BTF3L4 is a 158-residue NAC-beta-family protein with a conserved NAC-A/B domain. It reproducibly associates with NACA in targeted affinity purification and independent proteome-scale AP-MS, co-fractionation, and XL-MS datasets, consistent with an alternative beta-chain partner in the nascent polypeptide-associated complex. Unlike canonical BTF3, direct BTF3L4-specific ribosome binding, nascent-chain targeting, prevention of endoplasmic-reticulum mistargeting, and DNA-binding or transcription-factor activity have not been demonstrated. Mouse mesenchymal-stem-cell studies place Btf3l4 in BMP-2-induced chondrogenic differentiation, while human glioma and gastric-cancer models and mouse acetaminophen-hepatotoxicity models reveal context-dependent proliferation, invasion, apoptosis, oxidative-stress, and inflammatory phenotypes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: A proteome-scale binary-interaction screen detected BTF3L4 interactions with TXLNA and TXLNB. The interaction records can be retained, but generic protein binding is not an informative molecular function. Reason: Yeast-two-hybrid evidence supports the reported physical interactions, not a partner-specific biochemical activity of BTF3L4. GO:0005515 therefore overstates the functional content of the experiment while conveying less information than the underlying interactor records. Supporting Evidence: PMID:25416956 a systematic map of ?14,000 high-quality human binary protein-protein interactions |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: HuRI detected BTF3L4 interactions with TXLNA and SMYD2. These are useful interaction observations, but GO:0005515 is too generic to describe a molecular function. Reason: The high-throughput binary assay establishes physical interaction under the screening conditions. It does not establish that BTF3L4 independently enables a defined binding or catalytic activity, so the generic molecular-function term should not be treated as a core function. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: A multimodal U2OS cell map detected a BTF3L4-TXLNA association. The source interaction is retained, but generic protein binding does not define a BTF3L4 molecular activity. Reason: The study integrates AP-MS interactions and imaging into data-driven protein assemblies. Its BTF3L4-TXLNA record supports association in that cell-map context but does not demonstrate a specific syntaxin-related or other biochemical activity for BTF3L4. Supporting Evidence: PMID:40205054 Proteins are purified from whole-cell biochemical extracts and their biophysical interactions are determined using AP-MS. |
| GO:0005854 nascent polypeptide-associated complex | IPI PMID:30948508 Dephosphorylation of the transcriptional cofactor NACA by th... | NEW | Summary: Proposed NACA-complex membership. Targeted NACA affinity purification explicitly recovered BTF3L4, and independent AP-MS, co-fractionation, and XL-MS datasets reproduce the NACA-BTF3L4 association. Reason: The recurrent NACA association, together with the BTF3L4 NAC-beta-family assignment and NAC-A/B domain, supports BTF3L4 as an alternative beta-chain component of a human nascent polypeptide-associated complex. This proposal is limited to complex membership; it does not transfer canonical BTF3 ribosome binding or cotranslational targeting activities to BTF3L4. Supporting Evidence: PMID:30948508 NACA dephosphorylation was associated with specific recruitment of novel NACA interactants, such as basic transcription factor 3 (BTF3) and its homolog BTF3L4. file:human/BTF3L4/BTF3L4-deep-research-manual.md BTF3L4 is an alternative beta-chain partner of NACA in a human nascent polypeptide-associated complex. |
| GO:0032332 positive regulation of chondrocyte differentiation | ISS PMID:20008835 Quantitative proteomics analysis of chondrogenic differentia... | NEW | Summary: Proposed non-core developmental annotation. Mouse Btf3l4 knockdown impaired BMP-2-induced chondrogenic differentiation and cartilage-matrix-gene expression in C3H10T1/2 mesenchymal stem cells. Reason: The experiment directly tests the mouse ortholog rather than human BTF3L4, so ISS is used for the conservative human transfer. This phenotype is informative but does not define the protein's molecular mechanism or core biochemical activity. Supporting Evidence: PMID:20008835 the biological roles of BTF3l4 and fibulin-5, two novel chondrogenesis-related proteins identified in the present study, were verified in the context of chondrogenic differentiation. |
| GO:0008284 positive regulation of cell population proliferation | IMP PMID:38320629 Basic Transcription Factor 3 Like 4 Enhances Malignant Pheno... | NEW | Summary: Proposed non-core cancer-context annotation. BTF3L4 down-regulation reduced proliferation in human glioma cells, with independent corroboration from BTF3L4 knockdown in human gastric-cancer cells. Reason: Perturbational evidence in two human cancer-cell contexts supports a positive effect of BTF3L4 on population proliferation. The annotation remains non-core because the phenotype is disease-context dependent and the underlying molecular mechanism is unresolved. Supporting Evidence: PMID:38320629 the down-regulation of BTF3L4 protein in the glioma cell line had a detrimental effect on cell migration, invasion, and proliferation. PMID:39425187 knockdown of BTF3L4 significantly recovered the promotion effect of MIR194-2HG knockdown on GC cell proliferation and invasion |
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Download this section (compressed HTML)Q: Does endogenous BTF3L4 substitute for BTF3 as the NACA beta-chain partner on translating ribosomes, or does it form a regulated non-ribosomal NACA complex?
Q: Which BTF3L4 isoforms bind NACA, given that isoforms 2 and 3 remove or disrupt substantial portions of the NAC-A/B domain?
Q: Do the chondrogenesis, cancer-cell, and acetaminophen-injury phenotypes arise from altered cotranslational proteostasis or from a separate NACA-dependent nuclear or signaling mechanism?
Experiment: Perform reciprocal endogenous NACA-BTF3L4 co-immunoprecipitation and targeted XL-MS, followed by sucrose-gradient polysome profiling. Quantify BTF3 in the same fractions and rescue BTF3L4-null cells with each of the three isoforms to test whether the intact NAC-A/B domain is required for NACA and ribosome association.
Hypothesis: BTF3L4 forms an endogenous, isoform-dependent complex with NACA that can associate with translating ribosomes.
Experiment: Compare BTF3 and BTF3L4 single and combined acute-depletion cells using ribosome-proximal proteomics, nascent-chain folding reporters, and an endoplasmic-reticulum mistargeting reporter. Rescue with wild-type and NACA-binding-defective BTF3L4 variants to separate complex assembly from function.
Hypothesis: BTF3 and BTF3L4 have partially redundant but distinguishable cotranslational targeting functions.
Experiment: In chondrogenic differentiation and glioma-cell models, combine BTF3L4 perturbation with quantitative translation profiling and NACA-interaction mutants, then contrast these results with chromatin occupancy and transcriptome measurements to distinguish cotranslational from nuclear regulatory mechanisms.
Hypothesis: The contextual developmental and disease phenotypes depend on the same NACA-associated mechanism.
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