Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: High-throughput interactome partners (e.g. KRT40, MDFI) captured by IntAct. Bare protein binding is uninformative as a function. 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. Supporting Evidence: file:human/FBXO34/FBXO34-uniprot.txt Q9NWN3; Q6A162: KRT40; NbExp=3; IntAct=EBI-719816, EBI-10171697
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	KEEP AS NON CORE	Summary: Interaction with MTUS2 captured in a study of variant-driven interactome disruption. Bare protein binding is uninformative. Reason: A real high-throughput interaction (MTUS2 isoform) but the bare protein binding term is uninformative and not a core function. Supporting Evidence: file:human/FBXO34/FBXO34-uniprot.txt Q9NWN3; Q5JR59-3: MTUS2; NbExp=4; IntAct=EBI-719816, EBI-11522433
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	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. 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. Supporting Evidence: file:human/FBXO34/FBXO34-uniprot.txt Q9NWN3; Q9BYR2: KRTAP4-5; NbExp=5; IntAct=EBI-719816, EBI-11993254
GO:0019005 SCF ubiquitin ligase complex	NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso...	ACCEPT	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. 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. Supporting Evidence: file:human/FBXO34/FBXO34-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso...	ACCEPT	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. 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. Supporting Evidence: file:human/FBXO34/FBXO34-uniprot.txt promoting ubiquitination and proteasomal degradation of specific target proteins including HNRNPU

Core Functions

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:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

In Complex:

SCF ubiquitin ligase complex

Supporting Evidence:

file:human/FBXO34/FBXO34-uniprot.txt
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

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:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

In Complex:

SCF ubiquitin ligase complex

Supporting Evidence:

file:human/FBXO34/FBXO34-deep-research-falcon.md
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.

References

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:31515488

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:34445249

The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.

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.

PMID:36285453

FBXO34 promotes latent HIV-1 activation by post-transcriptional modulation.

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.

file:human/FBXO34/FBXO34-deep-research-falcon.md

Falcon deep research report for human FBXO34

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.

"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**."
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.

"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 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.

"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."
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.

"In mouse oocytes, FBXO34 was reported to localize mainly in the **nucleus** and to **colocalize with F-actin** during meiotic maturation."

Suggested Experiments

Experiment: 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.

Experiment: 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.

Experiment: 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

What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).

Gap: 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.

OPEN BIOLOGYCURATION MF_DARK

What is known: 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.

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.

What would resolve it: 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 (the field's own admissions):

"Across the retrieved literature, **hnRNP U** is the only clearly identified substrate/target of human FBXO34 with direct mechanistic support." — file:human/FBXO34/FBXO34-deep-research-falcon.md
"direct biochemical details (e.g., linkage type, E2 usage, proteasome-inhibition rescue) were not captured in the available evidence snippets." — file:human/FBXO34/FBXO34-deep-research-falcon.md
"broader roles in cell-cycle or disease biology remain plausible but underdefined." — file:human/FBXO34/FBXO34-deep-research-falcon.md

Gap: 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.

OPEN BIOLOGYCURATION BP_DARK

What is known: 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.

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.

What would resolve it: 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 (the field's own admissions):

"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." — file:human/FBXO34/FBXO34-deep-research-falcon.md
"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." — file:human/FBXO34/FBXO34-deep-research-falcon.md
"This is informative for function but is **not direct human evidence**." — file:human/FBXO34/FBXO34-deep-research-falcon.md

Gap: 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.

OPEN BIOLOGYCURATION CC_DARK

What is known: 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.

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.

What would resolve it: 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 (the field's own admissions):

"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." — file:human/FBXO34/FBXO34-deep-research-falcon.md
"In mouse oocytes, FBXO34 was reported to localize mainly in the **nucleus** and to **colocalize with F-actin** during meiotic maturation." — file:human/FBXO34/FBXO34-deep-research-falcon.md

Deep Research

Falcon

(FBXO34-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 9 citations 2 artifacts 2026-06-13T06:48:04.160908

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000014 Figure 3 demonstrates that FBXO34 interacts with hnRNP U and promotes its ubiquitination and degradation. The figure includes: - ** (image/png)

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.

Comprehensive research report: FBXO34 (UniProt Q9NWN3; Homo sapiens)

0) Target verification (mandatory)

The evidence base retrieved here consistently refers to FBXO34 as F-box protein 34 / F-box only protein 34, a member of the F-box family and part of a CUL1-associated E3 ubiquitin ligase context (i.e., an SCF-like substrate receptor role), which matches the UniProt-described identity for human FBXO34 (UniProt: Q9NWN3). No conflicting gene/protein identity with the same symbol was encountered in the mechanistic studies used. Mouse studies are explicitly labeled as non-human orthology/context. (yang2022fbxo34promoteslatent pages 2-3, yang2022fbxo34promoteslatent pages 5-7)

1) Key concepts and definitions (current understanding)

1.1 What an “F-box only” protein is

F-box proteins are commonly described as core elements of E3 ubiquitin ligase complexes that recognize and recruit downstream proteins for ubiquitination, thereby controlling protein stability and cellular function. In the most widely known architecture, an F-box protein acts as a substrate receptor in an SCF-type (Skp1–Cullin1–F-box) cullin–RING E3 ligase. In the retrieved primary literature on FBXO34, the authors explicitly frame FBXO34 within this paradigm. (yang2022fbxo34promoteslatent pages 5-7)

1.2 What “substrate” means in this context

For an F-box substrate receptor, a “substrate” (or “client”) is the protein targeted for ubiquitination (often polyubiquitination) that can lead to proteasomal degradation or other ubiquitin-dependent outcomes. The strongest direct human evidence currently available from the retrieved corpus identifies heterogeneous nuclear ribonucleoprotein U (hnRNP U / HNRNPU) as an FBXO34-interacting target whose ubiquitination and degradation is promoted by FBXO34. (yang2022fbxo34promoteslatent pages 1-2, yang2022fbxo34promoteslatent pages 5-7)

2) Molecular function and mechanism (best-supported, with evidence)

2.1 Primary supported function: ubiquitination-linked control of hnRNP U (human)

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. (yang2022fbxo34promoteslatent pages 1-2, yang2022fbxo34promoteslatent pages 5-7)

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. (yang2022fbxo34promoteslatent pages 1-2)

