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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005854
nascent polypeptide-associated complex
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Conserved NAC-complex membership is strongly supported for human BTF3 and matches the PN NAC-component placement.
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.
Supporting Evidence:
file:human/BTF3/BTF3-notes.md
BTF3/P20290 is the human NAC-beta subunit and the NAC heterodimer associates with ribosomes through BTF3.
file:human/BTF3/BTF3-deep-research-falcon.md
human BTF3 (Basic Transcription Factor 3), which is also known as NAC-beta / NACB
|
|
GO:0005829
cytosol
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Cytosolic localization is consistent with the conserved ribosome-associated NAC role.
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.
|
|
GO:0005515
protein binding
|
IPI
PMID:18433331 Identification of a novel transcriptional repressor (HEPIS) ... |
MARK AS OVER ANNOTATED |
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.
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.
Supporting Evidence:
PMID:18433331
we co-immunoprecipitated HEPIS with BTF3, a component of the RNA pol II initiation complex
|
|
GO:0005515
protein binding
|
IPI
PMID:25416956 A proteome-scale map of the human interactome network. |
MARK AS OVER ANNOTATED |
Summary: A large-scale interactome map supports association data but not an informative BTF3-specific MF term.
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.
|
|
GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
MARK AS OVER ANNOTATED |
Summary: The BioPlex-style AP-MS network supports physical association but not a specific core MF for BTF3.
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.
|
|
GO:0005634
nucleus
|
IEA
GO_REF:0000044 |
KEEP AS NON CORE |
Summary: Nuclear localization is plausible and supported by UniProt, but it is not the PN-core role for BTF3.
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.
Supporting Evidence:
file:human/BTF3/BTF3-notes.md
UniProt also reports BTF3 in both cytoplasm and nucleus, while noting that the heterodimer with NACA is cytoplasmic.
|
|
GO:0005737
cytoplasm
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: Cytoplasmic localization is consistent with the NAC heterodimer and nascent-chain handling role.
Reason: UniProt and experimental evidence both place BTF3 in the cytoplasm, which is the appropriate compartment for the NAC-dependent nascent-chain sorting function.
|
|
GO:0005829
cytosol
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: Human Protein Atlas immunofluorescence supports cytosolic localization.
Reason: Direct localization evidence is consistent with BTF3 acting on ribosome-emergent nascent chains in the cytosolic translation environment.
|
|
GO:0005737
cytoplasm
|
IDA
PMID:10982809 The alpha and beta subunit of the nascent polypeptide-associ... |
ACCEPT |
Summary: The NAC functional paper directly supports cytoplasmic localization.
Reason: PMID:10982809, as summarized in UniProt, places BTF3 in the cytoplasm and ties that location to the cytoplasmic NACA-BTF3 heterodimer.
|
|
GO:1905551
negative regulation of protein localization to endoplasmic reticulum
|
IDA
PMID:10982809 The alpha and beta subunit of the nascent polypeptide-associ... |
ACCEPT |
Summary: This term captures the PN-relevant NAC role and is supported by the curated human literature summary.
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.
Supporting Evidence:
PMID:10982809
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.
file:human/BTF3/BTF3-deep-research-falcon.md
BTF3-NACA binding prevents inappropriate targeting of non-secretory nascent polypeptides from ribosomes to the ER
|
|
GO:0043022
ribosome binding
|
IDA
PMID:10982809 The alpha and beta subunit of the nascent polypeptide-associ... |
NEW |
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.
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.
Supporting Evidence:
PMID:10982809
However, betaNAC alone directly binds to the ribosome and is sufficient to prevent ribosome binding to the endoplasmic reticulum membrane.
file:human/BTF3/BTF3-uniprot.txt
NAC associates with ribosomes through the BTF3/NACB subunit.
file:human/BTF3/BTF3-deep-research-falcon.md
NAC is positioned at the ribosome exit tunnel and BTF3’s N-terminal tail extends into the tunnel
|
|
GO:0005515
protein binding
|
IPI
PMID:30242148 Gap junction protein Connexin-43 is a direct transcriptional... |
MARK AS OVER ANNOTATED |
Summary: The Connexin-43 paper supports a contextual transcription-related interaction, but protein binding remains too generic for GO curation.
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.
Supporting Evidence:
file:human/BTF3/BTF3-notes.md
PMID:30242148 supports a contextual transcription-related interaction for BTF3 rather than the PN core role.
|
|
GO:0005634
nucleus
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Orthology-based nuclear localization is plausible but should remain 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.
|
|
GO:0003723
RNA binding
|
HDA
PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... |
MARK AS OVER ANNOTATED |
Summary: Global mRNA-interactome capture is insufficient here to establish a specific core RNA-binding function for BTF3.
