FBXO47

UniProt ID: Q5MNV8
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

FBXO47 (F-box only protein 47) is a 452-residue F-box-domain-containing protein (F-box at residues 41-91, plus an FBXO47-specific armadillo-like region) belonging to the FBXO ("F-box only") subfamily of F-box proteins, which canonically act as substrate-recognition receptors that, together with SKP1, CUL1 and RBX1, assemble SCF (SKP1-cullin-F-box) E3 ubiquitin ligase complexes. FBXO47 is strongly enriched in testis (HPA testis-enriched; expressed in male germline cells) and was originally cloned from a testis library. Functional studies in mouse have established FBXO47 as a germ-cell protein essential for meiotic prophase I in spermatocytes: Fbxo47-null males are infertile with spermatocytes arresting around late zygotene/pachytene, showing incomplete homologous synapsis, persistent autosomal gamma-H2AX, and failure to form XY bodies. Mechanistically, FBXO47 acts at meiotic chromosome subcompartments through SKP1-associated regulation: it localizes to the nuclear periphery and co-localizes with the shelterin component TRF2, where it promotes telomere-inner nuclear membrane attachment by stabilizing TRF2 (impairing TRF2 ubiquitination) during the bouquet stage; FBXO47 also interacts with SKP1 and the axis protein HORMAD1, contributing to HORMAD1 turnover and meiotic double-strand-break/ recombination homeostasis, and has been proposed to act in a centromeric SCF module that preserves centromeric SKP1 to support centromere pairing. Notably, several of its documented activities involve preventing rather than promoting substrate degradation (TRF2, SKP1), so its in vivo role may diverge from a classical SCF substrate receptor that drives degradation. A curated SCF E3 ligase complex variant containing FBXO47 has been recorded (ComplexPortal CPX-8006). FBXO47 maps to 17q12; human genetics associates the locus with azoospermia, and a missense variant has been reported as a candidate in autosomal recessive intellectual disability.

Proposed New Ontology Terms

telomere attachment to nuclear envelope involved in meiotic telomere clustering (bouquet formation)

Definition: A meiotic-prophase-I biological process in which telomeres become tethered to and cluster at the inner nuclear membrane (the bouquet stage), facilitating homologous chromosome pairing and recombination. FBXO47's best-supported in vivo role is promoting this telomere-inner-nuclear-membrane attachment via stabilization of the shelterin protein TRF2; no existing FBXO47 annotation captures this specific telomere-INM/bouquet process. Proposed label and definition only; no GO ID invented.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0019005 SCF ubiquitin ligase complex
NAS
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromoso... 		KEEP AS NON CORE
Summary: ComplexPortal NAS assertion that FBXO47 is part of an SCF E3 ubiquitin ligase complex, consistent with its F-box domain and the curated FBXO47-variant SCF complex (CPX-8006). FBXO47's essential, experimentally established biology is in meiotic prophase, not canonical SCF catalysis, so this is retained as non-core.
Reason: FBXO47 has an F-box domain and a curated SCF-complex variant (CPX-8006), and UniProt states it is part of an SCF complex, but this is inferred by similarity (ECO:0000250) and asserted (NAS) from a general SCF review (PMID:34445249) rather than demonstrated for FBXO47 specifically. Falcon-sourced primary literature (Hua 2019; Ma 2024) shows FBXO47 physically interacts with the SCF core component SKP1 in germ cells, which biochemically supports SCF-machinery association; however the in vivo essential function is in meiotic prophase (telomere-INM integration via TRF2 stabilization, centromere pairing) and several activities prevent rather than promote substrate degradation, so SCF-complex membership is kept as a non-core annotation rather than promoted to a core function. This is consistent with the functional placement of FBXO47 as an F-box/SCF (CRL1) substrate-recognition module while keeping the meiotic biology central.
Supporting Evidence:
file:human/FBXO47/FBXO47-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex.
file:human/FBXO47/FBXO47-deep-research-falcon.md
Evidence from co-immunoprecipitation indicates FBXO47 **interacts with SKP1**, supporting a model in which FBXO47 can act as an F-box/SCF-associated factor
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
NAS
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromoso... 		UNDECIDED
Summary: ComplexPortal NAS assertion that FBXO47 participates in SCF-dependent proteasomal protein degradation. This is inferred from F-box family membership and a general SCF review, and the UniProt FUNCTION itself is only a "Probably" statement by similarity; the experimentally documented FBXO47 function is in meiosis and may not proceed via canonical SCF-dependent degradation in vivo.
Reason: The annotation rests on family-level inference (UniProt FUNCTION is a "Probably recognizes... promotes their ubiquitination and degradation" ECO:0000250 statement) and an NAS citation to a general SCF review (PMID:34445249) that does not characterize FBXO47. Falcon-sourced primary literature complicates rather than confirms this term: while one study reports FBXO47 can target HORMAD1 for polyubiquitination and degradation (supporting some SCF-dependent catabolic activity), the best-characterized FBXO47 activities are protective/stabilizing (impairing ubiquitination of TRF2 and of SKP1), i.e. opposing degradation. The functionally validated in vivo role of FBXO47 (mouse knockouts) is in meiotic prophase / telomere-INM integration / centromere pairing; whether FBXO47's essential function proceeds via canonical SCF-dependent proteasomal degradation of substrates in vivo is not established. Marked UNDECIDED rather than ACCEPT/REMOVE because the underlying biochemical claim cannot be verified from the available evidence and the gene's documented activities point in both directions.
Supporting Evidence:
file:human/FBXO47/FBXO47-uniprot.txt
Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation.
file:human/FBXO47/FBXO47-deep-research-falcon.md
FBXO47 interacts with SKP1 and HORMAD1 and targets HORMAD1 for polyubiquitination and degradation in HEK293T cells

Core Functions

F-box-domain protein expressed in male germ cells that is essential for meiotic prophase I. FBXO47 acts at meiotic chromosome subcompartments through SKP1-associated regulation: it localizes to the nuclear periphery, co-localizes with the shelterin protein TRF2, and promotes telomere-inner nuclear membrane attachment (bouquet formation) by stabilizing TRF2 (impairing its ubiquitination); it also engages SKP1 and the axis protein HORMAD1 and is implicated in HORMAD1 turnover, homologous synapsis, and meiotic double-strand-break/recombination homeostasis. FBXO47 carries the F-box motif characteristic of SCF substrate-recognition receptors and is recorded as part of a curated FBXO47-variant SCF E3 ligase complex, but several of its documented activities prevent rather than promote substrate degradation, so its essential meiotic role may be partly distinct from canonical SCF-mediated proteasomal degradation; a direct in vivo SCF substrate-receptor catalytic role for FBXO47 has not been firmly established.

Molecular Function:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
homologous chromosome pairing at meiosis
Cellular Locations:
condensed nuclear chromosome
Supporting Evidence:
  • file:human/FBXO47/FBXO47-uniprot.txt
    Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation.
  • file:human/FBXO47/FBXO47-uniprot.txt
    DOMAIN 41..91
  • file:human/FBXO47/FBXO47-deep-research-falcon.md
    Most supported primary function: FBXO47 is a meiosis-associated F‑box protein that interacts with SCF machinery (via SKP1) and regulates key meiotic chromosomal proteins to ensure proper meiotic prophase progression.