Figure-level evidence: Figure 3 in the same paper visually summarizes co-IP/MS interaction evidence and supports the proposed ubiquitination/degradation relationship between FBXO34 and hnRNP U. (yang2022fbxo34promoteslatent media bea8ea97)

2.2 Quantitative/experimental readouts in human cell models (statistics)

In the latent HIV GFP-reporter C11 model, dCas9–sgRNA activation of FBXO34 increased GFP reporter positivity to ~25%, interpreted as increased HIV latency reactivation. (yang2022fbxo34promoteslatent pages 5-7)

In the same experimental context, CRISPR knockout of hnRNP U increased GFP positivity to ~30%, consistent with hnRNP U acting as a latency-maintaining factor whose removal promotes reactivation. (yang2022fbxo34promoteslatent pages 5-7)

The paper reports statistical testing across experiments (mean ± SD, n=3, t-test; significance indicated as p < 0.01 and p < 0.001 for relevant validation comparisons). (yang2022fbxo34promoteslatent pages 5-7)

2.3 What remains unclear mechanistically

Within the extracted text, FBXO34 is stated to “belong to the Cul1 family of E3 ubiquitin ligases,” but canonical SCF component names (e.g., SKP1, RBX1) are not explicitly provided in the retrieved excerpts, and direct biochemical details (e.g., linkage type, E2 usage, proteasome-inhibition rescue) were not captured in the available evidence snippets. Therefore, the safest conclusion from the retrieved corpus is that FBXO34 functions as a CUL1-family / SCF-like substrate adaptor with a supported substrate (hnRNP U), while detailed complex composition and ubiquitin-chain biochemistry remain incompletely specified here. (yang2022fbxo34promoteslatent pages 5-7)

3) Biological processes, pathways, and cellular roles

3.1 HIV latency (human; direct mechanistic evidence)

The best-supported pathway-level role for human FBXO34 in the retrieved literature is in HIV-1 latency control at a post-transcriptional (translation) level, mediated through the FBXO34 → hnRNP U ubiquitination/degradation → reduced hnRNP U–HIV mRNA interaction → increased translation/reactivation axis. (yang2022fbxo34promoteslatent pages 1-2, yang2022fbxo34promoteslatent pages 5-7)

3.2 Cell-cycle/meiosis control (mouse; orthology/context)

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. These phenotypes were interpreted in the SCF/UPS framework but without identification of a direct substrate in that system. This evidence is not human-specific but suggests conserved roles in cell-cycle regulatory protein turnover. (zhao2021fbxo34regulatesthe pages 1-2, kinterova2022scfligasesand pages 8-9)

A review summarizing SCF ligases in oogenesis highlights these Fbxo34 findings and explicitly notes that a direct FBXO34 substrate was unknown in that context (pre-dating/independent of the later human hnRNP U mechanism). (kinterova2022scfligasesand pages 8-9)

4) Subcellular localization

4.1 Human localization: limited direct evidence in retrieved corpus

The retrieved human mechanistic study (HIV latency context) provides strong functional/interaction evidence but did not yield explicit localization statements for FBXO34 in the extracted passages. (yang2022fbxo34promoteslatent pages 5-7)

4.2 Mouse oocyte localization (non-human; hypothesis-generating for human)

In mouse oocytes, FBXO34 was reported to be mainly nuclear and to colocalize with F-actin during meiotic maturation. While not directly transferable to human somatic cells, it suggests FBXO34 can occupy nuclear compartments and may have cytoskeletal association in some contexts. (zhao2021fbxo34regulatesthe pages 1-2)

5) Recent developments (prioritizing 2023–2024)

5.1 Direct 2023–2024 mechanistic literature specific to FBXO34

Within the tool-retrieved and accessible full-text set, no additional 2023–2024 primary mechanistic papers specifically characterizing human FBXO34 beyond indirect mentions were obtained. The most detailed mechanistic characterization in the retrieved corpus remains the 2022 HIV latency study. (yang2022fbxo34promoteslatent pages 1-2, yang2022fbxo34promoteslatent pages 5-7)

5.2 2024 topical relevance via host RNA-binding proteins / viral infection context

A 2024 phosphoproteomics study in primary human hepatocytes (HBV infection context) discusses functional roles for RNA-binding proteins including HNRNPU in antiviral response phenotypes; however, it does not connect this to FBXO34 in the retrieved excerpts. This is relevant as biological context for the FBXO34 substrate hnRNP U rather than direct FBXO34 evidence. (pastor2024 phosphoproteomics text retrieved but not evidentially linked to FBXO34 in the extracted snippets)

6) Current applications and real-world implementations

6.1 Therapeutic concept: targeting the FBXO34/hnRNP U axis in HIV reservoir control

The HIV latency study explicitly frames the FBXO34/hnRNP U axis as a new pathway involved in HIV-1 latency and suggests it “may be directly targeted to control HIV reservoirs” in the future. This represents a translational hypothesis rather than a validated therapy, but it is the clearest real-world application direction in the retrieved evidence. (yang2022fbxo34promoteslatent pages 1-2)

7) Disease associations and human genetics (database-level evidence)

Open Targets aggregates GWAS credible-set evidence implicating FBXO34 in several disease/trait groupings, including hypercholesterolemia, osteoarthritis, pyogenic granuloma, inguinal hernia, and broader “skeletal system disease.” The excerpted Open Targets evidence provides association scores (e.g., hypercholesterolemia score ~0.171; pyogenic granuloma score ~0.181) and cites PMID 39024449, but it does not provide effect sizes, p-values, or cohort details in the retrieved snippet. These associations should therefore be interpreted as hypothesis-generating genetic links rather than validated mechanistic roles. (OpenTargets Search: -FBXO34)

8) Expert analysis and interpretation (authoritative synthesis anchored to evidence)

FBXO34 is currently a sparsely characterized human F-box protein in the accessible mechanistic literature. The strongest direct functional annotation supported here is that FBXO34 can act in a CUL1-family E3 context to reduce abundance of an RNA-binding protein substrate (hnRNP U) by ubiquitination-linked degradation. (yang2022fbxo34promoteslatent pages 1-2, yang2022fbxo34promoteslatent pages 5-7)
The substrate identification (hnRNP U) is notable because it connects an F-box substrate receptor to post-transcriptional regulation (translation) via an RBP, rather than the more classic narrative of SCF ligases acting chiefly on canonical cell-cycle regulators; this expands plausible FBXO34 biology into RNP/RNA-metabolism-linked proteostasis. (yang2022fbxo34promoteslatent pages 1-2)
Broader physiological roles remain open: 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. (kinterova2022scfligasesand pages 8-9, zhao2021fbxo34regulatesthe pages 1-2)

Evidence summary table

The following table consolidates claims, systems, methods, quantitative details, and citations.

