id: Q9NWN3 gene_symbol: FBXO34 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXO34 (F-box only protein 34, FBX34) is a 711-amino-acid F-box protein that serves as the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. Its C-terminal F-box domain (residues ~572-624) docks onto SKP1, linking the complex (via CUL1 and the catalytic RING subunit RBX1) to specific substrates that FBXO34 selects for K48-linked polyubiquitination and proteasomal degradation; FBXO34 itself is the substrate receptor and is not the catalytic core. Reported substrates and roles are still sparse: it promotes ubiquitination and degradation of the RNA- binding protein HNRNPU (hnRNP U), and through this can modulate latent HIV-1 reactivation. hnRNP U normally binds the HIV-1 mRNA Rev element region and suppresses HIV-1 translation to maintain latency; FBXO34-driven degradation of hnRNP U abolishes this interaction and relieves the translational block, so FBXO34 was identified in a CRISPR-activation screen as a host factor promoting latency reversal. By similarity to its rodent ortholog (where it localizes mainly to the nucleus and colocalizes with F-actin in oocytes) it has been implicated in cell-cycle control of the G2/M transition and anaphase entry in meiotic oocytes, acting upstream of CCNB1/MPF (Fbxo34 depletion lowers MPF activity and is rescued by exogenous CCNB1, whereas overexpression triggers spindle-assembly-checkpoint activation and metaphase-I arrest); a direct cell-cycle substrate has not been identified. Much of the N-terminal half of the protein is intrinsically disordered, and the protein is broadly expressed across tissues with low tissue specificity. Overall FBXO34 is a poorly characterized member of the large F-box protein family whose best-supported molecular function is acting as an SCF substrate-recognition adaptor. existing_annotations: - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: High-throughput interactome partners (e.g. KRT40, MDFI) captured by IntAct. Bare protein binding is uninformative as a function. action: KEEP_AS_NON_CORE reason: Records real binary interactions but the bare protein binding term gives no functional information per curation guidelines; the candidate partners have not been validated as SCF/FBXO34 substrates. supported_by: - reference_id: file:human/FBXO34/FBXO34-uniprot.txt supporting_text: 'Q9NWN3; Q6A162: KRT40; NbExp=3; IntAct=EBI-719816, EBI-10171697' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31515488 qualifier: enables review: summary: Interaction with MTUS2 captured in a study of variant-driven interactome disruption. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: A real high-throughput interaction (MTUS2 isoform) but the bare protein binding term is uninformative and not a core function. supported_by: - reference_id: file:human/FBXO34/FBXO34-uniprot.txt supporting_text: 'Q9NWN3; Q5JR59-3: MTUS2; NbExp=4; IntAct=EBI-719816, EBI-11522433' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Binary interactome reference map capturing numerous FBXO34 partners, predominantly keratin-associated proteins (KRTAPs) and other proteins (e.g. ALPP, COL8A1, DISC1, FGF14, OIT3). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput binary interactions; bare protein binding is uninformative and the partners are not established substrates. Many KRTAP hits are likely sticky/promiscuous Y2H partners rather than physiological SCF substrates. supported_by: - reference_id: file:human/FBXO34/FBXO34-uniprot.txt supporting_text: 'Q9NWN3; Q9BYR2: KRTAP4-5; NbExp=5; IntAct=EBI-719816, EBI-11993254' - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:34445249 qualifier: part_of review: summary: ComplexPortal assignment that FBXO34 is the variable F-box subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex. This is the core cellular context of an F-box protein. action: ACCEPT reason: Consistent with FBXO34 being an SCF substrate-recognition subunit; UniProt records direct SKP1 and CUL1 interaction, and ComplexPortal defines the FBXO34-variant SCF complex (CPX-7975). Core compartment/complex annotation for this gene. supported_by: - reference_id: file:human/FBXO34/FBXO34-uniprot.txt supporting_text: 'Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex' - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:34445249 qualifier: involved_in review: summary: ComplexPortal assignment that FBXO34, as an SCF substrate receptor, contributes to SCF-dependent proteasomal ubiquitin-dependent protein catabolism. This is the core biological process of an F-box