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.
Supporting Evidence:
file:human/BTF3/BTF3-notes.md
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.
|
|
GO:0003723
RNA binding
|
HDA
PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... |
MARK AS OVER ANNOTATED |
Summary: The second interactome-capture paper has the same limitation as the Cell 2012 study for BTF3.
Reason: Recovery in a global mRNA-bound proteome dataset does not by itself establish a well-defined, conserved RNA-binding molecular function for BTF3.
|
Q: Do human BTF3 isoforms partition NAC-linked cotranslational function versus contextual nuclear/transcription-related roles?
Q: Is the reported RNA binding of human BTF3 direct, or does it mainly reflect indirect capture through ribosome- or mRNP-associated proximity?
Experiment: Isoform-resolved complementation after BTF3 depletion, measuring NAC assembly, ribosome association, and mistargeting of non-secretory reporters to the ER.
Type: cell biology and rescue assay
Experiment: 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.
Type: RNA-binding validation
Experiment: Acute perturbation of BTF3 followed by ribosome profiling or SRP-engagement assays on secretory versus non-secretory nascent chains.
Type: cotranslational targeting assay
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The literature synthesized below pertains to human BTF3 (Basic Transcription Factor 3), which is also known as NAC-beta / NACB, the beta subunit of the nascent polypeptide-associated complex (NAC). Multiple peer-reviewed sources explicitly equate BTF3 = NAC-beta/NACB and describe the complex as a heterodimer with NACA (NAC-alpha), matching the UniProt description and NAC-beta family/domain context. (zheng2022thenascentpolypeptideassociated pages 1-2, wang2021molecularcharacterizationof pages 1-2)
NAC (nascent polypeptide-associated complex) is a ribosome-associated complex positioned at/near the ribosome exit tunnel and composed of NACA (alpha) and BTF3/NACB (beta). Structural evidence discussed in a high-quality mechanistic study places the BTF3 N-terminal tail within the exit tunnel, supporting a direct physical relationship between BTF3-containing NAC and emerging nascent chains. (zheng2022thenascentpolypeptideassociated pages 1-2)
NAC/BTF3 is described as interacting with short nascent peptide sequences, “escorting” emerging chains, and modulating how nascent chains engage other ribosome-associated factors such as signal recognition particle (SRP) and methionine aminopeptidase; NAC also has described chaperone/anti-aggregation functions. (zheng2022thenascentpolypeptideassociated pages 1-2)
A representative schematic showing NAC associated with a translating ribosome and the tunnel-proximal NAC tail is available (Figure schematic) and supports this spatial model of NAC action at the exit tunnel. (zheng2022thenascentpolypeptideassociated media 2bfdbb98)
BTF3 has also been described as a transcription factor that can initiate transcription via promoter elements, with isoform-specific activity (BTF3a transcriptionally active; BTF3b inactive) in prior literature summarized in a mechanistic cancer study. (wang2021molecularcharacterizationof pages 1-2)
In colorectal cancer mechanistic work, BTF3 was directly studied both as a transcription factor and as part of the NAC complex; this dual framing is consistent with broad evidence that BTF3 can participate in nuclear transcriptional regulation while also being a ribosome-associated NAC subunit. (wang2021molecularcharacterizationof pages 2-4)
Ribosome-associated localization (NAC role). NAC is described as being present at the ribosome exit tunnel with structural placement of the BTF3 tail in the tunnel, directly implying a primarily cytosolic ribosome-associated functional context for BTF3 in its NAC role. (zheng2022thenascentpolypeptideassociated pages 1-2)
Evidence consistent with ribosome/ER targeting functions. In a colorectal cancer study using BTF3 immunoprecipitation-mass spectrometry (IP–MS), gene ontology enrichments among BTF3-associated proteins included cytosolic ribosome and protein targeting to the ER, consistent with established NAC functions in cotranslational triage and targeting control. (wang2021molecularcharacterizationof pages 6-7)
Nuclear/transcriptional role. The same colorectal cancer work investigated BTF3 transcriptional targets using combined RNA-seq + ChIP-seq and targeted ChIP assays, supporting a nuclear mode of action for at least a subset of BTF3 function in that context. (wang2021molecularcharacterizationof pages 2-4)