Claim/Topic	Evidence summary (what was shown)	Experimental system & methods	Key quantitative/statistical details	Interpretation (what it implies about function/pathway/localization)	Source (authors, year, journal)	URL/DOI	Citation ID
Human evidence: FBXO34 promotes HIV-1 latency reversal by targeting hnRNP U	FBXO34 was identified in a genome-wide CRISPR activation screen as a host factor whose activation increases latent HIV-1 reactivation. Affinity purification/MS and co-IP identified hnRNP U as an FBXO34 interactor/substrate. FBXO34 promoted hnRNP U ubiquitination and reduced hnRNP U protein levels; hnRNP U normally binds HIV-1 mRNA and suppresses translation, thereby supporting latency.	Human latent HIV-1 cell models (C11, J-Lat 10.6, ACH2), HEK293T/293T cells, primary CD4+ T-cell latency model; lentiSAM CRISPR activation screen, flow cytometry (GFP reporter), p24 ELISA, RT-qPCR, Western blot, co-immunoprecipitation, affinity purification mass spectrometry, knockout/overexpression assays	FBXO34 activation increased GFP-positive latent C11 cells to ~25%; hnRNP U knockout increased GFP-positive cells to ~30%; significance markers reported as p < 0.01 and p < 0.001 in validation experiments	Strongest direct functional evidence for human FBXO34: it behaves as an F-box/CUL1-family E3 ubiquitin ligase substrate receptor that regulates a post-transcriptional HIV-1 latency pathway via hnRNP U ubiquitination/degradation. Supports a predominantly intracellular role linked to RNA regulation and ubiquitin-mediated proteostasis, though explicit subcellular localization in human cells was not provided in the extracted text.	Yang et al., 2022, Emerging Microbes & Infections	https://doi.org/10.1080/22221751.2022.2140605	(yang2022fbxo34promoteslatent pages 5-7, yang2022fbxo34promoteslatent pages 2-3, yang2022fbxo34promoteslatent pages 1-2, yang2022fbxo34promoteslatent media bea8ea97)
Non-human evidence (mouse): FBXO34 regulates meiotic G2/M transition and anaphase entry	Depletion of Fbxo34 in mouse oocytes caused failure of meiotic resumption due to low MPF activity; exogenous CCNB1 rescued the phenotype. Overexpression promoted GVBD but caused persistent SAC activation, MI arrest, failed homolog separation, and impaired spindle migration.	Mouse oocytes; mRNA microinjection, overexpression/depletion, live-cell imaging, chromosome spreading, localization by tagged protein imaging	Quantitative effect sizes were not extracted here, but rescue by CCNB1 and opposing loss-/gain-of-function phenotypes were reported	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. This is informative for function but is not direct human evidence.	Zhao et al., 2021, Frontiers in Cell and Developmental Biology	https://doi.org/10.3389/fcell.2021.647103	(zhao2021fbxo34regulatesthe pages 1-2)
Non-human evidence (mouse): subcellular localization during oocyte maturation	In mouse oocytes, FBXO34 was reported to localize mainly in the nucleus and to colocalize with F-actin during meiotic maturation.	Mouse oocytes; microinjection of FBXO34-MYC mRNA and imaging across maturation stages	No extracted numeric localization statistics	Suggests intracellular/nuclear localization with possible cytoskeletal association in oocytes; useful as a localization hypothesis for human FBXO34 but should be treated as orthology-based, non-human evidence.	Zhao et al., 2021, Frontiers in Cell and Developmental Biology	https://doi.org/10.3389/fcell.2021.647103	(zhao2021fbxo34regulatesthe pages 1-2)
Review/context (non-primary): FBXO34 in oogenesis/SCF biology	Review summarizes Zhao et al. findings: FBXO34 is required for oocyte maturation; depletion lowers MPF activity and CCNB1-dependent meiotic progression, whereas overexpression causes MI arrest and failed anaphase entry. Review emphasizes that the direct FBXO34 substrate remained unknown at that time.	Narrative review synthesizing animal studies on SCF ligases in oogenesis/embryogenesis	No new quantitative data; contextual synthesis only	Useful for expert interpretation: before the 2022 human HIV study, FBXO34 was viewed mainly as a poorly characterized F-box/SCF adaptor with meiotic roles but no defined substrate. This helps place the hnRNP U finding in context.	Kinterová et al., 2022, Cells	https://doi.org/10.3390/cells11020234	(kinterova2022scfligasesand pages 7-8, kinterova2022scfligasesand pages 8-9)
Database inference (human genetics): disease/trait associations from GWAS credible sets	Open Targets lists FBXO34 associations to multiple human disease/trait terms based on GWAS credible-set evidence, citing literature PMID 39024449. Reported conditions include skeletal system disease, inguinal hernia, hypercholesterolemia, osteoarthritis, and pyogenic granuloma.	Open Targets Platform aggregation of human genetic association evidence	Association scores reported: skeletal system disease 0.1573, inguinal hernia 0.0591, hypercholesterolemia 0.1712, osteoarthritis 0.0497, pyogenic granuloma 0.1813; evidence resource scores 0.4906 and 0.4631	Indicates that human genetics may implicate FBXO34 in several traits/diseases, but these are database-level inferences, not mechanistic functional annotation. No causal mechanism, tissue context, or effect-size/p-value details were provided in the extracted evidence.	Open Targets Platform entry for FBXO34, queried 2025; underlying GWAS evidence cites PMID 39024449	https://platform.opentargets.org/target/ENSG00000178974	(OpenTargets Search: -FBXO34)
Current evidence gap / expert synthesis	Across the retrieved literature, hnRNP U is the only clearly identified substrate/target of human FBXO34 with direct mechanistic support. No extracted evidence explicitly named canonical SCF components (e.g., SKP1/RBX1) in the human experiments, and no direct human subcellular localization study was retrieved.	Cross-source synthesis from primary paper, review, and database evidence	n/a	Current understanding is that human FBXO34 is a poorly characterized F-box protein whose best-supported function is as a likely SCF/CUL1-family ubiquitin ligase adaptor affecting RNA-associated regulation of HIV latency through hnRNP U degradation; broader roles in cell-cycle or disease biology remain plausible but underdefined.	Evidence synthesis from retrieved sources	Primary mechanistic source: https://doi.org/10.1080/22221751.2022.2140605	(yang2022fbxo34promoteslatent pages 5-7, yang2022fbxo34promoteslatent pages 2-3, yang2022fbxo34promoteslatent pages 1-2, zhao2021fbxo34regulatesthe pages 1-2, kinterova2022scfligasesand pages 7-8, OpenTargets Search: -FBXO34)

Table: This table summarizes the strongest available evidence for functional annotation of human FBXO34 (UniProt Q9NWN3), distinguishing direct human mechanistic data from mouse orthology evidence and database-level genetic associations. It is useful for identifying what is firmly established versus what remains inferential.