protein. action: ACCEPT reason: Directly consistent with FBXO34's documented role in promoting ubiquitination and proteasomal degradation of target proteins (e.g. HNRNPU) as the substrate-recognition subunit of an SCF complex. Core biological process for this gene. supported_by: - reference_id: file:human/FBXO34/FBXO34-uniprot.txt supporting_text: promoting ubiquitination and proteasomal degradation of specific target proteins including HNRNPU references: - 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 (full text available); source of bare protein binding annotations (e.g. KRT40, MDFI). Partners not validated as FBXO34/SCF substrates. - 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 study (full text available); source of a bare protein binding annotation (MTUS2). - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Binary interactome reference map (full text available); source of multiple bare protein binding annotations, predominantly KRTAPs likely to be sticky Y2H partners. - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: - statement: Review of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase family in which the variable F-box subunit determines substrate specificity; provides the basis for the ComplexPortal NAS annotations placing FBXO34 in an SCF complex and SCF-dependent proteasomal degradation. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text not in cache; a family-level SCF review used by ComplexPortal to support FBXO34 SCF-complex membership and SCF-dependent catabolic process. Does not provide FBXO34-specific experimental detail. - id: PMID:36285453 title: FBXO34 promotes latent HIV-1 activation by post-transcriptional modulation. findings: - statement: FBXO34 is a substrate-recognition component of an SCF-type E3 ubiquitin ligase that promotes ubiquitination and proteasomal degradation of HNRNPU/hnRNP U; degradation of hnRNP U abolishes its interaction with HIV-1 Rev mRNA and thereby promotes latent HIV-1 activation. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (Emerg Microbes Infect 2022, DOI 10.1080/22221751.2022.2140605); the key FBXO34 functional study and the UniProt FUNCTION source (ECO:0000269). Full text not in cache, so supporting_text is quoted from the UniProt record that cites this paper. - id: file:human/FBXO34/FBXO34-deep-research-falcon.md title: Falcon deep research report for human FBXO34 findings: - statement: A genome-wide CRISPR-Cas9 activation screen identified FBXO34 as a host factor whose activation promotes latent HIV-1 reactivation, and AP-MS/co-IP identified hnRNP U as an FBXO34-interacting substrate whose ubiquitination and degradation FBXO34 promotes. supporting_text: >- A genome-wide **CRISPR-Cas9 activation** screen in a latent HIV model identified **FBXO34** as a host factor whose activation promotes latent HIV reactivation. The study then used **affinity purification mass spectrometry** and **co-immunoprecipitation** to identify **hnRNP U** as an FBXO34-interacting protein and presents evidence consistent with FBXO34 promoting **hnRNP U ubiquitination** and **decreasing hnRNP U protein abundance**. - statement: hnRNP U binds HIV-1 mRNA and suppresses its translation to support latency; FBXO34-driven ubiquitination/degradation of hnRNP U abolishes this interaction and relieves the translational block. supporting_text: >- Mechanistically, the authors report that hnRNP U binds HIV-1 mRNA (Rev element region; amino acids 1–339 of hnRNP U are implicated in the RNA interaction) and **hinders HIV-1 translation**, supporting latency; FBXO34-driven ubiquitination/degradation of hnRNP U abolishes this interaction and thus relieves the translational block. - statement: In mouse oocytes Fbxo34 regulates meiotic cell-cycle progression upstream of CCNB1/MPF; depletion lowers MPF activity (rescued by CCNB1) while overexpression triggers spindle-assembly-checkpoint activation and metaphase-I arrest, but no direct substrate was identified. supporting_text: >- In mouse oocytes, Fbxo34 perturbation suggests an important role in meiotic cell-cycle progression: depletion causes failure of meiotic resumption associated with low maturation-promoting factor (MPF) activity and can be rescued by exogenous CCNB1; overexpression promotes GVBD but causes SAC activation and MI arrest. - statement: In mouse oocytes FBXO34 was reported to localize mainly in the nucleus and to colocalize with F-actin during meiotic maturation, providing an orthology-based localization hypothesis for human FBXO34. supporting_text: >- In mouse oocytes, FBXO34 was reported