References

PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  • General review of the 69 SCF E3 ubiquitin ligase complexes, in which variable F-box proteins determine substrate specificity and target substrates for proteasomal degradation; does not specifically characterize FBXO47.
file:human/FBXO47/FBXO47-uniprot.txt
UniProt entry Q5MNV8 (FBX47_HUMAN), F-box only protein 47
  • UniProt FUNCTION and SUBUNIT for FBXO47 are inferred by similarity (ECO:0000250); FBXO47 is testis-enriched and contains an F-box domain (residues 41-91).
file:human/FBXO47/FBXO47-deep-research-falcon.md
Falcon deep research report for human FBXO47
  • FBXO47 is a meiosis-associated F-box protein that interacts with the SCF core component SKP1 and regulates meiotic chromosomal proteins (TRF2, HORMAD1) during meiotic prophase I.
    "Most supported primary function: FBXO47 is a meiosis-associated F‑box protein that interacts with SCF machinery (via SKP1) and regulates key meiotic chromosomal proteins to ensure proper meiotic prophase progression."
  • In the meiotic context FBXO47 stabilizes the shelterin protein TRF2 (impairing its ubiquitination) at the telomere-inner nuclear membrane interface, rather than promoting TRF2 degradation.
    "Ubiquitination assays indicate FBXO47 overexpression can **impair TRF2 ubiquitination** (without similarly affecting TRF1), consistent with **TRF2 stabilization**"
  • FBXO47 interacts with SKP1 and HORMAD1 and can target HORMAD1 for polyubiquitination/degradation, linking SCF activity to control of meiotic DSB homeostasis.
    "FBXO47 interacts with SKP1 and HORMAD1 and targets HORMAD1 for polyubiquitination and degradation in HEK293T cells"
  • A 2024 model proposes FBXO47 acts in a centromeric SCF module that suppresses SKP1 ubiquitination to preserve centromeric SKP1 and promote centromere pairing and pachytene progression.
    "FBXO47 is a component of a **centromeric SCF E3 ligase** and that FBXO47 can **reduce SKP1 ubiquitination**, helping preserve SKP1 levels at centromeres/chromosome axes"

Suggested Questions for Experts

Q: Does FBXO47 assemble a canonical SCF (SKP1-CUL1-RBX1) E3 ligase complex in germ cells and ubiquitinate substrates for proteasomal degradation, or does its essential meiotic function (telomere-INM integration, centromere pairing) operate via non-degradative, stabilizing activities (e.g. shielding TRF2 and SKP1 from ubiquitination)?

Q: Are the telomere-centric (TRF2/bouquet) and centromere-centric (SKP1/centromere pairing) models of FBXO47 reconcilable as a single SKP1-dependent meiotic surveillance activity, or do they reflect distinct chromosome-subcompartment functions and/or antibody/knockout-method artefacts?

Q: Is the human FBXO47 azoospermia association causal, and does the reported intellectual-disability missense variant (R182G) affect FBXO47 function or reflect linkage at 17q12?

Suggested Experiments

Experiment: Generate F-box-deletion or F-box point-mutant FBXO47 alleles (disrupting SKP1 binding) in a germ-cell or mouse model and assess whether SKP1/SCF association is required for telomere-INM integration, TRF2 stabilization, and centromere pairing, distinguishing degradative SCF function from non-degradative stabilizing roles.

Experiment: Perform affinity-purification mass spectrometry of FBXO47 from testis across meiotic stages to define its complex composition (SKP1/CUL1/RBX1 versus shelterin/axis partners such as TRF2 and HORMAD1) and candidate ubiquitination substrates, followed by in vitro reconstitution and ubiquitination/deubiquitination assays to test whether FBXO47 promotes or restrains substrate ubiquitination.

Experiment: Use super-resolution and electron microscopy of Fbxo47 wild-type versus knockout spermatocytes to map FBXO47 localization at telomere-INM versus centromeric/axis sites and directly test the telomere-centric versus centromere-centric models.

Deep Research

Falcon

(FBXO47-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 13 citations 2 artifacts 2026-06-13T06:59:47.959660
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000010 The requested visual information can be found in Figures 1 and 4 of the document: - **FBXO47 colocalization with TRF2 at the nuclea (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.

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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.

Research report: Human FBXO47 (UniProt Q5MNV8) — functional annotation

0) Target verification (critical identity checks)

The target gene/protein in this report is human FBXO47 (F‑box only protein 47), matching UniProt accession Q5MNV8 and the expected functional class of an F‑box protein, i.e., a substrate-recognition factor that typically binds SKP1 within a SCF (SKP1–CUL1–F‑box) E3 ubiquitin ligase. Evidence discussed below consistently treats FBXO47 as an F‑box protein that physically interacts with SKP1 and regulates key meiotic proteins (TRF2; HORMAD1), aligning with the UniProt-provided identity and domain expectations (F-box-like domain). (hua2019fbxo47regulatestelomereinner pages 10-11, ma2024fbxo47regulatescentromere pages 8-9)

1) Key concepts and definitions (current understanding)

1.1 F‑box proteins and SCF E3 ubiquitin ligases

F‑box proteins are generally understood as substrate adaptors of SCF-type E3 ubiquitin ligase complexes, enabling selective ubiquitination that can lead to proteasomal degradation or other ubiquitin-dependent regulation of target proteins. In the FBXO47 context, primary studies explicitly show FBXO47–SKP1 interaction, consistent with SCF membership, and functional ubiquitination-related assays affecting meiotic proteins (TRF2; HORMAD1; SKP1) (hua2019fbxo47regulatestelomereinner pages 10-11, ma2024fbxo47regulatescentromere pages 8-9).

1.2 Meiotic telomere–nuclear envelope attachment (“bouquet”) and shelterin factors

During meiotic prophase I, telomeres tether to the inner nuclear membrane (INM) and cluster (bouquet stage), helping homolog pairing and recombination. A central telomere complex is shelterin, including TRF1/TRF2. In a key mechanistic study, FBXO47 is positioned as a regulator of telomere–INM integration by influencing shelterin component stability—particularly TRF2 (hua2019fbxo47regulatestelomereinner pages 8-10, hua2019fbxo47regulatestelomereinner pages 10-11).

1.3 Centromere pairing and synapsis integrity

Beyond telomeres, meiotic chromosome behavior depends on centromere pairing and synaptonemal complex organization. A 2024 study proposes FBXO47 functions in a centromeric SCF module that maintains centromeric SCF components (notably SKP1) to promote centromere pairing and pachytene progression (ma2024fbxo47regulatescentromere pages 1-2, ma2024fbxo47regulatescentromere pages 8-9).

2) Molecular function of FBXO47: mechanisms, partners, substrates

2.1 FBXO47 interacts with SCF core component SKP1

Evidence from co-immunoprecipitation indicates FBXO47 interacts with SKP1, supporting a model in which FBXO47 can act as an F-box/SCF-associated factor (hua2019fbxo47regulatestelomereinner pages 10-11). A more recent mechanistic proposal highlights FBXO47–SKP1 binding and argues FBXO47 helps preserve SKP1 by modulating its ubiquitination (ma2024fbxo47regulatescentromere pages 8-9).

2.2 Regulation of telomere proteins TRF1/TRF2; stabilization of TRF2

A central mechanistic claim is that FBXO47 interacts with TRF1 and TRF2 and preferentially stabilizes TRF2:
* Co-IP experiments support FBXO47 interaction with TRF1/TRF2 (hua2019fbxo47regulatestelomereinner pages 11-11).
* Ubiquitination assays indicate FBXO47 overexpression can impair TRF2 ubiquitination (without similarly affecting TRF1), consistent with TRF2 stabilization (hua2019fbxo47regulatestelomereinner pages 11-11).
* Quantitative immunofluorescence intensity measurements reported TRF1 signal intensity was not reduced in knockouts (8.769 ± 0.351 vs 9.786 ± 0.6768), while TRF2 intensity decreased in Fbxo47−/− spermatocytes across stages (e.g., zygotene 38.046 ± 7.281 vs 18.953 ± 13.110) (hua2019fbxo47regulatestelomereinner pages 10-11).