Key URLs and publication dates (from retrieved sources)

Yang et al. (Received 5 Jun 2022; Accepted 21 Oct 2022; published 2022), Emerging Microbes & Infections: https://doi.org/10.1080/22221751.2022.2140605 (yang2022fbxo34promoteslatent pages 1-2)
Zhao et al. (Published 25 Mar 2021), Frontiers in Cell and Developmental Biology: https://doi.org/10.3389/fcell.2021.647103 (zhao2021fbxo34regulatesthe pages 1-2)
Kinterová et al. (Jan 2022), Cells: https://doi.org/10.3390/cells11020234 (kinterova2022scfligasesand pages 7-8)
Open Targets FBXO34 target page (queried from tool context; platform URL): https://platform.opentargets.org/target/ENSG00000178974 (OpenTargets Search: -FBXO34)

Limitations of this report (evidence-bounded)

Despite targeted searching, 2023–2024 FBXO34-specific mechanistic studies were not available in the retrieved accessible corpus; therefore, “latest research” is represented primarily by a 2022 mechanistic study and 2024 genetics/database context where available.
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. (zhao2021fbxo34regulatesthe pages 1-2)

References

(yang2022fbxo34promoteslatent pages 2-3): Xinyi Yang, Xiaying Zhao, Yuqi Zhu, Jingna Xun, Q. Wen, Hanyu Pan, Jinlong Yang, Jing Wang, Zhiming Liang, Xiaoting Shen, Yue-Lan Liang, Q. Lin, Huitong Liang, Min Li, Jun Chen, Shibo Jiang, Jianqing Xu, Hongzhou Lu, and Huanzhang Zhu. Fbxo34 promotes latent hiv-1 activation by post-transcriptional modulation. Nov 2022. URL: https://doi.org/10.1080/22221751.2022.2140605, doi:10.1080/22221751.2022.2140605. This article has 13 citations and is from a domain leading peer-reviewed journal.
(yang2022fbxo34promoteslatent pages 5-7): Xinyi Yang, Xiaying Zhao, Yuqi Zhu, Jingna Xun, Q. Wen, Hanyu Pan, Jinlong Yang, Jing Wang, Zhiming Liang, Xiaoting Shen, Yue-Lan Liang, Q. Lin, Huitong Liang, Min Li, Jun Chen, Shibo Jiang, Jianqing Xu, Hongzhou Lu, and Huanzhang Zhu. Fbxo34 promotes latent hiv-1 activation by post-transcriptional modulation. Nov 2022. URL: https://doi.org/10.1080/22221751.2022.2140605, doi:10.1080/22221751.2022.2140605. This article has 13 citations and is from a domain leading peer-reviewed journal.
(yang2022fbxo34promoteslatent pages 1-2): Xinyi Yang, Xiaying Zhao, Yuqi Zhu, Jingna Xun, Q. Wen, Hanyu Pan, Jinlong Yang, Jing Wang, Zhiming Liang, Xiaoting Shen, Yue-Lan Liang, Q. Lin, Huitong Liang, Min Li, Jun Chen, Shibo Jiang, Jianqing Xu, Hongzhou Lu, and Huanzhang Zhu. Fbxo34 promotes latent hiv-1 activation by post-transcriptional modulation. Nov 2022. URL: https://doi.org/10.1080/22221751.2022.2140605, doi:10.1080/22221751.2022.2140605. This article has 13 citations and is from a domain leading peer-reviewed journal.
(yang2022fbxo34promoteslatent media bea8ea97): Xinyi Yang, Xiaying Zhao, Yuqi Zhu, Jingna Xun, Q. Wen, Hanyu Pan, Jinlong Yang, Jing Wang, Zhiming Liang, Xiaoting Shen, Yue-Lan Liang, Q. Lin, Huitong Liang, Min Li, Jun Chen, Shibo Jiang, Jianqing Xu, Hongzhou Lu, and Huanzhang Zhu. Fbxo34 promotes latent hiv-1 activation by post-transcriptional modulation. Nov 2022. URL: https://doi.org/10.1080/22221751.2022.2140605, doi:10.1080/22221751.2022.2140605. This article has 13 citations and is from a domain leading peer-reviewed journal.
(zhao2021fbxo34regulatesthe pages 1-2): Bing-Wang Zhao, Si-Min Sun, Ke Xu, Yuan-Yuan Li, Wen-Long Lei, Li Li, Sai-Li Liu, Ying-Chun Ouyang, Qing-Yuan Sun, and Zhen-Bo Wang. Fbxo34 regulates the g2/m transition and anaphase entry in meiotic oocytes. Frontiers in Cell and Developmental Biology, Mar 2021. URL: https://doi.org/10.3389/fcell.2021.647103, doi:10.3389/fcell.2021.647103. This article has 14 citations.
(kinterova2022scfligasesand pages 8-9): Veronika Kinterová, Jiří Kaňka, Alexandra Bartková, and Tereza Toralová. Scf ligases and their functions in oogenesis and embryogenesis—summary of the most important findings throughout the animal kingdom. Cells, 11:234, Jan 2022. URL: https://doi.org/10.3390/cells11020234, doi:10.3390/cells11020234. This article has 22 citations.
(OpenTargets Search: -FBXO34): Open Targets Query (-FBXO34, 6 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(kinterova2022scfligasesand pages 7-8): Veronika Kinterová, Jiří Kaňka, Alexandra Bartková, and Tereza Toralová. Scf ligases and their functions in oogenesis and embryogenesis—summary of the most important findings throughout the animal kingdom. Cells, 11:234, Jan 2022. URL: https://doi.org/10.3390/cells11020234, doi:10.3390/cells11020234. This article has 22 citations.