BTF3–NACA interaction (NAC heterodimer). In colorectal cancer work, BTF3 is explicitly treated as a NAC subunit, and NACA was identified as a BTF3-binding partner in BTF3 IP–MS. (wang2021molecularcharacterizationof pages 6-7)
Broad interaction landscape. BTF3 IP–MS identified 542 BTF3-associated proteins, and enrichment analyses spanned ribosomal/ER-targeting annotations as well as nuclear/DNA-binding-associated annotations, supporting a multi-compartment functional footprint in cancer cell contexts. (wang2021molecularcharacterizationof pages 6-7)
Cotranslational quality control / nascent-chain triage. NAC/BTF3 is described as interacting with nascent peptides and shielding them from proteolysis or inappropriate interactions, and modulating interactions with SRP and other ribosome-associated factors. (zheng2022thenascentpolypeptideassociated pages 1-2)
Translation initiation regulation in cis. A mechanistic NAC study reports that NAC controls translation initiation in cis (via nucleolin recruitment mechanisms), linking the BTF3-containing NAC complex to translational regulation rather than only cotranslational chaperoning. (zheng2022thenascentpolypeptideassociated pages 8-8, zheng2022thenascentpolypeptideassociated pages 1-2)
ER targeting prevention. Prior work summarized in colorectal cancer mechanistic context states that binding of BTF3 with NACA helps prevent inappropriate targeting of non-secretory nascent polypeptides to the ER. (wang2021molecularcharacterizationof pages 1-2)
A 2023 peer-reviewed study in Cancer Biology & Therapy (June 2023; https://doi.org/10.1080/15384047.2023.2225884) reports BTF3 upregulation in HCC and presents functional evidence that BTF3 promotes proliferation and glycolysis via a FOXM1/GLUT1 axis. BTF3 knockdown reduced proliferation and multiple glycolysis-associated readouts (e.g., ECAR, glucose consumption, lactate production), and FOXM1 overexpression rescued these effects; a direct interaction between BTF3 and FOXM1 was supported by luciferase and co-IP assays. (wang2023btf3promotesproliferation pages 1-2, wang2023btf3promotesproliferation pages 2-3)
A 2024 peer-reviewed study in Molecular Medicine (December 2024; https://doi.org/10.1186/s10020-024-01044-x) reports that BTF3 is upregulated in HCC and that high BTF3 expression is associated with poorer prognosis based on TCGA and ICGC analyses (qualitative in accessible excerpts). Mechanistically, BTF3 is reported to transcriptionally upregulate PDCD2L, with PDCD2L restraining the p53 pathway, forming a proposed BTF3/PDCD2L/p53 axis. The study identifies 680 genes positively correlated with BTF3 using a correlation coefficient threshold > 0.5, and used ChIP/qRT-PCR and promoter luciferase assays to support promoter-level regulation. (kong2024btf3affectshepatocellular pages 1-2, kong2024btf3affectshepatocellular pages 12-13)
A 2024 peer-reviewed study in Clinical and Translational Medicine (January 2024; https://doi.org/10.1002/ctm2.1539) describes an epigenetic-to-inflammatory mechanism in APS models in which LINC01128 promotes formation of a BTF3/STAT3 complex, enhancing STAT3 phosphorylation, and (via p-STAT3 promoter binding) upregulating NLRP3 to drive pyroptosis/apoptosis programs. Evidence included RNA pull-down/mass spectrometry, RIP, ChIRP, co-IP, and ChIP-qPCR for promoter occupancy, with functional validation in THP-1 cells, primary monocytes, and a β2GPI-induced mouse model. (tan2024arid5b‐mediatedlinc01128epigenetically pages 1-3, tan2024arid5b‐mediatedlinc01128epigenetically pages 13-16, tan2024arid5b‐mediatedlinc01128epigenetically pages 6-8)
A 2024 peer-reviewed Journal of Personalized Medicine analysis (August 2024; https://doi.org/10.3390/jpm14080831) integrating proteomics and survival datasets in chronic lymphocytic leukemia (CLL) reports BTF3 among top upregulated proteins (listed within the top five). Kaplan–Meier analyses were performed; the authors state BTF3 “seems to affect survival only during the initial days of disease development” (no hazard ratio or p-value for BTF3 was present in retrieved excerpts). (mavridou2024integrativeanalysisof pages 7-10, mavridou2024integrativeanalysisof pages 5-7)
Across cancers, BTF3 is frequently assessed as an overexpressed gene/protein associated with disease progression, with mechanistic studies (e.g., HCC PDCD2L/p53; HCC FOXM1/GLUT1 glycolysis; CRC p53-regulatory hypotheses) providing biological rationale for its evaluation as a biomarker or target. (kong2024btf3affectshepatocellular pages 1-2, wang2023btf3promotesproliferation pages 1-2, wang2021molecularcharacterizationof pages 6-7)
