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.