FBXO43

UniProt ID: Q4G163
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

FBXO43 (Endogenous meiotic inhibitor 2, EMI2/ERP1) is a meiotic cell-cycle regulator and the closest paralog of FBXO5/EMI1. Despite containing an F-box, its established function is as a direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase rather than as a canonical SCF substrate receptor. FBXO43 is the key component of cytostatic factor (CSF) activity that establishes and maintains the arrest of vertebrate oocytes at metaphase of the second meiotic division (MII) until fertilization, acting by binding and inhibiting the APC/C to stabilize cyclin B1 (CCNB1) and sustain CDK1 activity. Mechanistically, EMI2 docks onto the APC/C through a short C-terminal RL tail, and its C-terminal zinc-binding region (ZBR) both impairs association of the coactivator CDC20 with the APC/C core and inhibits APC/C catalytic activity (including UBE2C-dependent ubiquitin chain formation), so that inhibition reflects direct perturbation of APC/C rather than simple pseudosubstrate competition. Upon fertilization, a calcium signal triggers phosphorylation of FBXO43 (at residues including Ser76, Thr234 and Ser334 by kinases such as CaMKII and PLK1), generating a beta-TrCP-recognized phosphodegron that drives its ubiquitination and proteasomal degradation, relieving APC/C inhibition and allowing exit from MII and the metaphase-to-anaphase transition. FBXO43 binds directly to multiple APC/C subunits (ANAPC2, ANAPC4, CDC16, CDC23, ANAPC10, CDC26). It is expressed predominantly in the gonads (testis and oocyte), and loss-of-function variants cause human infertility: oocyte/embryo maturation arrest in females (OZEMA12) and spermatogenic failure/non-obstructive azoospermia with meiotic arrest in males (SPGF64).