However, in the retrieved excerpts, common clinical-performance statistics (AUC, hazard ratios with confidence intervals) were generally not available; therefore, this report refrains from asserting specific performance metrics beyond what is explicitly stated in accessible texts. (kong2024btf3affectshepatocellular pages 1-2, mavridou2024integrativeanalysisof pages 7-10)
A 2024 Scientific Reports study (December 2024; https://doi.org/10.1038/s41598-024-79789-y) examining dapivirine in MDA-MB-231 triple-negative breast cancer (TNBC) found BTF3 downregulation in proteomic profiling and linked this to potential effects on “stem-like” tumor cell populations; the authors proposed that limited bioavailability might be addressed using delivery strategies such as antibody–drug conjugates or nanoparticle approaches. Quantitatively, the proteomics table reported BTF3 downregulation with a fold-change of −1.8 (minus indicating downregulation). (patil2024multifacetedimpactof pages 13-14, patil2024multifacetedimpactof pages 7-10)
A consistent theme is that BTF3 is mechanistically anchored in ribosome biology through its identity as NAC-beta, with structural placement at the exit tunnel and direct nascent-chain engagement supporting a core role in cotranslational triage and translation-linked regulation. (zheng2022thenascentpolypeptideassociated pages 1-2)
In parallel, multiple cancer-mechanism studies operationalize BTF3 as a transcriptional regulator (ChIP-seq-defined targets; promoter luciferase; transcriptional upregulation of PDCD2L), indicating that in disease states BTF3’s functional readouts can be nuclear and promoter-centric. (wang2021molecularcharacterizationof pages 2-4, kong2024btf3affectshepatocellular pages 12-13)
One plausible synthesis—consistent with the evidence but not claiming more than the data support—is that BTF3 may exert context-dependent functions: as a constitutive NAC subunit at ribosomes and as a transcriptional regulator in specific cellular programs (especially cancer). (wang2021molecularcharacterizationof pages 6-7, zheng2022thenascentpolypeptideassociated pages 1-2)
The CRC IP–MS dataset’s 542 interactors and enrichment across ribosomal/ER-targeting and nuclear annotations suggest BTF3 participates in broad protein networks rather than a single linear pathway. Such breadth supports why diverse downstream phenotypes (glycolysis, apoptosis, EMT, inflammatory pyroptosis) can appear in different contexts when BTF3 is perturbed. (wang2021molecularcharacterizationof pages 6-7, wang2023btf3promotesproliferation pages 1-2, tan2024arid5b‐mediatedlinc01128epigenetically pages 13-16)
The following table consolidates functions, mechanisms, experimental evidence types, localization implications, and source details.
| Functional aspect | Key evidence (brief) | Experimental approach | Subcellular localization implication | Source with year and URL/DOI | Citation ID |
|---|---|---|---|---|---|
| NAC/ribosome | Human BTF3 is explicitly identified as NAC-beta/NACB, the beta subunit of the nascent polypeptide-associated complex with NACA; NAC is positioned at the ribosome exit tunnel and BTF3’s N-terminal tail extends into the tunnel. | Structural/crystallography evidence cited in review-style mechanistic discussion; biochemical NAC literature synthesis. | Cytosolic, ribosome-exit-tunnel-associated. | Zheng et al., 2022, Nucleic Acids Research; https://doi.org/10.1093/nar/gkac751 | (zheng2022thenascentpolypeptideassociated pages 1-2) |
| Translation initiation control | NAC controls translation initiation in cis by recruiting nucleolin to the encoding mRNA after nascent peptide sensing; this establishes BTF3-containing NAC as a translation-regulatory complex. | Translation inhibition assays, RNA/protein interaction assays, mechanistic cell biology in NAC study. | Ribosome-associated cytosol; functionally linked to translating mRNPs. | Zheng et al., 2022, Nucleic Acids Research; https://doi.org/10.1093/nar/gkac751 | (zheng2022thenascentpolypeptideassociated pages 1-2, zheng2022thenascentpolypeptideassociated pages 8-8) |
| Nascent-chain chaperone | NAC/BTF3 binds short nascent peptide sequences, escorts emerging chains, shields them from proteolysis, and modulates access of other ribosome-associated factors. | Structural studies cited plus mechanistic biochemical evidence from NAC field summarized in paper. | Ribosome exit tunnel / nascent-chain interface in cytosol. | Zheng et al., 2022, Nucleic Acids Research; https://doi.org/10.1093/nar/gkac751 | (zheng2022thenascentpolypeptideassociated pages 1-2) |