to localize mainly in the **nucleus** and to **colocalize with F-actin** during meiotic maturation. reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: >- Falcon (Edison Scientific) deep-research synthesis. The human HNRNPU/HIV- latency mechanism is cross-checked against the UniProt FUNCTION block and the primary paper already cited in this review (PMID:36285453, Yang 2022). The mouse meiotic/CCNB1 and nuclear/F-actin localization claims are orthology-based (Zhao 2021 Front Cell Dev Biol; Kinterova 2022 Cells) and are not human-specific. Cites author-year/DOIs rather than PMIDs, so individual primary claims remain UNVERIFIED here. core_functions: - description: Substrate-recognition (F-box) subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex that selects specific substrates such as HNRNPU for ubiquitination and proteasomal degradation; FBXO34 bridges the substrate to the catalytic SCF core via SKP1 and is not itself the catalytic subunit. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXO34/FBXO34-uniprot.txt supporting_text: 'Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex promoting ubiquitination and proteasomal degradation of specific target proteins including HNRNPU' in_complex: id: GO:0019005 label: SCF ubiquitin ligase complex directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: As the SCF(FBXO34) substrate receptor, targets the RNA-binding protein HNRNPU (hnRNP U) for ubiquitination and proteasomal degradation; because hnRNP U binds HIV-1 mRNA and suppresses its translation to maintain latency, FBXO34-driven hnRNP U degradation relieves this translational block and promotes latent HIV-1 reactivation. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXO34/FBXO34-deep-research-falcon.md supporting_text: >- Mechanistically, the authors report that hnRNP U binds HIV-1 mRNA (Rev element region; amino acids 1–339 of hnRNP U are implicated in the RNA interaction) and **hinders HIV-1 translation**, supporting latency; FBXO34-driven ubiquitination/degradation of hnRNP U abolishes this interaction and thus relieves the translational block. in_complex: id: GO:0019005 label: SCF ubiquitin ligase complex directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process proposed_new_terms: [] suggested_questions: - question: Beyond HNRNPU, what is the physiological substrate repertoire of the FBXO34-SCF complex, and which of the high-throughput interactome partners (if any) are bona fide ubiquitination substrates versus non-physiological binders? - question: Are the cell-cycle roles (G2/M transition and meiotic anaphase entry) inferred by similarity to the rodent ortholog also operative for human FBXO34, and through which substrates are they mediated? suggested_experiments: - description: Reconstitute the FBXO34 SCF complex (SKP1-CUL1-RBX1-FBXO34) in vitro with purified components and an E1/E2/ubiquitin system to demonstrate direct, F-box-dependent ubiquitination of candidate substrates (starting with HNRNPU) and to map ubiquitin-chain linkage type. - description: Perform quantitative proteomics/ubiquitinomics in FBXO34-knockout versus wild-type cells (and with a substrate-binding-deficient mutant) to define the endogenous substrate set and distinguish degradative substrates from non-substrate interactors. - description: Test the substrate-receptor model directly by co-immunoprecipitation and degradation assays confirming SKP1/CUL1 association via the F-box domain and substrate stabilization upon FBXO34 loss or proteasome inhibition. knowledge_gaps: - gap_statement: >- The endogenous substrate repertoire of human FBXO34-SCF remains largely undefined. HNRNPU is the only clearly supported human substrate in the retrieved mechanistic literature, while many high-throughput protein-binding partners have not been shown to be FBXO34-dependent ubiquitination substrates. boundary: >- The review supports FBXO34 as an SCF substrate-recognition adaptor and accepts HNRNPU-linked ubiquitination/degradation as the best-supported human substrate example. The gap is which additional interactors, if any, are bona fide physiological substrates and whether the inferred SCF adaptor function has broader substrate-specific biological roles. gap_kind: - BIOLOGY - CURATION dark_aspect: MF_DARK status: OPEN significance: >- Substrate scope determines whether FBXO34 should receive only the generic ubiquitin-like ligase-substrate adaptor annotation or additional substrate/pathway-specific process annotations. It also determines whether current protein-binding annotations should remain non-core interactome