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005634 nucleus
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetic assignment of nuclear localization, transferred across the EMI1/EMI2 family.
Reason: Plausible by family inference, but FBXO43 acts on the APC/C during meiotic divisions where the nuclear envelope has broken down; the localization is not experimentally established for human FBXO43 and is non-core.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
Acts by inhibiting the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase
GO:0007088 regulation of mitotic nuclear division
IBA
GO_REF:0000033 		MARK AS OVER ANNOTATED
Summary: Phylogenetic assignment of regulation of mitotic nuclear division, transferred from the EMI1/EMI2 family.
Reason: FBXO43/EMI2 acts specifically in the meiotic cell cycle (oocyte MII arrest, spermatogenesis); a mitotic-division role is a family-level over-propagation from the mitotic paralog EMI1/FBXO5 and is not supported for FBXO43.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
Required to establish and maintain the arrest of oocytes at the second meiotic metaphase until fertilization
GO:0045835 negative regulation of meiotic nuclear division
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assignment of negative regulation of meiotic nuclear division, consistent with FBXO43's CSF-mediated MII arrest via APC/C inhibition. Core process.
Reason: Core biological process; FBXO43 inhibits APC/C to arrest oocytes at meiotic metaphase II, directly supported by functional and disease studies.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
Required to establish and maintain the arrest of oocytes at the second meiotic metaphase until fertilization
GO:0007088 regulation of mitotic nuclear division
IEA
GO_REF:0000002 		MARK AS OVER ANNOTATED
Summary: InterPro-based electronic assignment of regulation of mitotic nuclear division.
Reason: FBXO43 is a meiotic regulator; the mitotic-division annotation is a family-level over-propagation from the FBX5_43 InterPro signature shared with mitotic EMI1.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
Required to establish and maintain the arrest of oocytes at the second meiotic metaphase until fertilization
GO:0045835 negative regulation of meiotic nuclear division
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro-based electronic assignment of negative regulation of meiotic nuclear division. Core process.
Reason: Core biological process; redundant with the IBA and experimental support for meiotic arrest via APC/C inhibition.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
Required to establish and maintain the arrest of oocytes at the second meiotic metaphase until fertilization
GO:0008270 zinc ion binding
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: InterPro/keyword-based assignment of zinc ion binding via the ZBR-type zinc-finger domain (residues 636-684) that coordinates two zinc ions.
Reason: Accurate structural feature of the ZBR domain (important for APC/C inhibition), but a structural attribute subsidiary to the core APC/C-inhibitor function rather than a standalone core function.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
ZN_FING 636..684
GO:0010948 negative regulation of cell cycle process
IEA
GO_REF:0000117 		ACCEPT
Summary: ARBA machine-learning assignment of negative regulation of a cell-cycle process, consistent with FBXO43's APC/C inhibition arresting the meiotic cell cycle.
Reason: Correct (generic parent of the specific meiotic-arrest process); consistent with the IMP-supported negative regulation of the meiotic cell cycle.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
Acts by inhibiting the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase
GO:0045835 negative regulation of meiotic nuclear division
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro-based electronic assignment of negative regulation of meiotic nuclear division. Core process. (Second InterPro record.)
Reason: Core biological process; redundant with the IBA and experimental support for meiotic arrest via APC/C inhibition.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
Required to establish and maintain the arrest of oocytes at the second meiotic metaphase until fertilization
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 interaction (e.g. PPP2R1A/SKP1). Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
Q4G163; P30153: PPP2R1A; NbExp=3; IntAct=EBI-12053217, EBI-302388;
GO:1990090 cellular response to nerve growth factor stimulus
IEA
GO_REF:0000107 		REMOVE
Summary: Ortholog-based electronic transfer of a cellular response to nerve growth factor. There is no biological support for FBXO43 acting in NGF signaling; FBXO43 is a gonad-restricted meiotic APC/C inhibitor.
Reason: Biologically implausible electronic over-propagation. FBXO43 is expressed in testis/oocyte and functions in meiotic APC/C inhibition; an NGF-response role contradicts its tissue specificity and documented function, and rests only on Ensembl Compara ortholog transfer.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
Expressed in the testis
GO:0016567 protein ubiquitination
IEA
GO_REF:0000041 		MARK AS OVER ANNOTATED
Summary: UniPathway-derived generic protein ubiquitination annotation, propagated from the F-box/UPA00143 mapping.