| ER targeting prevention | BTF3-NACA binding prevents inappropriate targeting of non-secretory nascent polypeptides from ribosomes to the ER. | Prior mechanistic studies cited; CRC review/introduction summarizes established NAC function. | Cytosolic ribosome surface with consequences for ER targeting. | Wang et al., 2021, Frontiers in Cell and Developmental Biology; https://doi.org/10.3389/fcell.2020.601502 | (wang2021molecularcharacterizationof pages 1-2) |
| Transcription factor activity | BTF3 is described as a transcription factor that initiates transcription via promoter elements; BTF3a is transcriptionally active whereas BTF3b is inactive. In CRC, ChIP/ChIP-seq identified transcriptional targets including CHD1L. | ChIP-seq, targeted ChIP, RNA-seq integration; promoter-binding analysis. | Nuclear localization/function in transcriptional regulation. | Wang et al., 2021, Frontiers in Cell and Developmental Biology; https://doi.org/10.3389/fcell.2020.601502 | (wang2021molecularcharacterizationof pages 1-2, wang2021molecularcharacterizationof pages 2-4) |
| NAC complex interactions and dual localization | IP-MS identified NACA as a BTF3 interactor and 542 BTF3-associated proteins; enrichment implicated cytosolic ribosome, protein targeting to ER, RNA binding, and nuclear DNA-binding proteins, supporting dual NAC and transcription roles. | BTF3 immunoprecipitation-mass spectrometry, GO enrichment, interaction network analysis. | Supports both cytosolic/ribosomal/ER-associated and nuclear roles. | Wang et al., 2021, Frontiers in Cell and Developmental Biology; https://doi.org/10.3389/fcell.2020.601502 | (wang2021molecularcharacterizationof pages 6-7) |
| Cancer mechanism: FOXM1/GLUT1 glycolysis axis | In HCC, BTF3 is upregulated and promotes proliferation and glycolysis by increasing FOXM1 and GLUT1; BTF3 directly interacts with FOXM1, and FOXM1 overexpression rescues the effects of BTF3 knockdown. | RT-qPCR, western blot, dual-luciferase reporter, co-IP, shRNA knockdown, EdU/CCK-8, Seahorse ECAR, xenograft. | Primarily functional evidence in tumor cells; consistent with transcription-related nuclear activity plus broader cellular expression. | Wang et al., 2023, Cancer Biology & Therapy; https://doi.org/10.1080/15384047.2023.2225884 | (wang2023btf3promotesproliferation pages 1-2, wang2023btf3promotesproliferation pages 2-3) |
| Cancer mechanism: PDCD2L/p53 axis | In HCC, BTF3 transcriptionally upregulates PDCD2L, which restrains p53 signaling; BTF3 knockdown reduces proliferation and increases apoptosis, supporting an oncogenic BTF3/PDCD2L/p53 axis. | ChIP/qRT-PCR, dual-luciferase promoter assays, knockdown, apoptosis/proliferation assays, IHC, xenografts, TCGA/ICGC analyses. | Strongly supports nuclear transcriptional action in cancer cells. | Kong et al., 2024, Molecular Medicine; https://doi.org/10.1186/s10020-024-01044-x | (kong2024btf3affectshepatocellular pages 1-2, kong2024btf3affectshepatocellular pages 12-13) |
| p53 ubiquitination via HERC2 | CRC study proposed that BTF3 may inhibit or modulate HERC2-mediated p53 ubiquitination/degradation; HERC2 emerged repeatedly in E3-ligase analyses and prior literature links BTF3 to p53 stabilization. | IP-MS context plus E3 ligase prediction/analysis (Ubibrowser, iUUCD); literature-supported mechanism. | More consistent with regulatory/nuclear signaling effects than a purely ribosomal role. | Wang et al., 2021, Frontiers in Cell and Developmental Biology; https://doi.org/10.3389/fcell.2020.601502 | (wang2021molecularcharacterizationof pages 6-7) |
| miRNA regulation | miR-497-5p negatively regulates BTF3 in CRC; decreased miR-497-5p expression contributes to elevated BTF3. | Bioinformatic prediction, GEO dataset comparison, mimic transfection in HT29 cells, qPCR/validation. | Post-transcriptional regulation of BTF3 expression; no unique compartment implication beyond cellular mRNA regulation. | Wang et al., 2021, Frontiers in Cell and Developmental Biology; https://doi.org/10.3389/fcell.2020.601502 | (wang2021molecularcharacterizationof pages 6-7) |
Table: This table summarizes the best-supported functional annotations for human BTF3/NAC-beta, integrating its ribosome-associated NAC biology, transcription-related activities, and cancer-linked mechanisms. It also maps each function to the main experimental approaches, localization implications, and source citations.