Interpretation: in the meiotic context, FBXO47 may function less like a “classic” SCF adaptor that triggers target degradation, and more like a regulator that prevents inappropriate ubiquitination/turnover of TRF2 during meiotic telomere–INM integration (hua2019fbxo47regulatestelomereinner pages 11-11, hua2019fbxo47regulatestelomereinner pages 10-11).

2.3 Connection to HORMAD1 and meiotic DSB homeostasis

A 2022 Nucleic Acids Research study (focused on SCF core factor SKP1 in meiosis) reports a mechanistic link wherein FBXO47 interacts with SKP1 and HORMAD1 and targets HORMAD1 for polyubiquitination and degradation in HEK293T cells, supporting a model where SCF helps restrain hyperactive DSB formation by modulating HORMAD1 abundance and upstream DSB machinery recruitment (hua2019fbxo47regulatestelomereinner pages 4-4). In 2024, a centromere-focused study further interprets that FBXO47 “probably regulates HORMAD1” (building on prior work) to ensure proper HORMAD1 unloading from synapsed regions (ma2024fbxo47regulatescentromere pages 8-9).

2.4 Proposed centromeric SCF mechanism via SKP1 stabilization (2024)

Ma et al. (Communications Biology, published online 2024-09; https://doi.org/10.1038/s42003-024-06782-6) propose FBXO47 is a component of a centromeric SCF E3 ligase and that FBXO47 can reduce SKP1 ubiquitination, helping preserve SKP1 levels at centromeres/chromosome axes. They report a quantitative metric: average SKP1 centromeric-end/counterpart signal ratio = 3.62, and multiple significant comparisons in figures (p = 0.0003, p = 0.0016, p < 0.0001) (ma2024fbxo47regulatescentromere pages 8-9).

3) Biological processes and pathways

3.1 Meiotic prophase I progression, homolog synapsis, and telomere–INM integration

A mechanistic study (Nucleic Acids Research, 2019-11; https://doi.org/10.1093/nar/gkz992) positions FBXO47 as required for proper telomere–INM integration: FBXO47 localizes to the nuclear periphery in early prophase and co-localizes with TRF2, and loss of Fbxo47 leads to increased detached/internal telomeres measured as internal TRF1 foci (n > 30 cells/genotype; ***P < 0.001) (hua2019fbxo47regulatestelomereinner pages 8-10, hua2019fbxo47regulatestelomereinner media f09c33b9, hua2019fbxo47regulatestelomereinner media c8432221).

These findings support a pathway-level role: FBXO47 → TRF2 stabilization → telomere attachment/bouquet progression → synapsis and recombination fidelity (hua2019fbxo47regulatestelomereinner pages 8-10, hua2019fbxo47regulatestelomereinner pages 10-11).

3.2 Meiotic DSB regulation via SCF components and axis proteins

The SCF ubiquitin ligase system is implicated in restraining excessive DSB formation and coordinating recombination; a key mechanistic component is HORMAD1 accumulation and its influence on the pre-DSB complex. Evidence supports FBXO47 as one meiotic F-box protein that can link SCF to HORMAD1 ubiquitin-dependent turnover (in cell assays), providing a plausible pathway connection: FBXO47–SCF → HORMAD1 regulation → DSB homeostasis and synapsis initiation (hua2019fbxo47regulatestelomereinner pages 4-4).

3.3 Centromere pairing and pachytene progression (2024 model)

Ma et al. (2024-09) propose that a centromeric SCF including FBXO47 promotes centromere pairing and synapsis integrity; knockout phenotypes described include leptotene/zygotene delay, pachytene-like arrest, crossover failure, and altered HORMAD1 behavior at centromeric ends (ma2024fbxo47regulatescentromere pages 8-9, ma2024fbxo47regulatescentromere pages 1-2).

4) Subcellular localization and where the gene product acts

4.1 Nuclear periphery / telomere–INM interface

FBXO47 was reported to form foci on the nuclear surface during early meiotic prophase I and co-localize with TRF2 at the nuclear periphery, consistent with a role at telomeres as they attach to the INM (hua2019fbxo47regulatestelomereinner pages 5-6, hua2019fbxo47regulatestelomereinner media f09c33b9).

4.2 Centromeres / chromosome axes (alternative or additional localization)

A 2024 Communications Biology paper emphasizes centromeric localization of FBXO47 and interprets FBXO47 as part of a centromeric SCF module that affects centromere pairing and synapsis integrity (ma2024fbxo47regulatescentromere pages 1-2, ma2024fbxo47regulatescentromere pages 8-9).

4.3 Current uncertainty: telomere-centric vs centromere-centric models

The 2024 centromere-focused paper explicitly notes conflicting prior reports emphasizing telomere roles and suggests technical factors (e.g., antibody quality; KO methods) may contribute to discrepancies (ma2024fbxo47regulatescentromere pages 1-2). A 2024 review focused on spermatogenesis largely frames FBXO47 as telomere/NE-associated (xuan2024theemergingand pages 5-7, xuan2024theemergingand pages 7-8). Overall, the most defensible current view is that FBXO47 is a meiotic nuclear protein that may function at multiple chromosome subcompartments (telomere/NE interface and/or centromeres) through SCF-related regulation (ma2024fbxo47regulatescentromere pages 8-9, xuan2024theemergingand pages 7-8).

5) Recent developments and latest research (prioritizing 2023–2024)

5.1 2024: FBXO47 as a centromeric SCF component regulating SKP1 ubiquitination

The major 2024 primary advance is the proposal and supporting evidence that FBXO47 participates in a centromeric SCF E3 ligase in spermatocytes, binds SKP1, and reduces SKP1 ubiquitination, maintaining centromeric SKP1 abundance and centromere pairing (Communications Biology; 2024-09; https://doi.org/10.1038/s42003-024-06782-6) (ma2024fbxo47regulatescentromere pages 8-9, ma2024fbxo47regulatescentromere pages 1-2).

5.2 2024: Expert synthesis (review) emphasizing telomere–NE and meiotic arrest phenotypes

A 2024 review in Cell Regeneration (published 2024-06; https://doi.org/10.1186/s13619-024-00196-9) summarizes FBXO47 as a meiotic F-box protein involved in telomere–NE integration; the review interprets knockout phenotypes (late-zygotene arrest, incomplete synapsis, impaired DSB repair signals such as autosomal γH2AX retention, lack of XY bodies) as evidence FBXO47 is necessary for telomere-mediated meiotic progression and male fertility (xuan2024theemergingand pages 7-8).

6) Human disease relevance, applications, and real-world implementations

6.1 Evidence for association with male infertility/azoospermia

Open Targets reports an association between human FBXO47 (ENSG00000204952) and azoospermia (evidence score ~0.105; 5 evidence items) (OpenTargets Search: -FBXO47). While the strongest mechanistic evidence is from mouse genetics and cell assays, the disease association is biologically plausible given the meiosis-specific roles described in mammalian spermatocytes (hua2019fbxo47regulatestelomereinner pages 8-10, ma2024fbxo47regulatescentromere pages 8-9).

