id: P20290 gene_symbol: BTF3 product_type: PROTEIN aliases: - NACB status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- BTF3 encodes the beta subunit of the nascent polypeptide-associated complex (NAC), a conserved ribosome-associated factor that helps sort emerging nascent chains and prevents inappropriate SRP-dependent delivery of non-secretory proteins to the ER. Human BTF3 is also reported in the nucleus and retains legacy transcription-factor literature, but its best-supported core role is cytoplasmic cotranslational nascent-peptide handling rather than broad transcriptional regulation. alternative_products: - name: 1 (BTF3a) id: P20290-1 - name: 2 (BTF3b) id: P20290-2 sequence_note: VSP_013587 existing_annotations: - term: id: GO:0005854 label: nascent polypeptide-associated complex evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: Conserved NAC-complex membership is strongly supported for human BTF3 and matches the PN NAC-component placement. action: ACCEPT reason: BTF3 is the human NAC-beta subunit; orthology-based propagation is consistent with direct human structural and UniProt evidence that BTF3 heterodimerizes with NACA in the nascent polypeptide-associated complex. supported_by: - reference_id: file:human/BTF3/BTF3-notes.md supporting_text: BTF3/P20290 is the human NAC-beta subunit and the NAC heterodimer associates with ribosomes through BTF3. - reference_id: file:human/BTF3/BTF3-deep-research-falcon.md supporting_text: human BTF3 (Basic Transcription Factor 3), which is also known as NAC-beta / NACB - term: id: GO:0005829 label: cytosol evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: Cytosolic localization is consistent with the conserved ribosome-associated NAC role. action: ACCEPT reason: The propagated cytosol annotation is supported by direct human localization evidence and by the fact that the NACA-BTF3 heterodimer acts on nascent chains emerging from cytosolic ribosomes. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18433331 review: summary: The SARS nsp10 interaction paper supports a context-specific physical association, but protein binding is too generic to retain as a useful core MF annotation. action: MARK_AS_OVER_ANNOTATED reason: The underlying study describes a specific viral-interaction context rather than a distinctive molecular function for BTF3; retaining generic protein binding would add little beyond an undifferentiated interaction claim. supported_by: - reference_id: PMID:18433331 supporting_text: we co-immunoprecipitated HEPIS with BTF3, a component of the RNA pol II initiation complex - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 review: summary: A large-scale interactome map supports association data but not an informative BTF3-specific MF term. action: MARK_AS_OVER_ANNOTATED reason: Proteome-scale interactome resources can justify partner lists, but generic protein binding is discouraged and does not capture the PN-relevant NAC biology. This PMID contributes two GOA interaction rows for distinct partners (TXLNA and TXLNB), but both claims reduce to the same non-informative generic binding assertion for BTF3. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 review: summary: The BioPlex-style AP-MS network supports physical association but not a specific core MF for BTF3. action: MARK_AS_OVER_ANNOTATED reason: This is another large-scale interaction dataset; it does not define a distinctive BTF3 molecular activity and is better treated as background association evidence than as GO protein binding. - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 review: summary: Nuclear localization is plausible and supported by UniProt, but it is not the PN-core role for BTF3. action: KEEP_AS_NON_CORE reason: Human BTF3 is reported in the nucleus, yet UniProt explicitly notes that the NACA heterodimer is cytoplasmic. The nuclear/transcriptional side of BTF3 should therefore be preserved as contextual rather than elevated to core proteostasis biology. supported_by: - reference_id: file:human/BTF3/BTF3-notes.md supporting_text: UniProt also reports BTF3 in both cytoplasm and nucleus, while noting that the heterodimer with NACA is cytoplasmic. - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 review: summary: Cytoplasmic localization is consistent with the NAC heterodimer and nascent-chain handling role. action: ACCEPT reason: UniProt and experimental evidence both place BTF3 in the cytoplasm, which is the appropriate compartment for the NAC-dependent nascent-chain sorting function. - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 review: summary: Human Protein Atlas immunofluorescence supports cytosolic localization. action: ACCEPT reason: Direct localization evidence is consistent with BTF3 acting on ribosome-emergent nascent chains in the cytosolic translation environment. - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:10982809 review: summary: The NAC functional paper directly supports cytoplasmic localization. action: ACCEPT reason: PMID:10982809, as summarized in UniProt, places BTF3 in the cytoplasm and ties that location to the cytoplasmic NACA-BTF3 heterodimer. - term: id: GO:1905551 label: negative regulation of protein localization to endoplasmic reticulum evidence_type: IDA original_reference_id: PMID:10982809 review: summary: This term captures the PN-relevant NAC role and is supported by the curated human literature summary. action: ACCEPT reason: PMID:10982809 reports that both NAC subunits contribute to preventing inappropriate nascent-chain interactions and that betaNAC alone directly binds the ribosome and is sufficient to prevent ribosome binding to the ER membrane. That supports assigning this ER-targeting control process to BTF3 as the NAC-beta complex component in human. supported_by: - reference_id: PMID:10982809 supporting_text: both subunits are in direct contact with nascent polypeptide chains on the ribosome and that both contribute to the prevention of inappropriate interactions. However, betaNAC alone directly binds to the ribosome and is sufficient to prevent ribosome binding to the endoplasmic reticulum membrane. - reference_id: file:human/BTF3/BTF3-deep-research-falcon.md supporting_text: BTF3-NACA binding prevents inappropriate targeting of non-secretory nascent polypeptides from ribosomes to the ER - term: id: GO:0043022 label: ribosome binding evidence_type: IDA original_reference_id: PMID:10982809 review: summary: New annotation for BTF3's direct ribosome-binding molecular function. The Beatrix et al. abstract explicitly assigns ribosome binding to betaNAC, which fills the main missing MF gap in the current GOA. action: NEW reason: PMID:10982809 directly supports ribosome binding by the BTF3/NAC-beta subunit. This is a core MF for human BTF3 and is more specific and informative than the generic protein-binding annotations already reviewed. supported_by: - reference_id: PMID:10982809 supporting_text: However, betaNAC alone directly binds to the ribosome and is sufficient to prevent ribosome binding to the endoplasmic reticulum membrane. - reference_id: file:human/BTF3/BTF3-uniprot.txt supporting_text: NAC associates with ribosomes through the BTF3/NACB subunit. - reference_id: file:human/BTF3/BTF3-deep-research-falcon.md supporting_text: NAC is positioned at the ribosome exit tunnel and BTF3’s N-terminal tail extends into the tunnel - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:30242148 review: summary: The Connexin-43 paper supports a contextual transcription-related interaction, but protein binding remains too generic for GO curation. action: MARK_AS_OVER_ANNOTATED reason: PMID:30242148 is useful for contextual nuclear/transcription-related biology, not for defining a core BTF3 molecular function. Generic protein binding obscures that distinction. supported_by: - reference_id: file:human/BTF3/BTF3-notes.md supporting_text: PMID:30242148 supports a contextual transcription-related interaction for BTF3 rather than the PN core role. - term: id: GO:0005634 label: nucleus evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: Orthology-based nuclear localization is plausible but should remain non-core. action: KEEP_AS_NON_CORE reason: The propagated nucleus annotation is not contradicted, but the strongest proteostasis evidence for BTF3 concerns the cytoplasmic NAC heterodimer. Nuclear presence is better retained as secondary context. - term: id: GO:0003723 label: RNA binding evidence_type: HDA original_reference_id: PMID:22658674 review: summary: Global mRNA-interactome capture is insufficient here to establish a specific core RNA-binding function for BTF3. action: MARK_AS_OVER_ANNOTATED reason: The accessible evidence shows BTF3 was recovered in a broad high-throughput RBP atlas, but that does not distinguish direct RNA recognition from indirect ribosome- or mRNP-associated capture. The term is therefore too strong as a standalone MF annotation. supported_by: - reference_id: file:human/BTF3/BTF3-notes.md supporting_text: The large-scale RNA interactome and protein-interactome papers support association calls but do not, from the accessible text here, define a specific core molecular function beyond NAC-linked nascent-chain handling. - term: id: GO:0003723 label: RNA binding evidence_type: HDA original_reference_id: PMID:22681889 review: summary: The second interactome-capture paper has the same limitation as the Cell 2012 study for BTF3. action: MARK_AS_OVER_ANNOTATED reason: Recovery in a global mRNA-bound proteome dataset does not by itself establish a well-defined, conserved RNA-binding molecular function for BTF3. references: - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity. 