References
(zheng2022thenascentpolypeptideassociated pages 1-2): Alice J L Zheng, Aikaterini Thermou, Chrysoula Daskalogianni, Laurence Malbert-Colas, Konstantinos Karakostis, Ronan Le Sénéchal, Van Trang Dinh, Maria C Tovar Fernandez, Sébastien Apcher, Sa Chen, Marc Blondel, and Robin Fahraeus. The nascent polypeptide-associated complex (nac) controls translation initiation in cis by recruiting nucleolin to the encoding mrna. Nucleic Acids Research, 50:10110-10122, Sep 2022. URL: https://doi.org/10.1093/nar/gkac751, doi:10.1093/nar/gkac751. This article has 8 citations and is from a highest quality peer-reviewed journal.
(wang2021molecularcharacterizationof pages 1-2): Han-tao Wang, Junjie Xing, Wei Wang, Guifen Lv, Haiyan He, Yeqing Lu, Mei Sun, Haiyan Chen, and Xu Li. Molecular characterization of the oncogene btf3 and its targets in colorectal cancer. Frontiers in Cell and Developmental Biology, Feb 2021. URL: https://doi.org/10.3389/fcell.2020.601502, doi:10.3389/fcell.2020.601502. This article has 12 citations.
(zheng2022thenascentpolypeptideassociated media 2bfdbb98): Alice J L Zheng, Aikaterini Thermou, Chrysoula Daskalogianni, Laurence Malbert-Colas, Konstantinos Karakostis, Ronan Le Sénéchal, Van Trang Dinh, Maria C Tovar Fernandez, Sébastien Apcher, Sa Chen, Marc Blondel, and Robin Fahraeus. The nascent polypeptide-associated complex (nac) controls translation initiation in cis by recruiting nucleolin to the encoding mrna. Nucleic Acids Research, 50:10110-10122, Sep 2022. URL: https://doi.org/10.1093/nar/gkac751, doi:10.1093/nar/gkac751. This article has 8 citations and is from a highest quality peer-reviewed journal.
(wang2021molecularcharacterizationof pages 2-4): Han-tao Wang, Junjie Xing, Wei Wang, Guifen Lv, Haiyan He, Yeqing Lu, Mei Sun, Haiyan Chen, and Xu Li. Molecular characterization of the oncogene btf3 and its targets in colorectal cancer. Frontiers in Cell and Developmental Biology, Feb 2021. URL: https://doi.org/10.3389/fcell.2020.601502, doi:10.3389/fcell.2020.601502. This article has 12 citations.
(wang2021molecularcharacterizationof pages 6-7): Han-tao Wang, Junjie Xing, Wei Wang, Guifen Lv, Haiyan He, Yeqing Lu, Mei Sun, Haiyan Chen, and Xu Li. Molecular characterization of the oncogene btf3 and its targets in colorectal cancer. Frontiers in Cell and Developmental Biology, Feb 2021. URL: https://doi.org/10.3389/fcell.2020.601502, doi:10.3389/fcell.2020.601502. This article has 12 citations.
(zheng2022thenascentpolypeptideassociated pages 8-8): Alice J L Zheng, Aikaterini Thermou, Chrysoula Daskalogianni, Laurence Malbert-Colas, Konstantinos Karakostis, Ronan Le Sénéchal, Van Trang Dinh, Maria C Tovar Fernandez, Sébastien Apcher, Sa Chen, Marc Blondel, and Robin Fahraeus. The nascent polypeptide-associated complex (nac) controls translation initiation in cis by recruiting nucleolin to the encoding mrna. Nucleic Acids Research, 50:10110-10122, Sep 2022. URL: https://doi.org/10.1093/nar/gkac751, doi:10.1093/nar/gkac751. This article has 8 citations and is from a highest quality peer-reviewed journal.
(wang2023btf3promotesproliferation pages 1-2): Peng Wang, Jian-Min Sun, Chengming Sun, Haoran Zhao, Yubao Zhang, and Jing Chen. Btf3 promotes proliferation and glycolysis in hepatocellular carcinoma by regulating glut1. Cancer Biology & Therapy, Jun 2023. URL: https://doi.org/10.1080/15384047.2023.2225884, doi:10.1080/15384047.2023.2225884. This article has 23 citations and is from a peer-reviewed journal.
(wang2023btf3promotesproliferation pages 2-3): Peng Wang, Jian-Min Sun, Chengming Sun, Haoran Zhao, Yubao Zhang, and Jing Chen. Btf3 promotes proliferation and glycolysis in hepatocellular carcinoma by regulating glut1. Cancer Biology & Therapy, Jun 2023. URL: https://doi.org/10.1080/15384047.2023.2225884, doi:10.1080/15384047.2023.2225884. This article has 23 citations and is from a peer-reviewed journal.