6.2 Epidemiology/statistics: azoospermia burden (context for applications)

A Scientific Reports analysis of azoospermia/male infertility transcriptomic datasets notes that azoospermia affects ~1% of all men and is prevalent in up to 10–15% of infertile males, highlighting clinical relevance and diagnostic need (published 2022-02; https://doi.org/10.1038/s41598-022-06476-1) (omolaoye2022usingpubliclyavailable pages 8-9).

6.3 Diagnostics/biomarkers: current state

A 2022 paper mining public testis transcriptomic datasets discusses the limited literature tying F-box proteins to male infertility and largely cites model-organism mechanisms (including FBXO47’s role with TRF1/2 and bouquet progression) rather than presenting FBXO47 as a validated human biomarker with effect sizes in patient cohorts (omolaoye2022usingpubliclyavailable pages 8-9). Therefore, FBXO47 is best viewed currently as a candidate gene for mechanistic panels and sequencing-based etiologic workups, rather than a stand-alone clinically validated biomarker in routine diagnostics (OpenTargets Search: -FBXO47, omolaoye2022usingpubliclyavailable pages 8-9).

6.4 Therapeutics and contraception: present limitations

Given FBXO47’s essential role in meiosis and its highly germline-enriched functional framing, it is conceptually relevant to non-hormonal male contraception and infertility therapeutics; however, no FBXO47-targeted interventions or trials were identified in the clinical-trials search performed here, indicating no direct clinical implementation at present (OpenTargets Search: -FBXO47).

7) Evidence-backed statistics and data highlights

  • Detached telomeres / internal TRF1 foci: n > 30 cells per genotype; P < 0.001 in Fbxo47−/− vs wild type (Hua et al. 2019; figure-based quantification) (hua2019fbxo47regulatestelomereinner pages 8-10, hua2019fbxo47regulatestelomereinner media c8432221).
  • TRF1 vs TRF2 quantitative intensity (meiotic spreads): TRF1 not reduced (8.769 ± 0.351 vs 9.786 ± 0.6768), but TRF2 reduced in Fbxo47−/− spermatocytes (examples reported for leptotene and zygotene) (hua2019fbxo47regulatestelomereinner pages 10-11).
  • Centromeric SKP1 signal metric (2024): SKP1 centromeric-end/counterpart signal ratio 3.62; multiple significant comparisons (p = 0.0003, p = 0.0016, p < 0.0001) (ma2024fbxo47regulatescentromere pages 8-9).
  • Clinical prevalence context: azoospermia affects ~1% of all men; up to 10–15% of infertile males (Omolaoye et al. 2022) (omolaoye2022usingpubliclyavailable pages 8-9).

8) Visual evidence from primary literature

Key figure panels from Hua et al. (2019) show (i) FBXO47 colocalization with TRF2 at the nuclear periphery and (ii) quantification of detached/internal telomeres using internal TRF1 foci counts and bar graphs with n > 30 and P < 0.001 (hua2019fbxo47regulatestelomereinner media f09c33b9, hua2019fbxo47regulatestelomereinner media c8432221).

9) Summary and consensus functional annotation (with explicit uncertainty)

Most supported primary function: FBXO47 is a meiosis-associated F‑box protein that interacts with SCF machinery (via SKP1) and regulates key meiotic chromosomal proteins to ensure proper meiotic prophase progression. The strongest mechanistic evidence links FBXO47 to telomere–INM integration via TRF2 stabilization and to broader SCF-mediated control of meiotic chromosome axis factors (HORMAD1) influencing recombination/DSB homeostasis (hua2019fbxo47regulatestelomereinner pages 10-11, hua2019fbxo47regulatestelomereinner pages 4-4).

Localization: Evidence supports action at the nuclear periphery/telomere–NE interface during early meiotic prophase (hua2019fbxo47regulatestelomereinner pages 5-6, hua2019fbxo47regulatestelomereinner media f09c33b9). Newer 2024 work argues for an additional or alternative centromeric SCF role influencing centromere pairing and SKP1 stability (ma2024fbxo47regulatescentromere pages 8-9, ma2024fbxo47regulatescentromere pages 1-2).

Human relevance: Direct human functional studies remain limited in the retrieved corpus, but aggregated disease-genetics resources associate FBXO47 with azoospermia, consistent with compelling meiotic phenotypes in mammalian systems (OpenTargets Search: -FBXO47, xuan2024theemergingand pages 7-8).

Evidence summary table

Evidence type Biological context (meiosis stage/cell type) Molecular function claim Key partners/substrates Subcellular localization Experimental approach Quantitative/statistical notes Species (mouse/human cells) Citation (include DOI URL + year)
Primary Early meiotic prophase I spermatocytes; bouquet/telomere attachment stage FBXO47 is an F-box/SCF-associated factor required for telomere-inner nuclear envelope integration and stabilizes TRF2 rather than promoting its degradation SKP1; TRF1; TRF2 Nuclear periphery; telomere-associated sites at the inner nuclear membrane CRISPR FLAG knock-in, co-immunoprecipitation, HEK293T co-expression, ubiquitination assays, cycloheximide chase, IF on chromosome spreads, EM/FIB-SEM n > 30 cells/genotype for internal TRF1 foci; P < 0.001; TRF1 intensity not decreased (8.769 ± 0.351 vs 9.786 ± 0.6768), while TRF2 intensity decreased in knockout spermatocytes (leptotene 23.873 ± 5.414 vs 19.660 ± 4.207; zygotene 38.046 ± 7.281 vs 18.953 ± 13.110) Mouse testes/spermatocytes; human HEK293T cells Hua et al., Nucleic Acids Research, 2019, https://doi.org/10.1093/nar/gkz992 (hua2019fbxo47regulatestelomereinner pages 4-4, hua2019fbxo47regulatestelomereinner pages 8-10, hua2019fbxo47regulatestelomereinner pages 11-11, hua2019fbxo47regulatestelomereinner pages 5-6, hua2019fbxo47regulatestelomereinner pages 4-5, hua2019fbxo47regulatestelomereinner pages 10-11, hua2019fbxo47regulatestelomereinner media f09c33b9)
Primary Early meiotic recombination in spermatocytes FBXO47 acts as a meiosis-specific F-box protein interacting with SKP1 and HORMAD1 and can target HORMAD1 for polyubiquitination/degradation, linking SCF activity to control of meiotic DSB homeostasis SKP1; HORMAD1 Meiotic chromosomal axis context inferred from HORMAD1 biology; exact FBXO47 localization not the main focus in extracted evidence Mouse meiotic genetics plus HEK293T interaction/ubiquitination assays No specific numeric effect sizes extracted here for FBXO47 itself; study supports mechanism that SCF restrains hyperactive DSB formation through HORMAD1 turnover Mouse germ cells; human HEK293T cells Guan et al., Nucleic Acids Research, 2022, https://doi.org/10.1093/nar/gkac304 (hua2019fbxo47regulatestelomereinner pages 10-11)
Primary Zygotene-to-pachytene spermatocytes; centromere pairing and pachynema progression FBXO47 is proposed as a centromeric SCF E3 ligase component that stabilizes SKP1 by suppressing its ubiquitination and thereby promotes centromere pairing, synapsis integrity, and meiotic progression SKP1; HORMAD1 (regulatory connection proposed) Centromeres; chromosome axes; study also notes effects on telomere-NE attachment Co-IP in HEK293T, ubiquitination assays, chromosome spreads, IF localization across meiotic stages Reported centromeric-end/counterpart SKP1 signal ratio 3.62; figure-level significance includes p = 0.0003, p = 0.0016, p < 0.0001; knockout causes leptotene/zygotene delay, pachytene-like arrest, crossover failure Mouse spermatocytes; human HEK293T cells Ma et al., Communications Biology, 2024, https://doi.org/10.1038/s42003-024-06782-6 (ma2024fbxo47regulatescentromere pages 1-2, ma2024fbxo47regulatescentromere pages 8-9)
Review Spermatogenesis, especially meiotic prophase I in spermatocytes Expert synthesis: FBXO47 is a meiotic F-box protein essential for telomere-NE integration, homologous chromosome synapsis, bouquet-stage progression, and male fertility; current literature supports a telomere-centric role, though newer work introduces centromere-focused models TRF1; TRF2; broader SCF machinery Nuclear surface/telomere-NE interface during meiosis Narrative review of primary literature in mouse and comparative systems Summarizes phenotypes such as reduced testis weight, abnormal spermatocyte-like cells, late-zygotene arrest, autosomal gamma-H2AX retention, and absence of XY bodies; no new original quantitative dataset Review of mouse and other model-organism data Xuan et al., Cell Regeneration, 2024, https://doi.org/10.1186/s13619-024-00196-9 (xuan2024theemergingand pages 5-7, xuan2024theemergingand pages 7-8)
Database Human disease association landscape Human FBXO47 is associated most strongly with azoospermia in Open Targets, consistent with meiosis/spermatogenesis biology; other weaker associations are present but less biologically specific Disease association evidence linked to literature rather than direct substrate data Not applicable Integrated disease-target evidence aggregation Open Targets evidence score for azoospermia association 0.1046948485 with 5 evidence items; additional lower-confidence associations include hypertension, hypothyroidism, facial pain, and partial chromosome Y deletion Human Open Targets Platform, FBXO47 target page, https://platform.opentargets.org/target/ENSG00000204952 (OpenTargets Search: -FBXO47)