Reason: FBXO43's established role is inhibition of the APC/C ubiquitin ligase, and it is itself a phosphodegron substrate; UniProt notes that SKP1 interaction does not occur (PMID:34595750). A generic productive-ubiquitination annotation overstates a catalytic role; the UniProt FUNCTION line about promoting ubiquitination is hedged ("probably") and not experimentally established.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
According to PubMed:34595750 interaction with SKP1 does not occur
GO:0019005 SCF ubiquitin ligase complex
NAS
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromoso... 		MARK AS OVER ANNOTATED
Summary: ComplexPortal author-statement assigning FBXO43 to an SCF ubiquitin ligase complex based on its F-box. However, UniProt records that FBXO43 does not interact with SKP1 (PMID:34595750), and FBXO43 instead binds directly to APC/C subunits.
Reason: The SCF assignment is a default F-box-family inference. The experimental record indicates FBXO43 does not bind SKP1 and acts as an APC/C inhibitor, not an SCF substrate receptor. Retaining it as part_of SCF over-states a complex membership not supported for FBXO43.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
According to PubMed:34595750 interaction with SKP1 does not occur
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
NAS
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromoso... 		MARK AS OVER ANNOTATED
Summary: ComplexPortal author-statement assigning FBXO43 to SCF-dependent proteasomal protein catabolism. FBXO43 is itself degraded by the ubiquitin-proteasome system after calcium-triggered phosphorylation; no productive SCF substrate-receptor role is established and SKP1 interaction is reported not to occur.
Reason: Over-extension from the F-box-family default. FBXO43's documented ubiquitin/proteasome link is as a substrate, and its core activity is APC/C inhibition; an SCF-dependent catabolic involved_in annotation is not supported.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
Ubiquitinated in response to calcium, which promotes proteasomal degradation
GO:0005515 protein binding
IPI
PMID:34595750
A homozygous loss-of-function mutation in FBXO43 causes huma... 		KEEP AS NON CORE
Summary: Interactions demonstrated with APC/C subunits (ANAPC2, ANAPC4, CDC16, CDC23, ANAPC10, CDC26) during spermatogenesis. These direct contacts, together with the C-terminal RL-tail docking module and ZBR, underlie EMI2's inhibition of the APC/C. Bare protein binding is uninformative.
Reason: Records the functionally central direct interactions with APC/C subunits, but bare protein binding is uninformative; the inhibitory APC/C relationship is captured by the meiotic-division annotations. EMI2 docks via an RL tail and uses its ZBR to disrupt CDC20 association and UBE2C-dependent ubiquitylation.
Supporting Evidence:
file:human/FBXO43/FBXO43-uniprot.txt
Interacts with ANAPC2; the interaction is direct, ANAPC4, CDC16, CDC23; the interaction is direct, ANAPC10; the interaction is direct and CDC26, during spermatogenesis
file:human/FBXO43/FBXO43-deep-research-falcon.md
EMI2 requires a short **C-terminal RL tail** for physical docking to the APC/C; this docking is required for inhibitory activity, facilitating the functional engagement of other inhibitory regions (including ZBR).
GO:0010948 negative regulation of cell cycle process
IMP
PMID:34052850
FBXO43 variants in patients with female infertility characte... 		ACCEPT
Summary: Mutant-phenotype evidence (FBXO43 infertility variants; failure to upregulate CCNB1; failure to rescue mouse oocyte phenotype) that FBXO43 negatively regulates the meiotic cell-cycle by inhibiting APC/C. Core process.
Reason: Core biological process with direct mutant-phenotype support; FBXO43 restrains the meiotic cell cycle (MII arrest) via APC/C inhibition and CCNB1 stabilization.
Supporting Evidence:
PMID:34052850
FBXO43, an inhibitor of the anaphase-promoting complex/cyclosome, mediates Metaphase II arrest as a component of the cytostatic factor in oocytes
GO:1990948 ubiquitin ligase inhibitor activity
IMP
PMID:34595750
A homozygous loss-of-function mutation in FBXO43 causes huma... 		NEW
Summary: Proposed molecular function annotation. FBXO43 acts as a direct inhibitor of the APC/C ubiquitin ligase; loss-of-function abolishes this inhibition, causing meiotic arrest. This captures the core molecular function not represented in the seeded GOA.
Reason: FBXO43's core molecular function is inhibition of the APC/C E3 ligase (a ubiquitin ligase inhibitor activity, GO:1990948, consistent with its EMI1/FBXO5 paralog), directly supported by the disease loss-of-function study; this term is absent from the existing GOA and is added here. Mechanistically the ZBR impairs CDC20 coactivator association and inhibits UBE2C-dependent ubiquitin chain formation, so inhibition is a direct perturbation of APC/C activity.
Supporting Evidence:
PMID:34595750
FBXO43 is a direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C) E3 ligase
file:human/FBXO43/FBXO43-deep-research-falcon.md
the ZBR can (i) **impair association of the APC/C coactivator CDC20 with the APC/C core**, and (ii) **inhibit APC/C catalytic activity**, including UBE2C-dependent ubiquitin chain formation/elongation steps—implying EMI2 is not merely a stoichiometric blocker but directly perturbs APC/C function.