noise or be converted into mechanistically supported substrate relationships. resolution: >- Endogenous FBXO34 knockout/rescue, substrate-trapping mutants, quantitative proteomics, ubiquitin-remnant profiling, and direct reconstitution of candidate ubiquitination reactions would distinguish degradative substrates from non-substrate interactors. provenance: - reference_id: file:human/FBXO34/FBXO34-deep-research-falcon.md supporting_text: Across the retrieved literature, **hnRNP U** is the only clearly identified substrate/target of human FBXO34 with direct mechanistic support. - reference_id: file:human/FBXO34/FBXO34-deep-research-falcon.md supporting_text: direct biochemical details (e.g., linkage type, E2 usage, proteasome-inhibition rescue) were not captured in the available evidence snippets. - reference_id: file:human/FBXO34/FBXO34-deep-research-falcon.md supporting_text: broader roles in cell-cycle or disease biology remain plausible but underdefined. - gap_statement: >- The relationship between FBXO34's human HNRNPU/HIV-latency function and the mouse oocyte cell-cycle phenotype remains unresolved. Mouse data suggest FBXO34 can influence meiotic G2/M transition, MPF/CCNB1 activity, spindle checkpoint behavior, and anaphase entry, but the direct substrate(s) and relevance to human FBXO34 biology are unknown. boundary: >- The review treats mouse oocyte findings as orthology-based, hypothesis- generating evidence, not as a direct human core biological-process annotation. HNRNPU degradation is the supported human pathway-level example. gap_kind: - BIOLOGY - CURATION dark_aspect: BP_DARK status: OPEN significance: >- Resolving this gap would determine whether FBXO34 should be annotated to cell-cycle or meiotic processes in human, or whether those findings should remain non-human context while the human review stays focused on HNRNPU-linked post-transcriptional regulation of HIV latency. resolution: >- Test FBXO34 perturbation in human germ-cell or cell-cycle models, identify FBXO34-dependent ubiquitination substrates in those systems, and ask whether CCNB1/MPF phenotypes can be rescued by substrate-specific manipulation. provenance: - reference_id: file:human/FBXO34/FBXO34-deep-research-falcon.md supporting_text: mouse oocyte phenotypes indicate FBXO34 can influence meiosis and checkpoint progression, but the direct substrate(s) in that setting are unknown, and the extent to which this translates to human tissues is not resolved by the retrieved evidence. - reference_id: file:human/FBXO34/FBXO34-deep-research-falcon.md supporting_text: Supports conserved biology for FBXO34 as an **SCF-type F-box regulator of cell-cycle control**, likely acting upstream of **CCNB1/CDK1/MPF** and checkpoint progression. - reference_id: file:human/FBXO34/FBXO34-deep-research-falcon.md supporting_text: This is informative for function but is **not direct human evidence**. - gap_statement: >- Human FBXO34 subcellular localization remains experimentally underdefined. Mouse oocyte data suggest nuclear and F-actin-associated localization, but direct human localization evidence, and the compartment in which FBXO34 acts on HNRNPU or other substrates, were not recovered. boundary: >- The review supports intracellular SCF-substrate-adaptor activity but does not assign a core cellular component beyond SCF complex membership. Mouse oocyte localization is treated as a hypothesis for human work, not a direct human cellular-component annotation. gap_kind: - BIOLOGY - CURATION dark_aspect: CC_DARK status: OPEN significance: >- Localization would refine where FBXO34 performs substrate recognition and would help separate generic SCF complex membership from human nuclear, cytoplasmic, RNP-associated, or cytoskeletal substrate contexts. resolution: >- Endogenous tagging or validated antibodies should map FBXO34 localization in human cells under basal, HIV-latency, proteasome-inhibited, and cell-cycle conditions, paired with substrate colocalization and compartment-specific degradation assays. provenance: - reference_id: file:human/FBXO34/FBXO34-deep-research-falcon.md supporting_text: Direct **human subcellular localization** data for FBXO34 was not recovered from the accessible text snippets; localization statements come from mouse oocytes and should be treated as context rather than definitive for human somatic cells. - reference_id: file:human/FBXO34/FBXO34-deep-research-falcon.md supporting_text: In mouse oocytes, FBXO34 was reported to localize mainly in the **nucleus** and to **colocalize with F-actin** during meiotic maturation.