Table: This table summarizes the main functional annotation evidence for human FBXO47 by integrating primary mechanistic studies, a recent review, and a disease-association database. It highlights the current consensus and controversy around FBXO47's meiotic role, binding partners, localization, and links to male infertility.

References

  1. (hua2019fbxo47regulatestelomereinner pages 10-11): Rong Hua, Huafang Wei, Chao Liu, Yue Zhang, Siyu Liu, Yueshuai Guo, Yiqiang Cui, Xin Zhang, Xuejiang Guo, Wei Li, and Mingxi Liu. Fbxo47 regulates telomere-inner nuclear envelope integration by stabilizing trf2 during meiosis. Nucleic Acids Research, 47:11755-11770, Nov 2019. URL: https://doi.org/10.1093/nar/gkz992, doi:10.1093/nar/gkz992. This article has 60 citations and is from a highest quality peer-reviewed journal.

  2. (ma2024fbxo47regulatescentromere pages 8-9): Ani Ma, Yali Yang, Lianbao Cao, Lijun Chen, and Jian V. Zhang. Fbxo47 regulates centromere pairing as key component of centromeric scf e3 ligase in mouse spermatocytes. Communications Biology, Sep 2024. URL: https://doi.org/10.1038/s42003-024-06782-6, doi:10.1038/s42003-024-06782-6. This article has 7 citations and is from a peer-reviewed journal.

  3. (hua2019fbxo47regulatestelomereinner pages 8-10): Rong Hua, Huafang Wei, Chao Liu, Yue Zhang, Siyu Liu, Yueshuai Guo, Yiqiang Cui, Xin Zhang, Xuejiang Guo, Wei Li, and Mingxi Liu. Fbxo47 regulates telomere-inner nuclear envelope integration by stabilizing trf2 during meiosis. Nucleic Acids Research, 47:11755-11770, Nov 2019. URL: https://doi.org/10.1093/nar/gkz992, doi:10.1093/nar/gkz992. This article has 60 citations and is from a highest quality peer-reviewed journal.

  4. (ma2024fbxo47regulatescentromere pages 1-2): Ani Ma, Yali Yang, Lianbao Cao, Lijun Chen, and Jian V. Zhang. Fbxo47 regulates centromere pairing as key component of centromeric scf e3 ligase in mouse spermatocytes. Communications Biology, Sep 2024. URL: https://doi.org/10.1038/s42003-024-06782-6, doi:10.1038/s42003-024-06782-6. This article has 7 citations and is from a peer-reviewed journal.

  5. (hua2019fbxo47regulatestelomereinner pages 11-11): Rong Hua, Huafang Wei, Chao Liu, Yue Zhang, Siyu Liu, Yueshuai Guo, Yiqiang Cui, Xin Zhang, Xuejiang Guo, Wei Li, and Mingxi Liu. Fbxo47 regulates telomere-inner nuclear envelope integration by stabilizing trf2 during meiosis. Nucleic Acids Research, 47:11755-11770, Nov 2019. URL: https://doi.org/10.1093/nar/gkz992, doi:10.1093/nar/gkz992. This article has 60 citations and is from a highest quality peer-reviewed journal.

  6. (hua2019fbxo47regulatestelomereinner pages 4-4): Rong Hua, Huafang Wei, Chao Liu, Yue Zhang, Siyu Liu, Yueshuai Guo, Yiqiang Cui, Xin Zhang, Xuejiang Guo, Wei Li, and Mingxi Liu. Fbxo47 regulates telomere-inner nuclear envelope integration by stabilizing trf2 during meiosis. Nucleic Acids Research, 47:11755-11770, Nov 2019. URL: https://doi.org/10.1093/nar/gkz992, doi:10.1093/nar/gkz992. This article has 60 citations and is from a highest quality peer-reviewed journal.

  7. (hua2019fbxo47regulatestelomereinner media f09c33b9): Rong Hua, Huafang Wei, Chao Liu, Yue Zhang, Siyu Liu, Yueshuai Guo, Yiqiang Cui, Xin Zhang, Xuejiang Guo, Wei Li, and Mingxi Liu. Fbxo47 regulates telomere-inner nuclear envelope integration by stabilizing trf2 during meiosis. Nucleic Acids Research, 47:11755-11770, Nov 2019. URL: https://doi.org/10.1093/nar/gkz992, doi:10.1093/nar/gkz992. This article has 60 citations and is from a highest quality peer-reviewed journal.

  8. (hua2019fbxo47regulatestelomereinner media c8432221): Rong Hua, Huafang Wei, Chao Liu, Yue Zhang, Siyu Liu, Yueshuai Guo, Yiqiang Cui, Xin Zhang, Xuejiang Guo, Wei Li, and Mingxi Liu. Fbxo47 regulates telomere-inner nuclear envelope integration by stabilizing trf2 during meiosis. Nucleic Acids Research, 47:11755-11770, Nov 2019. URL: https://doi.org/10.1093/nar/gkz992, doi:10.1093/nar/gkz992. This article has 60 citations and is from a highest quality peer-reviewed journal.

  9. (hua2019fbxo47regulatestelomereinner pages 5-6): Rong Hua, Huafang Wei, Chao Liu, Yue Zhang, Siyu Liu, Yueshuai Guo, Yiqiang Cui, Xin Zhang, Xuejiang Guo, Wei Li, and Mingxi Liu. Fbxo47 regulates telomere-inner nuclear envelope integration by stabilizing trf2 during meiosis. Nucleic Acids Research, 47:11755-11770, Nov 2019. URL: https://doi.org/10.1093/nar/gkz992, doi:10.1093/nar/gkz992. This article has 60 citations and is from a highest quality peer-reviewed journal.

  10. (xuan2024theemergingand pages 5-7): Zhuang Xuan, Jun Ruan, Canquan Zhou, and Zhi-ming Li. The emerging and diverse roles of f-box proteins in spermatogenesis and male infertility. Cell Regeneration, Jun 2024. URL: https://doi.org/10.1186/s13619-024-00196-9, doi:10.1186/s13619-024-00196-9. This article has 5 citations.