(kong2024btf3affectshepatocellular pages 1-2): Minyu Kong, Xiaoyi Shi, Jie Gao, and Wenzhi Guo. Btf3 affects hepatocellular carcinoma progression by transcriptionally upregulating pdcd2l and inactivating p53 signaling. Molecular Medicine, Dec 2024. URL: https://doi.org/10.1186/s10020-024-01044-x, doi:10.1186/s10020-024-01044-x. This article has 4 citations and is from a peer-reviewed journal.
(kong2024btf3affectshepatocellular pages 12-13): Minyu Kong, Xiaoyi Shi, Jie Gao, and Wenzhi Guo. Btf3 affects hepatocellular carcinoma progression by transcriptionally upregulating pdcd2l and inactivating p53 signaling. Molecular Medicine, Dec 2024. URL: https://doi.org/10.1186/s10020-024-01044-x, doi:10.1186/s10020-024-01044-x. This article has 4 citations and is from a peer-reviewed journal.
(tan2024arid5b‐mediatedlinc01128epigenetically pages 1-3): Yuan Tan, Jiao Qiao, Shuo Yang, Qingchen Wang, Hongchao Liu, Qi Liu, Weimin Feng, Boxin Yang, Zhongxin Li, and Liyan Cui. Arid5b‐mediated linc01128 epigenetically activated pyroptosis and apoptosis by promoting the formation of the btf3/stat3 complex in β2gpi/anti‐β2gpi‐treated monocytes. Clinical and Translational Medicine, Jan 2024. URL: https://doi.org/10.1002/ctm2.1539, doi:10.1002/ctm2.1539. This article has 8 citations and is from a peer-reviewed journal.
(tan2024arid5b‐mediatedlinc01128epigenetically pages 13-16): Yuan Tan, Jiao Qiao, Shuo Yang, Qingchen Wang, Hongchao Liu, Qi Liu, Weimin Feng, Boxin Yang, Zhongxin Li, and Liyan Cui. Arid5b‐mediated linc01128 epigenetically activated pyroptosis and apoptosis by promoting the formation of the btf3/stat3 complex in β2gpi/anti‐β2gpi‐treated monocytes. Clinical and Translational Medicine, Jan 2024. URL: https://doi.org/10.1002/ctm2.1539, doi:10.1002/ctm2.1539. This article has 8 citations and is from a peer-reviewed journal.
(tan2024arid5b‐mediatedlinc01128epigenetically pages 6-8): Yuan Tan, Jiao Qiao, Shuo Yang, Qingchen Wang, Hongchao Liu, Qi Liu, Weimin Feng, Boxin Yang, Zhongxin Li, and Liyan Cui. Arid5b‐mediated linc01128 epigenetically activated pyroptosis and apoptosis by promoting the formation of the btf3/stat3 complex in β2gpi/anti‐β2gpi‐treated monocytes. Clinical and Translational Medicine, Jan 2024. URL: https://doi.org/10.1002/ctm2.1539, doi:10.1002/ctm2.1539. This article has 8 citations and is from a peer-reviewed journal.
(mavridou2024integrativeanalysisof pages 7-10): Dimitra Mavridou, Konstantina Psatha, and Michalis Aivaliotis. Integrative analysis of multi-omics data to identify deregulated molecular pathways and druggable targets in chronic lymphocytic leukemia. Journal of Personalized Medicine, 14:831, Aug 2024. URL: https://doi.org/10.3390/jpm14080831, doi:10.3390/jpm14080831. This article has 4 citations.
(mavridou2024integrativeanalysisof pages 5-7): Dimitra Mavridou, Konstantina Psatha, and Michalis Aivaliotis. Integrative analysis of multi-omics data to identify deregulated molecular pathways and druggable targets in chronic lymphocytic leukemia. Journal of Personalized Medicine, 14:831, Aug 2024. URL: https://doi.org/10.3390/jpm14080831, doi:10.3390/jpm14080831. This article has 4 citations.
(patil2024multifacetedimpactof pages 13-14): Ketki Patil, Elizabeth Johnston, Joseph Novack, Garrett Wallace, Michelle Lin, and S. Balakrishna Pai. Multifaceted impact of hiv inhibitor dapivirine on triple negative breast cancer cells reveals potential entities as targets for novel therapy. Scientific Reports, Dec 2024. URL: https://doi.org/10.1038/s41598-024-79789-y, doi:10.1038/s41598-024-79789-y. This article has 3 citations and is from a peer-reviewed journal.
(patil2024multifacetedimpactof pages 7-10): Ketki Patil, Elizabeth Johnston, Joseph Novack, Garrett Wallace, Michelle Lin, and S. Balakrishna Pai. Multifaceted impact of hiv inhibitor dapivirine on triple negative breast cancer cells reveals potential entities as targets for novel therapy. Scientific Reports, Dec 2024. URL: https://doi.org/10.1038/s41598-024-79789-y, doi:10.1038/s41598-024-79789-y. This article has 3 citations and is from a peer-reviewed journal.
