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.
| 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 |
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Download this section (compressed HTML)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?
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.
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