Artifacts

Edison artifact artifact-00

Citations

kinterova2022scfligasesand pages 8-9
kinterova2022scfligasesand pages 7-8
https://doi.org/10.1080/22221751.2022.2140605
https://doi.org/10.3389/fcell.2021.647103
https://doi.org/10.3390/cells11020234
https://platform.opentargets.org/target/ENSG00000178974
https://doi.org/10.1080/22221751.2022.2140605,
https://doi.org/10.3389/fcell.2021.647103,
https://doi.org/10.3390/cells11020234,

FBXO34 Substrate Scope and SCF Adaptor Function: Evidence Review

(FBXO34-hypotheses/kgap-fbxo34-substrate-scope/openscientist.md)

citations file

FBXO34 Substrate Scope and SCF Adaptor Function: Evidence Review

Summary

FBXO34 (F-box only protein 34; UniProt Q9NWN3) is a confirmed SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase substrate-recognition adaptor with one well-validated degradative substrate: HNRNPU/hnRNP U. Among 38 unique interaction partners catalogued in IntAct, only HNRNPU has direct evidence of FBXO34-dependent ubiquitination leading to proteasomal degradation with functional consequences (HIV-1 latency reactivation). The remaining ~35 interactors derive exclusively from high-throughput screens (Y2H, AP-MS, XL-MS, LUMIER) and lack any mechanistic validation as substrates. Current GO-style curation correctly assigns FBXO34 broad "ubiquitin-like protein ligase substrate adaptor activity" but should also support a specific HNRNPU substrate annotation. High-throughput interactors should remain classified as non-core interaction leads until independent substrate-level evidence is obtained.

1. Evidence for SCF-FBXO34 Complex Formation

F-box Domain

FBXO34 contains a canonical F-box domain at residues 572-624 (UniProt annotation), which mediates binding to SKP1, the adaptor protein linking F-box proteins to the CUL1 scaffold.

SKP1 Interaction

Method: Yeast two-hybrid (Y2H) pooling approach
Source: Stelzl et al. 2005 (PMID: 16169070) — a large-scale human interactome screen of 4,456 baits × 5,632 preys
Evidence level: High-throughput detection; consistent with canonical F-box–SKP1 binding but not independently validated by targeted biochemistry

CUL1 Interaction

Method: Anti-tag co-immunoprecipitation (AP-MS)
Source: BioPlex 2.0, Huttlin et al. 2017 (PMID: 28514442)
Evidence level: Co-purification in a systematic AP-MS campaign; supports SCF complex assembly

UniProt Curation

UniProt annotates the SUBUNIT field as "Directly interacts with SKP1 and CUL1" based on ECO:0000250 (sequence similarity evidence). The GO annotation GO:0031146 ("SCF-dependent proteasomal ubiquitin-dependent protein catabolic process") is assigned by NAS (Non-traceable Author Statement) via ComplexPortal, referencing Thompson et al. 2021 (PMID: 34445249), a review of SCF complex roles.

Assessment

The combination of a canonical F-box domain, Y2H-detected SKP1 binding, and AP-MS-detected CUL1 co-purification provides strong but indirect support for a functional SCF-FBXO34 complex. No crystal structure, targeted co-IP, or in vitro reconstitution of the trimeric SCF-FBXO34 complex has been published. The current evidence is sufficient for annotation of SCF complex membership but would benefit from targeted validation.

2. HNRNPU as the Best-Supported Degradative Substrate

Key Study: Yang et al. 2022 (PMID: 36285453)

"FBXO34 promotes latent HIV-1 activation by post-transcriptional modulation" — Emerging Microbes & Infections 11(1):2785-2799.

Evidence Lines

Evidence Type	Result
Substrate identification	HNRNPU identified by affinity purification mass spectrometry (AP-MS) as FBXO34-associated protein
Ubiquitination	FBXO34 overexpression promotes HNRNPU ubiquitination
Degradation	FBXO34-dependent ubiquitination leads to HNRNPU proteasomal degradation
Functional consequence	HNRNPU degradation abolishes HNRNPU–HIV-1 Rev mRNA interaction
Phenocopy	HNRNPU knockout phenocopies FBXO34 overexpression (both activate latent HIV-1)
Multiple cell line validation	Tested in multiple latent HIV-1 cell lines
Primary cell validation	Confirmed in primary CD4+ T lymphocyte model
Clinical relevance	Differential HNRNPU expression in ART-treated patients vs. healthy controls
Domain mapping	HNRNPU amino acids 1-339 interact with HIV-1 Rev mRNA region

Substrate Evidence Grade: Strong (Tier 1)

HNRNPU meets all standard criteria for a bona fide E3 ligase substrate:
- Direct physical interaction (AP-MS)
- Direct ubiquitination (ubiquitination assay)
- Consequent degradation
- Functional phenocopy (knockout = overexpression of E3)
- Biological pathway validation

Important Mechanistic Context: HNRNPU's Dual Regulation by SCF Complexes

A remarkable finding from the literature is that HNRNPU has a contrasting relationship with a different F-box protein, β-TrCP (FBXW1):

SCF-FBXO34 → HNRNPU is a true degradative substrate (ubiquitinated and degraded; PMID: 36285453)
SCF-β-TrCP → HNRNPU is a stable pseudosubstrate (binds β-TrCP substrate pocket but is NOT degraded; PMID: 11850407, Davis et al. 2002)

In the β-TrCP context, HNRNPU occupies the substrate-binding WD domain of β-TrCP in a stoichiometric manner, stabilizes the E3, and determines its nuclear localization. This binding is competed by phospho-IκBα (a true substrate). The pseudosubstrate relationship serves as a regulatory mechanism controlling β-TrCP localization, stability, and substrate-binding threshold.

This dual regulation demonstrates that F-box protein identity, not merely substrate binding, determines whether HNRNPU is degraded or stabilized, providing a clear example of substrate fate determination by E3 ligase specificity.