  11. (xuan2024theemergingand pages 7-8): Zhuang Xuan, Jun Ruan, Canquan Zhou, and Zhi-ming Li. The emerging and diverse roles of f-box proteins in spermatogenesis and male infertility. Cell Regeneration, Jun 2024. URL: https://doi.org/10.1186/s13619-024-00196-9, doi:10.1186/s13619-024-00196-9. This article has 5 citations.

  12. (OpenTargets Search: -FBXO47): Open Targets Query (-FBXO47, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  13. (omolaoye2022usingpubliclyavailable pages 8-9): Temidayo S. Omolaoye, Mahmood Yaseen Hachim, and Stefan S. du Plessis. Using publicly available transcriptomic data to identify mechanistic and diagnostic biomarkers in azoospermia and overall male infertility. Scientific Reports, Feb 2022. URL: https://doi.org/10.1038/s41598-022-06476-1, doi:10.1038/s41598-022-06476-1. This article has 32 citations and is from a peer-reviewed journal.

  14. (hua2019fbxo47regulatestelomereinner pages 4-5): Rong Hua, Huafang Wei, Chao Liu, Yue Zhang, Siyu Liu, Yueshuai Guo, Yiqiang Cui, Xin Zhang, Xuejiang Guo, Wei Li, and Mingxi Liu. Fbxo47 regulates telomere-inner nuclear envelope integration by stabilizing trf2 during meiosis. Nucleic Acids Research, 47:11755-11770, Nov 2019. URL: https://doi.org/10.1093/nar/gkz992, doi:10.1093/nar/gkz992. This article has 60 citations and is from a highest quality peer-reviewed journal.

Artifacts

Citations

  1. xuan2024theemergingand pages 7-8
  2. omolaoye2022usingpubliclyavailable pages 8-9
  3. xuan2024theemergingand pages 5-7
  4. https://doi.org/10.1038/s42003-024-06782-6
  5. https://doi.org/10.1093/nar/gkz992
  6. https://doi.org/10.1186/s13619-024-00196-9
  7. https://doi.org/10.1038/s41598-022-06476-1
  8. https://doi.org/10.1093/nar/gkac304
  9. https://platform.opentargets.org/target/ENSG00000204952
  10. https://doi.org/10.1093/nar/gkz992,
  11. https://doi.org/10.1038/s42003-024-06782-6,
  12. https://doi.org/10.1186/s13619-024-00196-9,
  13. https://doi.org/10.1038/s41598-022-06476-1,

📚 Additional Documentation

Pn Notes

(FBXO47-pn-notes.md)

FBXO47 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q5MNV8
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-13
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • Description: FBXO47 (F-box only protein 47) is a 452-residue F-box-domain-containing protein (F-box at residues 41-91, plus an FBXO47-specific armadillo-like region) belonging to the FBXO ("F-box only") subfamily of F-box proteins, which canonically act as substrate-recognition receptors that, together with SKP1, CUL1 and RBX1, assemble SCF (SKP1-cullin-F-box) E3 ubiquitin ligase complexes. FBXO47 is strongly enriched in testis (HPA testis-enriched; expressed in male germline cells) and was originally cloned from a testis library. Functional studies in mouse have established FBXO47 as a germ-cell protein essential for meiotic prophase I in spermatocytes: Fbxo47-null males are infertile with spermatocytes arresting around late zygotene/pachytene, showing incomplete homologous synapsis, persistent autosomal gamma-H2AX, and failure to form XY bodies. Mechanistically, FBXO47 acts at meiotic chromosome subcompartments through SKP1-associated regulation: it localizes to the nuclear periphery and co-localizes with the shelterin component TRF2, where it promotes telomere-inner nuclear membrane attachment by stabilizing TRF2 (impairing TRF2 ubiquitination) during the bouquet stage; FBXO47 also interacts with SKP1 and the axis protein HORMAD1, contributing to HORMAD1 turnover and meiotic double-strand-break/ recombination homeostasis, and has been proposed to act in a centromeric SCF module that preserves centromeric SKP1 to support centromere pairing. Notably, several of its documented activities involve preventing rather than promoting substrate degradation (TRF2, SKP1), so its in vivo role may diverge from a classical SCF substrate receptor that drives degradation. A curated SCF E3 ligase complex variant containing FBXO47 has been recorded (ComplexPortal CPX-8006). FBXO47 maps to 17q12; human genetics associates the locus with azoospermia, and a missense variant has been reported as a candidate in autosomal recessive intellectual disability.
  • Existing/core annotation action counts: KEEP_AS_NON_CORE: 1; UNDECIDED: 1

PN Consistency Summary

  • Consistency: Mostly consistent with a notable tension. Deep research (Falcon: Hua 2019, Guan 2022, Ma 2024) and review YAML agree FBXO47 is a testis/germ-cell F-box protein essential for meiotic prophase I (telomere-INM/TRF2 stabilization, HORMAD1, centromere pairing), where several activities PREVENT rather than promote degradation. Review keeps SCF complex membership (GO:0019005) as KEEP_AS_NON_CORE and marks the SCF-dependent catabolism (GO:0031146) UNDECIDED — honest given conflicting stabilizing/degradative evidence. PN node projects GO:1990756 adaptor activity, which the review also uses as core MF, so they agree at the MF label even though the in vivo role is unusual.
  • PN story / NEW pressure: PN asserts only the generic adaptor role; the meiotic prophase biology is NOT in GOA. Review sets directly_involved_in GO:0007129 homologous chromosome pairing at meiosis (OLS-verified) and proposes a label-only NEW term for telomere-INM/bouquet attachment (no GO ID invented — candidate, unverified). Conclusion: meiotic-prophase role is real and under-captured; ADD GO:0007129 (in review); the bouquet/telomere-INM term is a defensible candidate but currently unverified (label only).
  • Evidence alignment: PN cites only "15340381 / rev." Review anchors on UniProt (by-similarity) and Falcon leads (Hua/Guan/Ma, UNVERIFIED, not in cache); PMID:34445249 NAS rated LOW_QUALITY for this gene. Divergence: review carries meiotic primaries as leads; neither side has cache-verified substrate-level PMIDs.
  • Verdict: Consistent at MF label; meiotic biology appropriately added (GO:0007129) with honest UNDECIDED on SCF catabolism. ACCEPT review. Recommended edits: none required; optionally [REF] verify Hua 2019 / Guan 2022 / Ma 2024 PMIDs and [YAML] convert the label-only bouquet term to a real GO ID if one exists (e.g. via OLS) before promotion.

