome; uninformative protein binding annotation.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: OpenCell interactome; uninformative protein binding annotation.
- id: PMID:35452614
  title: Ribosome-associated quality-control mechanisms from bacteria to humans.
  findings:
  - statement: Review summarizing RQC including TCF25/Rqc1 as an RQC complex component.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Authoritative RQC review used by ComplexPortal for NAS annotations.
- id: Reactome:R-HSA-9948318
  title: 'Reactome: TCF25 cytosol localization'
  findings: []
- id: Reactome:R-HSA-9948362
  title: 'Reactome: TCF25 cytosol localization'
  findings: []
- id: Reactome:R-HSA-9948427
  title: 'Reactome: TCF25 cytosol localization'
  findings: []
- id: file:human/TCF25/TCF25-uniprot.txt
  title: UniProt entry Q9BQ70 (TCF25_HUMAN), Ribosome quality control complex subunit TCF25
  findings:
  - statement: RQC complex subunit (with LTN1 and NEMF on the 60S subunit) required to promote formation of K48-linked polyubiquitin chains during LTN1-mediated ubiquitination of incompletely synthesized nascent chains; also reported as a mainly nuclear protein (Nulp1/hnulp1) with legacy roles in transcriptional repression and cell death.
    reference_section_type: OTHER
core_functions:
- description: Accessory subunit of the ribosome quality control (RQC) complex that, together with LTN1 and NEMF on the stalled 60S subunit, is required to promote formation of Lys48- linked polyubiquitin chains during ubiquitination of incompletely synthesized nascent chains, committing them to proteasomal degradation.
  contributes_to_molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  in_complex:
    id: GO:1990112
    label: RQC complex
  supported_by:
  - reference_id: PMID:30244831
    supporting_text: TCF25, a poorly characterized RQC component, ensures preferential formation of the K48-ubiquitin linkage
  - reference_id: file:human/TCF25/TCF25-uniprot.txt
    supporting_text: required to promote formation of 'Lys-48'-linked polyubiquitin chains during ubiquitination of incompletely synthesized proteins by LTN1
proposed_new_terms: []
suggested_questions:
- question: How does TCF25 mechanistically enforce K48-linkage specificity of LTN1 during RQC - by positioning the E2, the substrate lysine, or the growing chain?
- question: Is the nuclear pool of TCF25/Nulp1 functionally distinct from its RQC role, and does it retain any genuine transcriptional or cell-death-regulatory activity in human cells?
suggested_experiments:
- description: Reconstitute LTN1-mediated nascent-chain ubiquitination with and without TCF25 and measure ubiquitin chain linkage composition (K48 vs other) by mass spectrometry to define TCF25's effect on chain specificity.
- description: Map the TCF25 region(s) required for RQC versus nuclear localization by domain deletion, and test whether RQC-defective TCF25 retains the legacy transcriptional/XIAP- binding activities.