Citation-gating note: the initial OpenScientist draft cited PMID: 42348677 for an HNRNPU NEDDylation/RNA-binding-repertoire claim. PubMed verification on 2026-07-06 shows that PMID resolves to a 2026 Science article titled "Ubiquitin-like proteins NEDD8 and SUMO2 control epithelial homeostasis, regeneration, and inflammation," not the stated "Winge et al. 2026, Cell" citation. Treat the HNRNPU NEDDylation claim as an unverified/miscited lead unless full text or another verified source confirms direct HNRNPU evidence. It should not be propagated into FBXO34-ai-review.yaml as fact from this report.

3. Other Reported FBXO34 Interactors: Detailed Assessment

3A. CCNB1/Cyclin B1 — Functional Target, Not Direct Substrate (PMID: 33842473)

Study: Zhao et al. 2021, "FBXO34 Regulates the G2/M Transition and Anaphase Entry in Meiotic Oocytes" (mouse oocyte system)

Evidence	Present?
Physical interaction (co-IP/AP-MS)	No
Ubiquitination assay	No
Degradation assay	No
Half-life measurement	No
Functional rescue	Yes — CCNB1 overexpression rescues FBXO34-depletion phenotype

Assessment: CCNB1 is a functional pathway target but not a validated direct substrate. The rescue experiment shows that FBXO34 depletion leads to low MPF activity (CDK1/Cyclin B1), and CCNB1 overexpression can compensate. However, this is consistent with FBXO34 targeting an upstream inhibitor of MPF (e.g., a CDK inhibitor or Cyclin B1 degradation regulator) rather than CCNB1 directly. This work was performed in mouse oocytes; human relevance is inferred by sequence similarity.

Substrate evidence grade: Insufficient. Should not be annotated as a substrate without ubiquitination or degradation evidence.

3B. High-Throughput Binary Interactors (Y2H-Only)

Source 1: HuRI (PMID: 32296183)
Luck et al. 2020, "A reference map of the human binary protein interactome" — Nature 580:402-408.

17 partners detected, including:
- 10 KRTAPs (KRTAP4-5, 4-11, 4-12, 5-3, 9-2, 9-3, 9-8, 10-5, 10-8, 10-11, 12-4)
- ALPP, COL8A1, DISC1, FGF14, OIT3, VWC2L

Methods: Y2H array, two-hybrid prey pooling, validated two-hybrid (3 independent Y2H methods per pair in most cases)

Source 2: Rolland et al. (PMID: 25416956)
Rolland et al. 2014, "A proteome-scale map of the human interactome network" — Cell 159:1212-1226.

3 partners: MTUS2, KRT40, MDFI

Assessment: These are legitimate binary protein-protein interactions detected in well-controlled Y2H screens. However:
- No ubiquitination, degradation, half-life, or functional evidence for any of these partners
- The KRTAP enrichment (10/17 HuRI partners) is suspicious — KRTAPs are small, cysteine-rich proteins known to be promiscuous Y2H interactors. Their biological relevance to FBXO34 (a ubiquitin ligase adaptor) is unclear
- DISC1, FGF14, ALPP, COL8A1, OIT3 are biologically diverse proteins with no obvious connection to FBXO34's known ubiquitin ligase function

Substrate evidence grade: None. These should remain as non-core interaction leads in annotation databases.

3C. High-Throughput Co-complex Interactors (AP-MS)

Source: BioPlex 2.0/3.0 (PMID: 28514442, 33961781)
- Huttlin et al. 2017 and 2021

Partners: FBXO30, MYO6, YEATS4, NEXN, GSN, TMOD3, GAP43, ABRA, ERLEC1

Assessment: AP-MS co-purification indicates co-complex membership or proximity but does not distinguish direct binding from indirect association. CUL1 co-purification from the same studies is meaningful because it matches the expected SCF scaffold interaction. The other partners (cytoskeletal proteins MYO6/NEXN/GSN/TMOD3/GAP43/ABRA; ER lectin ERLEC1; chromatin factor YEATS4; another F-box protein FBXO30) lack any substrate-level evidence.

Substrate evidence grade: None.

3D. Other Detection Methods

Partner	Method	Source	Assessment
HSP90AB1	LUMIER	PMID: 22939624	Chaperone; likely recognizes FBXO34 as client protein
COA7, ITGB1, NCBP1	Cross-linking MS (XL-MS)	PMID: 30021884	Nuclear proximity; could be indirect
DISC1	Y2H fragment pooling	PMID: 31413325	Alzheimer's-associated dataset; no functional validation

Substrate evidence grade: None.

4. Summary Classification Table

Interactor	Evidence Types	Substrate Grade	Recommended Annotation
HNRNPU	AP-MS + ubiquitination + degradation + phenocopy + primary cells	Bona fide substrate	Substrate of SCF-FBXO34
SKP1	Y2H	SCF component	Core SCF complex partner
CUL1	AP-MS	SCF component	Core SCF complex partner
CCNB1	Functional rescue (mouse)	Indirect/pathway target	Functional pathway link, not substrate
KRTAPs (×10)	Y2H only	No evidence	HTP interactor; likely promiscuous
ALPP, COL8A1, DISC1, FGF14, etc.	Y2H only	No evidence	HTP interactor
FBXO30, MYO6, YEATS4, etc.	AP-MS only	No evidence	HTP co-complex
HSP90AB1	LUMIER only	No evidence	Chaperone-client
COA7, ITGB1, NCBP1	XL-MS only	No evidence	Nuclear proximity

5. Curation Recommendations

Current GO Annotations (Adequate)

GO:0031146 — SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (NAS): Correctly reflects FBXO34's role as an SCF adaptor

Recommended Additional Annotations

Substrate-specific annotation: HNRNPU should be annotated as a specific substrate of FBXO34 in GO/UniProt with experimental evidence (ECO:0000269) from PMID: 36285453. This supports a pathway-specific annotation beyond the broad "ubiquitin-like ligase substrate adaptor activity."
HIV-1 latency regulation: FBXO34's role in HIV-1 latency through HNRNPU degradation should be captured as a microbial infection-specific function (already present in UniProt FUNCTION field).
HTP interactors should NOT be converted to substrate annotations without additional evidence. The threshold for substrate annotation should require, at minimum:
Direct ubiquitination evidence (in vivo or in vitro ubiquitination assay)
Evidence of FBXO34-dependent degradation or protein level change
Ideally: functional rescue or reconstitution
Oocyte maturation function: The CCNB1 functional rescue (PMID: 33842473) supports a GO annotation for meiotic cell cycle regulation but should be qualified as "by similarity" (mouse data) and should NOT annotate CCNB1 as a substrate.