Full Consistency Review

  • UniProt: Q5MNV8 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE
  • PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|other ; PN-node mapping: F-box subtype/type = no_mapping; group = mapped, ok_for_propagation_to_go, GO:1990756; class = context_only/too_broad (GO:0061630).
  • Consistency: Mostly consistent with a notable tension. Deep research (Falcon: Hua 2019, Guan 2022, Ma 2024) and review YAML agree FBXO47 is a testis/germ-cell F-box protein essential for meiotic prophase I (telomere-INM/TRF2 stabilization, HORMAD1, centromere pairing), where several activities PREVENT rather than promote degradation. Review keeps SCF complex membership (GO:0019005) as KEEP_AS_NON_CORE and marks the SCF-dependent catabolism (GO:0031146) UNDECIDED — honest given conflicting stabilizing/degradative evidence. PN node projects GO:1990756 adaptor activity, which the review also uses as core MF, so they agree at the MF label even though the in vivo role is unusual.
  • PN story / NEW pressure: PN asserts only the generic adaptor role; the meiotic prophase biology is NOT in GOA. Review sets directly_involved_in GO:0007129 homologous chromosome pairing at meiosis (OLS-verified) and proposes a label-only NEW term for telomere-INM/bouquet attachment (no GO ID invented — candidate, unverified). Conclusion: meiotic-prophase role is real and under-captured; ADD GO:0007129 (in review); the bouquet/telomere-INM term is a defensible candidate but currently unverified (label only).
  • Mapping strategy: Gene does not force a node change, but FBXO47 is a borderline case (stabilizing/non-degradative activities; F-box "other," no firmly validated degradative substrate in vivo). GO:1990756 is acceptable as the family-level MF but the review rightly avoids asserting canonical SCF-dependent degradation. The meiotic terms are correctly kept review-local, not propagated to the broad node.
  • Evidence alignment: PN cites only "15340381 / rev." Review anchors on UniProt (by-similarity) and Falcon leads (Hua/Guan/Ma, UNVERIFIED, not in cache); PMID:34445249 NAS rated LOW_QUALITY for this gene. Divergence: review carries meiotic primaries as leads; neither side has cache-verified substrate-level PMIDs.
  • Verdict: Consistent at MF label; meiotic biology appropriately added (GO:0007129) with honest UNDECIDED on SCF catabolism. ACCEPT review. Recommended edits: none required; optionally [REF] verify Hua 2019 / Guan 2022 / Ma 2024 PMIDs and [YAML] convert the label-only bouquet term to a real GO ID if one exists (e.g. via OLS) before promotion.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/FBXO47/FBXO47-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: Q5MNV8
  • 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: Q5MNV8
gene_symbol: FBXO47
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXO47 (F-box only protein 47) is a 452-residue F-box-domain-containing
  protein (F-box at residues 41-91, plus an FBXO47-specific armadillo-like region)
  belonging to the FBXO ("F-box only") subfamily of F-box proteins, which
  canonically act as substrate-recognition receptors that, together with SKP1,
  CUL1 and RBX1, assemble SCF (SKP1-cullin-F-box) E3 ubiquitin ligase complexes.
  FBXO47 is strongly enriched in testis (HPA testis-enriched; expressed in male
  germline cells) and was originally cloned from a testis library. Functional
  studies in mouse have established FBXO47 as a germ-cell protein essential for
  meiotic prophase I in spermatocytes: Fbxo47-null males are infertile with
  spermatocytes arresting around late zygotene/pachytene, showing incomplete
  homologous synapsis, persistent autosomal gamma-H2AX, and failure to form XY
  bodies. Mechanistically, FBXO47 acts at meiotic chromosome subcompartments
  through SKP1-associated regulation: it localizes to the nuclear periphery and
  co-localizes with the shelterin component TRF2, where it promotes telomere-inner
  nuclear membrane attachment by stabilizing TRF2 (impairing TRF2 ubiquitination)
  during the bouquet stage; FBXO47 also interacts with SKP1 and the axis protein
  HORMAD1, contributing to HORMAD1 turnover and meiotic double-strand-break/
  recombination homeostasis, and has been proposed to act in a centromeric SCF
  module that preserves centromeric SKP1 to support centromere pairing. Notably,
  several of its documented activities involve preventing rather than promoting
  substrate degradation (TRF2, SKP1), so its in vivo role may diverge from a
  classical SCF substrate receptor that drives degradation. A curated SCF E3
  ligase complex variant containing FBXO47 has been recorded (ComplexPortal
  CPX-8006). FBXO47 maps to 17q12; human genetics associates the locus with
  azoospermia, and a missense variant has been reported as a candidate in
  autosomal recessive intellectual disability.
existing_annotations:
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: ComplexPortal NAS assertion that FBXO47 is part of an SCF E3 ubiquitin ligase complex, consistent with its F-box domain and the curated FBXO47-variant SCF complex (CPX-8006). FBXO47's essential, experimentally established biology is in meiotic prophase, not canonical SCF catalysis, so this is retained as non-core.
    action: KEEP_AS_NON_CORE
    reason: FBXO47 has an F-box domain and a curated SCF-complex variant (CPX-8006), and UniProt states it is part of an SCF complex, but this is inferred by similarity (ECO:0000250) and asserted (NAS) from a general SCF review (PMID:34445249) rather than demonstrated for FBXO47 specifically. Falcon-sourced primary literature (Hua 2019; Ma 2024) shows FBXO47 physically interacts with the SCF core component SKP1 in germ cells, which biochemically supports SCF-machinery association; however the in vivo essential function is in meiotic prophase (telomere-INM integration via TRF2 stabilization, centromere pairing) and several activities prevent rather than promote substrate degradation, so SCF-complex membership is kept as a non-core annotation rather than promoted to a core function. This is consistent with the functional placement of FBXO47 as an F-box/SCF (CRL1) substrate-recognition module while keeping the meiotic biology central.
    supported_by:
    - reference_id: file:human/FBXO47/FBXO47-uniprot.txt
      supporting_text: 'Part of a SCF (SKP1-cullin-F-box) protein ligase complex.'
    - reference_id: file:human/FBXO47/FBXO47-deep-research-falcon.md
      supporting_text: Evidence from co-immunoprecipitation indicates FBXO47 **interacts with SKP1**, supporting a model in which FBXO47 can act as an F-box/SCF-associated factor
- 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 NAS assertion that FBXO47 participates in SCF-dependent proteasomal protein degradation. This is inferred from F-box family membership and a general SCF review, and the UniProt FUNCTION itself is only a "Probably" statement by similarity; the experimentally documented FBXO47 function is in meiosis and may not proceed via canonical SCF-dependent degradation in vivo.
    action: UNDECIDED
    reason: >-
      The annotation rests on family-level inference (UniProt FUNCTION is a
      "Probably recognizes... promotes their ubiquitination and degradation"
      ECO:0000250 statement) and an NAS citation to a general SCF review
      (PMID:34445249) that does not characterize FBXO47. Falcon-sourced primary
      literature complicates rather than confirms this term: while one study
      reports FBXO47 can target HORMAD1 for polyubiquitination and degradation
      (supporting some SCF-dependent catabolic activity), the best-characterized
      FBXO47 activities are protective/stabilizing (impairing ubiquitination of
      TRF2 and of SKP1), i.e. opposing degradation. The functionally validated in
      vivo role of FBXO47 (mouse knockouts) is in meiotic prophase / telomere-INM
      integration / centromere pairing; whether FBXO47's essential function
      proceeds via canonical SCF-dependent proteasomal degradation of substrates
      in vivo is not established. Marked UNDECIDED rather than ACCEPT/REMOVE
      because the underlying biochemical claim cannot be verified from the
      available evidence and the gene's documented activities point in both
      directions.
    supported_by:
    - reference_id: file:human/FBXO47/FBXO47-uniprot.txt
      supporting_text: Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation.