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, accompanied by conservative changes to GO terms applied by UniProt. findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: PMID:10982809 title: The alpha and beta subunit of the nascent polypeptide-associated complex have distinct functions. findings: [] - id: PMID:18433331 title: Identification of a novel transcriptional repressor (HEPIS) that interacts with nsp-10 of SARS coronavirus. findings: [] - id: PMID:21203952 title: Crystal structures of NAC domains of human nascent polypeptide-associated complex (NAC) and its alphaNAC subunit. findings: [] - id: PMID:22658674 title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. findings: [] - id: PMID:22681889 title: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. findings: [] - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] - id: PMID:30242148 title: Gap junction protein Connexin-43 is a direct transcriptional regulator of N-cadherin in vivo. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: file:human/BTF3/BTF3-notes.md title: Curator notes on human BTF3 review findings: [] - id: file:human/BTF3/BTF3-uniprot.txt title: UniProt entry for human BTF3 (P20290) findings: [] - id: file:human/BTF3/BTF3-deep-research-falcon.md title: Falcon deep research report for BTF3 findings: - statement: Falcon research supports BTF3 as the NAC-beta subunit, a ribosome-associated nascent-chain triage factor that prevents inappropriate ER targeting of non-secretory nascent proteins. supporting_text: BTF3 is mechanistically anchored in ribosome biology through its identity as NAC-beta core_functions: - description: BTF3 is the beta subunit of the nascent polypeptide-associated complex (NAC). As a ribosome-associated component of the NACA-BTF3 heterodimer, it participates in cotranslational nascent-chain sorting and helps prevent inappropriate SRP-mediated delivery of non-secretory nascent polypeptides to the ER. molecular_function: id: GO:0043022 label: ribosome binding directly_involved_in: - id: GO:1905551 label: negative regulation of protein localization to endoplasmic reticulum locations: - id: GO:0005829 label: cytosol in_complex: id: GO:0005854 label: nascent polypeptide-associated complex supported_by: - reference_id: PMID:10982809 supporting_text: However, betaNAC alone directly binds to the ribosome and is sufficient to prevent ribosome binding to the endoplasmic reticulum membrane. - reference_id: file:human/BTF3/BTF3-uniprot.txt supporting_text: NAC associates with ribosomes through the BTF3/NACB subunit. - reference_id: file:human/BTF3/BTF3-deep-research-falcon.md supporting_text: BTF3 is mechanistically anchored in ribosome biology through its identity as NAC-beta - reference_id: file:human/BTF3/BTF3-deep-research-falcon.md supporting_text: BTF3-NACA binding prevents inappropriate targeting of non-secretory nascent polypeptides from ribosomes to the ER proposed_new_terms: [] suggested_questions: - question: Do human BTF3 isoforms partition NAC-linked cotranslational function versus contextual nuclear/transcription-related roles? - question: Is the reported RNA binding of human BTF3 direct, or does it mainly reflect indirect capture through ribosome- or mRNP-associated proximity? suggested_experiments: - description: Isoform-resolved complementation after BTF3 depletion, measuring NAC assembly, ribosome association, and mistargeting of non-secretory reporters to the ER. experiment_type: cell biology and rescue assay - description: Orthogonal RNA-binding assays such as eCLIP or UV-crosslinking with ribosome disruption controls to test whether BTF3 directly binds RNA outside the NAC/ribosome context. experiment_type: RNA-binding validation - description: Acute perturbation of BTF3 followed by ribosome profiling or SRP-engagement assays on secretory versus non-secretory nascent chains. experiment_type: cotranslational targeting assay