What Would Strengthen the FBXO34 Literature

In vitro reconstitution of SCF-FBXO34 ubiquitination of HNRNPU
Identification of the HNRNPU degron recognized by FBXO34
Crystal or cryo-EM structure of FBXO34 alone or in complex with SKP1
Cycloheximide chase experiments quantifying HNRNPU half-life ± FBXO34
Identification of additional substrates beyond HNRNPU with full validation
Confirmation of CCNB1 as direct or indirect target with mechanistic detail

6. Limitations

PMID: 36285453 (Yang et al. 2022) — The abstract was available but the full text was not systematically reviewed in this analysis. Specific experimental details (e.g., whether in vitro ubiquitination was performed, whether a degron motif was mapped) require full-text verification.
PMID: 33842473 (Zhao et al. 2021) — Mouse oocyte study; species extrapolation to human is annotated "by similarity" (ECO:0000250) in UniProt. The direct substrate in oocyte meiosis remains unidentified.
PMID: 42348677 was PubMed-verified as a real 2026 Science paper, but the report's original "HNRNPU NEDDylation regulation" wording is not verified by the PubMed title/metadata and may be miscited. Keep this as an unverified lead unless a curator checks the full text.
PMID: 40497153 was PubMed-verified as a 2025 Journal of Virus Eradication HIV-1 latency review. Treat it as background only unless full text is checked for a specific FBXO34 claim.
The HuRI/BioPlex interactors were assessed at the annotation level. Individual follow-up studies on any of these partners (beyond the original HTP screens) were not found in PubMed, suggesting they remain uncharacterized.
FBXO34 remains a relatively understudied F-box protein with only 5 primary PubMed entries as of this analysis, compared to dozens for well-characterized F-box proteins like β-TrCP, FBXW7, or SKP2.

7. Key Citations

PMID	Reference	Contribution
36285453	Yang et al. 2022, Emerg Microbes Infect	Primary FBXO34/HNRNPU substrate evidence
33842473	Zhao et al. 2021, Front Cell Dev Biol	FBXO34 in oocyte meiosis
11850407	Davis et al. 2002, Genes Dev	HNRNPU as pseudosubstrate of β-TrCP (contrast)
42348677	PubMed-verified 2026 Science article, "Ubiquitin-like proteins NEDD8 and SUMO2 control epithelial homeostasis, regeneration, and inflammation"	Citation-gating warning: original HNRNPU NEDDylation claim is unverified/may be miscited
20797629	Tsuchiya et al. 2010, Mol Cell	Nuclear IKKβ–β-TrCP–hnRNP-U axis
16169070	Stelzl et al. 2005, Cell	Y2H: FBXO34–SKP1 interaction
28514442	Huttlin et al. 2017, Nature	BioPlex 2.0: FBXO34–CUL1 and other AP-MS
33961781	Huttlin et al. 2021, Cell	BioPlex 3.0: additional AP-MS interactors
32296183	Luck et al. 2020, Nature	HuRI: Y2H binary interactors
25416956	Rolland et al. 2014, Cell	Y2H interactome: MTUS2, KRT40, MDFI
40497153	Yang et al. 2025, J Virus Erad	PubMed-verified HIV-1 latency review; background only unless full text confirms specific FBXO34 support
34445249	Thompson et al. 2021, IJMS	SCF complex review (GO annotation source)
22939624	Taipale et al. 2012, Cell	HSP90–FBXO34 LUMIER interaction
30021884	Fasci et al. 2018, MCP	XL-MS in nuclei
31413325	Sügis et al. 2019, Sci Data	HENA Alzheimer's dataset (DISC1)

Report generated: Iteration 1 of 1. Analysis based on PubMed literature search, UniProt (Q9NWN3), IntAct (89 interaction records, 38 unique partners), and BioGRID (58 interactions) as of July 2026.

OpenScientist prompt: FBXO34 substrate scope and SCF adaptor function

(FBXO34-hypotheses/kgap-fbxo34-substrate-scope/prompt.md)

OpenScientist prompt: FBXO34 substrate scope and SCF adaptor function

Investigate the evidence that human FBXO34 is an SCF ubiquitin-ligase substrate-recognition adaptor, and determine which reported interactors are bona fide physiological ubiquitination substrates.

Focus on:

direct evidence for SCF-FBXO34 complex formation and substrate-recognition activity;
HNRNPU/hnRNP U as the best-supported human substrate or target;
other reported FBXO34 interactors and whether they have direct FBXO34-dependent ubiquitination, degradation, half-life, rescue, or reconstitution evidence;
whether high-throughput protein-binding annotations should remain non-core interaction leads or be converted into mechanistically supported substrate relationships.

Please distinguish degradative substrates from non-substrate interactors and indirect pathway effects. Conclude whether current GO-style curation should stop at broad ubiquitin-like ligase-substrate adaptor activity or support additional substrate/pathway-specific annotations. Include PMIDs and flag uncached or uncertain citations.

📚 Additional Documentation

Pn Notes

(FBXO34-pn-notes.md)

FBXO34 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9NWN3
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FBXO34/FBXO34-ai-review.yaml
AIGR review HTML: missing - genes/human/FBXO34/FBXO34-ai-review.html
Gene notes: missing - genes/human/FBXO34/FBXO34-notes.md
GOA TSV: present - genes/human/FBXO34/FBXO34-goa.tsv
UniProt record: present - genes/human/FBXO34/FBXO34-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FBXO34.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FBXO34.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/FBXO34/FBXO34-deep-research-falcon.md

AIGR Review Snapshot

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/core annotation action counts: ACCEPT: 2; KEEP_AS_NON_CORE: 3