Core Functions

Direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase; binds directly to multiple APC/C subunits (ANAPC2, ANAPC4, CDC16, CDC23, ANAPC10, CDC26) to suppress its activity.

Molecular Function:
ubiquitin ligase inhibitor activity
Directly Involved In:
negative regulation of meiotic nuclear division
Supporting Evidence:
  • PMID:34595750
    FBXO43 is a direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C) E3 ligase

Cytostatic-factor (CSF) component that establishes and maintains arrest of oocytes at metaphase of the second meiotic division until fertilization, by inhibiting APC/C to stabilize cyclin B1 and sustain CDK1 activity; calcium-triggered degradation at fertilization relieves the arrest.

Molecular Function:
ubiquitin ligase inhibitor activity
Directly Involved In:
negative regulation of meiotic nuclear division
Supporting Evidence:
  • PMID:34052850
    FBXO43, an inhibitor of the anaphase-promoting complex/cyclosome, mediates Metaphase II arrest as a component of the cytostatic factor in oocytes

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000041
Gene Ontology annotation based on UniPathway vocabulary mapping
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
PMID:32296183
A reference map of the human binary protein interactome.
PMID:34052850
FBXO43 variants in patients with female infertility characterized by early embryonic arrest.
  • Homozygous FBXO43 variants cause female infertility with early embryonic arrest; FBXO43 inhibits the APC/C and mediates metaphase II arrest as a cytostatic-factor component, with the truncating variant failing to upregulate CCNB1 and failing to rescue the mouse oocyte phenotype.
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  • Review of the 69 SCF E3 ubiquitin ligase complexes in which variable F-box proteins determine substrate specificity.
PMID:34595750
A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia.
  • FBXO43 is a direct inhibitor of the APC/C E3 ligase; a homozygous nonsense mutation causes non-obstructive azoospermia with meiotic arrest at early diplotene; FBXO43 interacts directly with multiple APC/C subunits and does not interact with SKP1.
file:human/FBXO43/FBXO43-deep-research-falcon.md
Falcon deep research report for human FBXO43
  • FBXO43/EMI2 is the meiotic APC/C inhibitor underlying cytostatic-factor (CSF) metaphase-II arrest in vertebrate oocytes, suppressing APC/C-mediated cyclin B destruction to sustain MPF/CDK1 until fertilization.
    "FBXO43/EMI2 is best understood functionally as a **meiotic inhibitor of the anaphase-promoting complex/cyclosome (APC/C)**—a multi-subunit E3 ubiquitin ligase controlling anaphase onset and exit from M phase. In vertebrate oocytes, APC/C inhibition is the core biochemical requirement for maintaining **metaphase II arrest** (cytostatic factor/CSF arrest) until fertilization."
  • The EMI2 C-terminal zinc-binding region (ZBR) inhibits APC/C by both impairing CDC20 coactivator association with the APC/C core and inhibiting UBE2C-dependent ubiquitin chain formation, i.e. it directly perturbs APC/C catalytic activity rather than acting only as a stoichiometric/pseudosubstrate blocker.
    "the ZBR can (i) **impair association of the APC/C coactivator CDC20 with the APC/C core**, and (ii) **inhibit APC/C catalytic activity**, including UBE2C-dependent ubiquitin chain formation/elongation steps—implying EMI2 is not merely a stoichiometric blocker but directly perturbs APC/C function."
  • EMI2 requires a short C-terminal RL tail for physical docking to the APC/C, and this docking is required for its inhibitory activity, enabling engagement of the D-box and ZBR inhibitory modules.
    "EMI2 requires a short **C-terminal RL tail** for physical docking to the APC/C; this docking is required for inhibitory activity, facilitating the functional engagement of other inhibitory regions (including ZBR)."
  • At fertilization, Ca2+/CaMKII and Plx1/PLK1 phosphorylation generate a beta-TrCP-recognized phosphodegron driving EMI2 ubiquitination and degradation, releasing APC/C inhibition for meiotic exit.
    "Ca2+-activated signaling (via **CaMKII**) and **Plx1/Plk1** phosphorylation leads to **β-TrCP recognition**, ubiquitination, and degradation of EMI2, thereby releasing APC/C inhibition and allowing meiotic exit."

Suggested Questions for Experts

Q: Does human FBXO43/EMI2 ever assemble a functional SCF complex and target any substrate for ubiquitination, given that SKP1 interaction is reported not to occur and its dominant role is direct APC/C inhibition?

Q: How do the calcium-triggered phosphorylation events (CaMKII, PLK1) on FBXO43 quantitatively convert it from an APC/C inhibitor into a degradation substrate to time the metaphase-II-to-anaphase transition at fertilization?

Q: Does human FBXO43/EMI2 have a non-meiotic, post-mitotic role analogous to the reported Xenopus function in multiciliated-cell progenitors (transient APC/C^CDH1 inhibition enabling PLK1 activation and centriole amplification), and if so in which human tissues?

Suggested Experiments

Experiment: Reconstitute APC/C inhibition in vitro with purified human FBXO43 and APC/C(CDC20) and measure cyclin B1 ubiquitination, mapping which APC/C-subunit contacts (ANAPC2/ANAPC10/CDC23) are required for inhibition versus its proposed pseudosubstrate mode.

Experiment: In human or mouse oocytes, perform degron-tagged FBXO43 depletion/add-back with phosphosite mutants (Ser76, Thr234, Ser334) and live imaging of MII arrest and exit to test the requirement of each phosphorylation event for calcium-triggered destruction and anaphase onset.

Deep Research

Falcon

(FBXO43-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 31 citations 2 artifacts 2026-06-13T06:56:54.319090
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000012 Figure 7 on page 13 provides a comprehensive overview of the Emi2 zinc-binding region (ZBR). Panel A shows the surface and ribbon r (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.