2026-04-20: True human BTF3 for this review is UniProt P20290; UniProt
gene_exact:BTF3 queries also return BTN3A3 and BTN3A2 because BTF3
is carried as a synonym on those entries, so accession pinning was required
during fetch.
BTF3/P20290 is the human NAC-beta subunit and the NAC heterodimer associates
with ribosomes through BTF3. [file:human/BTF3/BTF3-uniprot.txt "Part of the
nascent polypeptide-associated complex (NAC), which is a heterodimer of NACA
and BTF3 (via NAC-A/B domains). NAC associates with ribosomes through the
BTF3/NACB subunit."; PMID:21203952 Crystal structures of NAC domains of human
nascent polypeptide-associated complex (NAC) and its alphaNAC subunit.,
"Nascent polypeptide associated complex (NAC) and its two isolated subunits,
αNAC and βNAC, play important roles in nascent peptide targeting."]
UniProt summarizes that, when associated with NACA, BTF3 prevents
inappropriate targeting of non-secretory polypeptides to the ER. The cached
abstract for PMID:10982809 supports assigning this process to BTF3 directly:
both subunits contribute to preventing inappropriate interactions, and
betaNAC alone binds ribosomes and is sufficient to prevent ribosome binding
to the ER membrane. [file:human/BTF3/BTF3-uniprot.txt "When associated with
NACA, prevents inappropriate targeting of non-secretory polypeptides to the
endoplasmic reticulum (ER). Binds to nascent polypeptide chains as they
emerge from the ribosome and blocks their interaction with the signal
recognition particle (SRP), which normally targets nascent secretory peptides
to the ER."; PMID:10982809 The alpha and beta subunit of the nascent
polypeptide-associated complex have distinct functions., "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."]
UniProt also reports BTF3 in both cytoplasm and nucleus, while noting that
the heterodimer with NACA is cytoplasmic. In PN framing, that supports
keeping the NAC-linked cytoplasmic role as core and the nuclear/transcription
role as contextual. [file:human/BTF3/BTF3-uniprot.txt "SUBCELLULAR LOCATION:
Cytoplasm {ECO:0000269|PubMed:10982809}. Nucleus
{ECO:0000269|PubMed:10982809}. Note=The heterodimer with NACA is
cytoplasmic."]
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.
[PMID:22658674 Insights into RNA biology from an atlas of mammalian
mRNA-binding proteins., "We identify 860 proteins that qualify as RBPs by
biochemical and statistical criteria"; PMID:22681889 The mRNA-bound proteome
and its global occupancy profile on protein-coding transcripts., "Application
to a human embryonic kidney cell line identified close to 800 proteins";
PMID:25416956 A proteome-scale map of the human interactome network.;
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of
the human interactome.]
PMID:18433331 documents BTF3 interaction with HEPIS (Q86VG3), a SARS
nsp10-binding repressor, which supports a context-specific physical
association claim but not a core GO molecular function for human BTF3.
[PMID:18433331 Identification of a novel transcriptional repressor (HEPIS)
that interacts with nsp-10 of SARS coronavirus., "we co-immunoprecipitated
HEPIS with BTF3, a component of the RNA pol II initiation complex"]
PMID:30242148 supports a contextual transcription-related interaction for BTF3
rather than the PN core role. The paper links BTF3 to Connexin-43-tail and
Pol II in an N-cadherin transcriptional mechanism that is separate from
conserved NAC-mediated nascent-chain sorting. [PMID:30242148 Gap junction
protein Connexin-43 is a direct transcriptional regulator of N-cadherin in
vivo., "we identify its mechanism of action, showing that Cx43 regulation of
N-cadherin is due to a direct interaction with the basic transcription factor
3 (BTF3)"]
The YAML description field was revised to keep it as a standalone biological summary. Project-specific curation framing moved here instead.
local_review_complete_not_phase1. PN placement: Translation > Cytosolic translation > Nascent peptide husbandry > Nascent peptide sorting > NAC component. Main issue: True human BTF3 (P20290) is a reviewed PN translation factor; BTN3A3 synonym confusion was the original tracking concernNo phase-1 dossier exists for this priority-only gene. This note preserves the current PROTEOSTASIS boundary or exception decision and should be superseded by a dossier section if the gene is promoted into a full phase-1 batch.
This file is generated from the current PROTEOSTASIS priority table, PN projection outputs, and local gene-review artifacts. Edit those source records rather than this generated note when correcting the underlying curation.
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