PN Consistency Summary

Consistency: Strong. Deep research (Falcon → HNRNPU substrate, HIV-1 latency reversal; mouse meiotic CCNB1/MPF role), UniProt and GOA agree on SCF substrate-receptor role. Review core MF = GO:1990756. No contradictions. PMID:36285453 (HNRNPU/HIV) verified, is the UniProt FUNCTION source.
PN story / NEW pressure: PN asserts only the generic adaptor MF. Like FBXO33, FBXO34's GOA has NO ubiquitin-ligase/transferase MF to MODIFY — only protein binding IPI (mostly sticky Y2H KRTAPs), SCF complex CC and SCF catabolism BP (both NAS/ComplexPortal). So GO:1990756 is inferred-only here too, justified by the HNRNPU degradation evidence. Substrate repertoire thin (one human substrate); review correctly proposes no substrate-specific NEW terms (proposed_new_terms empty). Conclusion: PN adaptor claim = defensible ADD to GOA (GO:1990756 verified real); flag adaptor MF as inferred-only with a single validated substrate.
Evidence alignment: PN cites only "15340381 / rev". Review anchored on PMID:36285453 (HNRNPU/HIV, verified) + Falcon (Yang 2022 human; Zhao 2021/Kinterova 2022 mouse meiosis, orthology-based UNVERIFIED) + interactome PMIDs + PMID:34445249. PN reference disjoint from review's.
Verdict: CONSISTENT — no edits required; flag GO:1990756 core MF as inferred-only (one validated substrate, HNRNPU).

Full Consistency Review

UniProt: Q9NWN3 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE (developed; poorly characterized gene, sparse GOA)
PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|other ; PN-node mapping: group=mapped GO:1990756; subtype/type/branch=no_mapping; class=context_only (GO:0061630).
Consistency: Strong. Deep research (Falcon → HNRNPU substrate, HIV-1 latency reversal; mouse meiotic CCNB1/MPF role), UniProt and GOA agree on SCF substrate-receptor role. Review core MF = GO:1990756. No contradictions. PMID:36285453 (HNRNPU/HIV) verified, is the UniProt FUNCTION source.
PN story / NEW pressure: PN asserts only the generic adaptor MF. Like FBXO33, FBXO34's GOA has NO ubiquitin-ligase/transferase MF to MODIFY — only protein binding IPI (mostly sticky Y2H KRTAPs), SCF complex CC and SCF catabolism BP (both NAS/ComplexPortal). So GO:1990756 is inferred-only here too, justified by the HNRNPU degradation evidence. Substrate repertoire thin (one human substrate); review correctly proposes no substrate-specific NEW terms (proposed_new_terms empty). Conclusion: PN adaptor claim = defensible ADD to GOA (GO:1990756 verified real); flag adaptor MF as inferred-only with a single validated substrate.
Mapping strategy: Correct; gene does not change the node. GO:1990756 equals the review's core MF and genuinely adds value (no MF in GOA). The large block of high-throughput protein-binding IPIs (KRTAPs, MTUS2, KRT40) are correctly kept non-core / flagged as likely non-physiological.
Evidence alignment: PN cites only "15340381 / rev". Review anchored on PMID:36285453 (HNRNPU/HIV, verified) + Falcon (Yang 2022 human; Zhao 2021/Kinterova 2022 mouse meiosis, orthology-based UNVERIFIED) + interactome PMIDs + PMID:34445249. PN reference disjoint from review's.
Verdict: CONSISTENT — no edits required; flag GO:1990756 core MF as inferred-only (one validated substrate, HNRNPU).

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/FBXO34/FBXO34-ai-review.yaml
PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | other

UniProt: Q9NWN3
In branches: UPS
Signature domains: IPR001810
Auxiliary domains: (none)
PN references (titles):
- 15340381 / rev
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|other
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
  status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
  rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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.

FBXO34

Gene Description

Existing Annotations Review

Core Functions

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.

References

Suggested Questions for Experts

Suggested Experiments

Knowledge Gaps

Deep Research

Falcon

Comprehensive research report: FBXO34 (UniProt Q9NWN3; Homo sapiens)

0) Target verification (mandatory)

1) Key concepts and definitions (current understanding)

1.1 What an “F-box only” protein is

1.2 What “substrate” means in this context

2) Molecular function and mechanism (best-supported, with evidence)

2.1 Primary supported function: ubiquitination-linked control of hnRNP U (human)

2.2 Quantitative/experimental readouts in human cell models (statistics)

2.3 What remains unclear mechanistically

3) Biological processes, pathways, and cellular roles

3.1 HIV latency (human; direct mechanistic evidence)

3.2 Cell-cycle/meiosis control (mouse; orthology/context)

4) Subcellular localization

4.1 Human localization: limited direct evidence in retrieved corpus

4.2 Mouse oocyte localization (non-human; hypothesis-generating for human)

5) Recent developments (prioritizing 2023–2024)

5.1 Direct 2023–2024 mechanistic literature specific to FBXO34

5.2 2024 topical relevance via host RNA-binding proteins / viral infection context

6) Current applications and real-world implementations

6.1 Therapeutic concept: targeting the FBXO34/hnRNP U axis in HIV reservoir control

7) Disease associations and human genetics (database-level evidence)

8) Expert analysis and interpretation (authoritative synthesis anchored to evidence)

Evidence summary table

Key URLs and publication dates (from retrieved sources)

Limitations of this report (evidence-bounded)

Artifacts

Citations

FBXO34 Substrate Scope and SCF Adaptor Function: Evidence Review

FBXO34 Substrate Scope and SCF Adaptor Function: Evidence Review

Summary

1. Evidence for SCF-FBXO34 Complex Formation

F-box Domain

SKP1 Interaction

CUL1 Interaction

UniProt Curation

Assessment

2. HNRNPU as the Best-Supported Degradative Substrate

Key Study: Yang et al. 2022 (PMID: 36285453)

Evidence Lines

Substrate Evidence Grade: Strong (Tier 1)

Important Mechanistic Context: HNRNPU's Dual Regulation by SCF Complexes

3. Other Reported FBXO34 Interactors: Detailed Assessment

3A. CCNB1/Cyclin B1 — Functional Target, Not Direct Substrate (PMID: 33842473)

3B. High-Throughput Binary Interactors (Y2H-Only)

3C. High-Throughput Co-complex Interactors (AP-MS)

3D. Other Detection Methods

4. Summary Classification Table

5. Curation Recommendations

Current GO Annotations (Adequate)

Recommended Additional Annotations

What Would Strengthen the FBXO34 Literature

6. Limitations

7. Key Citations

OpenScientist prompt: FBXO34 substrate scope and SCF adaptor function

OpenScientist prompt: FBXO34 substrate scope and SCF adaptor function

📚 Additional Documentation

Pn Notes

FBXO34 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | other

Projected GO annotations (1)

Note

📄 View Raw YAML