    - reference_id: file:human/FBXO47/FBXO47-deep-research-falcon.md
      supporting_text: FBXO47 interacts with SKP1 and HORMAD1 and targets HORMAD1 for polyubiquitination and degradation in HEK293T cells
references:
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings:
  - statement: General review of the 69 SCF E3 ubiquitin ligase complexes, in which variable F-box proteins determine substrate specificity and target substrates for proteasomal degradation; does not specifically characterize FBXO47.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      PubMed-verified (Int J Mol Sci 2021;22(16):8544, PMC8395177); abstract-only
      in cache (full_text_available: false). This is a general SCF-family review
      and does not establish FBXO47-specific function. It is the NAS source used
      by ComplexPortal for both FBXO47 SCF annotations, but it provides only
      family-level support, not direct evidence for FBXO47 acting as a canonical
      SCF substrate receptor.
- id: file:human/FBXO47/FBXO47-uniprot.txt
  title: UniProt entry Q5MNV8 (FBX47_HUMAN), F-box only protein 47
  findings:
  - statement: UniProt FUNCTION and SUBUNIT for FBXO47 are inferred by similarity (ECO:0000250); FBXO47 is testis-enriched and contains an F-box domain (residues 41-91).
    reference_section_type: OTHER
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Source of the SCF complex membership and substrate-receptor function
      statements, both flagged by UniProt as "by similarity" (ECO:0000250). Also
      documents testis tissue specificity and the F-box domain, supporting the
      germ-cell/meiotic context.
- id: file:human/FBXO47/FBXO47-deep-research-falcon.md
  title: Falcon deep research report for human FBXO47
  findings:
  - statement: FBXO47 is a meiosis-associated F-box protein that interacts with the SCF core component SKP1 and regulates meiotic chromosomal proteins (TRF2, HORMAD1) during meiotic prophase I.
    supporting_text: 'Most supported primary function: FBXO47 is a meiosis-associated F‑box protein that interacts with SCF machinery (via SKP1) and regulates key meiotic chromosomal proteins to ensure proper meiotic prophase progression.'
  - statement: In the meiotic context FBXO47 stabilizes the shelterin protein TRF2 (impairing its ubiquitination) at the telomere-inner nuclear membrane interface, rather than promoting TRF2 degradation.
    supporting_text: 'Ubiquitination assays indicate FBXO47 overexpression can **impair TRF2 ubiquitination** (without similarly affecting TRF1), consistent with **TRF2 stabilization**'
  - statement: FBXO47 interacts with SKP1 and HORMAD1 and can target HORMAD1 for polyubiquitination/degradation, linking SCF activity to control of meiotic DSB homeostasis.
    supporting_text: FBXO47 interacts with SKP1 and HORMAD1 and targets HORMAD1 for polyubiquitination and degradation in HEK293T cells
  - statement: A 2024 model proposes FBXO47 acts in a centromeric SCF module that suppresses SKP1 ubiquitination to preserve centromeric SKP1 and promote centromere pairing and pachytene progression.
    supporting_text: FBXO47 is a component of a **centromeric SCF E3 ligase** and that FBXO47 can **reduce SKP1 ubiquitination**, helping preserve SKP1 levels at centromeres/chromosome axes
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: >-
      Falcon synthesis of FBXO47 meiotic biology, anchored on Hua et al. 2019
      (Nucleic Acids Research, doi:10.1093/nar/gkz992; telomere-INM/TRF2), Guan et
      al. 2022 (NAR, doi:10.1093/nar/gkac304; SKP1/HORMAD1), and Ma et al. 2024
      (Communications Biology, doi:10.1038/s42003-024-06782-6; centromeric SCF).
      These are real, citable primary studies cross-consistent with the
      UniProt/HPA testis-enriched, F-box framing, but Falcon cites author-year/DOIs
      not PMIDs and the underlying papers are not in the local cache, so the
      molecular claims are treated as leads (UNVERIFIED) rather than independently
      verified here.
core_functions:
- description: >-
    F-box-domain protein expressed in male germ cells that is essential for
    meiotic prophase I. FBXO47 acts at meiotic chromosome subcompartments through
    SKP1-associated regulation: it localizes to the nuclear periphery, co-localizes
    with the shelterin protein TRF2, and promotes telomere-inner nuclear membrane
    attachment (bouquet formation) by stabilizing TRF2 (impairing its
    ubiquitination); it also engages SKP1 and the axis protein HORMAD1 and is
    implicated in HORMAD1 turnover, homologous synapsis, and meiotic
    double-strand-break/recombination homeostasis. FBXO47 carries the F-box motif
    characteristic of SCF substrate-recognition receptors and is recorded as part
    of a curated FBXO47-variant SCF E3 ligase complex, but several of its
    documented activities prevent rather than promote substrate degradation, so
    its essential meiotic role may be partly distinct from canonical SCF-mediated
    proteasomal degradation; a direct in vivo SCF substrate-receptor catalytic
    role for FBXO47 has not been firmly established.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  directly_involved_in:
  - id: GO:0007129
    label: homologous chromosome pairing at meiosis
  locations:
  - id: GO:0000794
    label: condensed nuclear chromosome
  supported_by:
  - reference_id: file:human/FBXO47/FBXO47-uniprot.txt
    supporting_text: Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation.
  - reference_id: file:human/FBXO47/FBXO47-uniprot.txt
    supporting_text: 'DOMAIN          41..91'
  - reference_id: file:human/FBXO47/FBXO47-deep-research-falcon.md
    supporting_text: 'Most supported primary function: FBXO47 is a meiosis-associated F‑box protein that interacts with SCF machinery (via SKP1) and regulates key meiotic chromosomal proteins to ensure proper meiotic prophase progression.'
proposed_new_terms:
- proposed_name: telomere attachment to nuclear envelope involved in meiotic telomere clustering (bouquet formation)
  proposed_definition: >-
    A meiotic-prophase-I biological process in which telomeres become tethered to
    and cluster at the inner nuclear membrane (the bouquet stage), facilitating
    homologous chromosome pairing and recombination. FBXO47's best-supported in
    vivo role is promoting this telomere-inner-nuclear-membrane attachment via
    stabilization of the shelterin protein TRF2; no existing FBXO47 annotation
    captures this specific telomere-INM/bouquet process. Proposed label and
    definition only; no GO ID invented.
suggested_questions:
- question: Does FBXO47 assemble a canonical SCF (SKP1-CUL1-RBX1) E3 ligase complex in germ cells and ubiquitinate substrates for proteasomal degradation, or does its essential meiotic function (telomere-INM integration, centromere pairing) operate via non-degradative, stabilizing activities (e.g. shielding TRF2 and SKP1 from ubiquitination)?
- question: Are the telomere-centric (TRF2/bouquet) and centromere-centric (SKP1/centromere pairing) models of FBXO47 reconcilable as a single SKP1-dependent meiotic surveillance activity, or do they reflect distinct chromosome-subcompartment functions and/or antibody/knockout-method artefacts?
- question: Is the human FBXO47 azoospermia association causal, and does the reported intellectual-disability missense variant (R182G) affect FBXO47 function or reflect linkage at 17q12?
suggested_experiments:
- description: Generate F-box-deletion or F-box point-mutant FBXO47 alleles (disrupting SKP1 binding) in a germ-cell or mouse model and assess whether SKP1/SCF association is required for telomere-INM integration, TRF2 stabilization, and centromere pairing, distinguishing degradative SCF function from non-degradative stabilizing roles.
- description: Perform affinity-purification mass spectrometry of FBXO47 from testis across meiotic stages to define its complex composition (SKP1/CUL1/RBX1 versus shelterin/axis partners such as TRF2 and HORMAD1) and candidate ubiquitination substrates, followed by in vitro reconstitution and ubiquitination/deubiquitination assays to test whether FBXO47 promotes or restrains substrate ubiquitination.
- description: Use super-resolution and electron microscopy of Fbxo47 wild-type versus knockout spermatocytes to map FBXO47 localization at telomere-INM versus centromeric/axis sites and directly test the telomere-centric versus centromere-centric models.