Research report: Human FBXO43 / EMI2 (UniProt Q4G163) — functional annotation

0) Target verification (gene/protein identity)

The requested target is the human protein FBXO43 (UniProt Q4G163), also widely referred to in the cell-cycle and reproductive biology literature as EMI2 (Endogenous meiotic inhibitor 2) and Erp1/XERP1. Multiple sources explicitly equate EMI2 with gene symbol FBXO43 and place it within the FBXO (F-box only) subclass of F-box proteins. (vadhan2020emi2expressionas pages 1-3, shoji2014thezincbindingregion pages 1-2)

1) Key concepts and current understanding

1.1 What FBXO43/EMI2 is (definitions)

FBXO43/EMI2 is best understood functionally as a meiotic inhibitor of the anaphase-promoting complex/cyclosome (APC/C)—a multi-subunit E3 ubiquitin ligase controlling anaphase onset and exit from M phase. In vertebrate oocytes, APC/C inhibition is the core biochemical requirement for maintaining metaphase II arrest (cytostatic factor/CSF arrest) until fertilization. (ohe2010emi2inhibitionof pages 1-2, tang2010regulationofanaphase pages 88-95)

1.2 Molecular mechanism: how EMI2 inhibits APC/C

Experimental and structural studies converge on a model in which EMI2 uses C-terminal inhibitory modules to suppress APC/C activity.

  • Zinc-binding region (ZBR): A C-terminal ZBR is central to inhibition. In vitro and cellular assays show this region contributes major inhibitory activity against APC/C rather than acting solely through substrate mimicry. (tang2010regulationofanaphase pages 95-100, shoji2014thezincbindingregion pages 13-14)
  • Dual inhibitory mechanisms of the ZBR: Structural/biochemical work indicates the ZBR can (i) impair association of the APC/C coactivator CDC20 with the APC/C core, and (ii) inhibit APC/C catalytic activity, including UBE2C-dependent ubiquitin chain formation/elongation steps—implying EMI2 is not merely a stoichiometric blocker but directly perturbs APC/C function. (shoji2014thezincbindingregion pages 1-2, shoji2014thezincbindingregion pages 13-14)
  • C-terminal RL tail as an APC/C docking module: EMI2 requires a short C-terminal RL tail for physical docking to the APC/C; this docking is required for inhibitory activity, facilitating the functional engagement of other inhibitory regions (including ZBR). (ohe2010emi2inhibitionof pages 1-2)

Visual mechanistic evidence: Shoji et al. provide structural representations of the ZBR and a mechanism schematic integrating ZBR and post-ZBR regions in APC/C inhibition. (shoji2014thezincbindingregion media 5e46d904)

1.3 Pathway context: cytostatic factor (CSF) arrest in meiosis II

In vertebrate oocytes, metaphase II arrest is maintained by sustaining high MPF/CDK1 activity (via cyclin B stability), which requires suppressing APC/C-mediated cyclin B destruction. EMI2 is a key molecular component that enforces this state by inhibiting APC/C^CDC20. (tang2010regulationofanaphase pages 88-95, ohe2010emi2inhibitionof pages 1-2)

2) Regulation, timing, and localization (where/when FBXO43 acts)

2.1 Regulation by phosphorylation and ubiquitin-mediated degradation

Mechanistic studies in vertebrate oocyte systems describe EMI2 as a highly regulated switch whose abundance and APC/C binding are controlled by phosphorylation and ubiquitin-dependent turnover:

  • Fertilization-triggered destruction: Ca2+-activated signaling (via CaMKII) and Plx1/Plk1 phosphorylation leads to β-TrCP recognition, ubiquitination, and degradation of EMI2, thereby releasing APC/C inhibition and allowing meiotic exit. (tang2010regulationofanaphase pages 57-65)
  • Meiosis I–II transition control: EMI2 undergoes Cdc2/CDK1-driven multisite phosphorylation during meiosis I that promotes degradation; subsequent stabilization allows accumulation to establish/maintain APC/C inhibition in meiosis II. (tang2010regulationofanaphase pages 88-95)
  • Phosphorylation-dependent APC/C binding: Clinical oncology-focused synthesis similarly describes Cdc2 phosphorylation of EMI2 C-terminal sites as weakening EMI2–APC/C interaction and enabling APC/C activation, while dephosphorylation can re-stabilize EMI2 association. (vadhan2020emi2expressionas pages 1-3)

2.2 Subcellular localization (operational localization)

Functionally, EMI2 acts in the oocyte cytoplasm in association with APC/C complexes; the requirement for an RL tail docking motif implies a direct physical interaction with APC/C as a proximal regulatory mechanism. (ohe2010emi2inhibitionof pages 1-2)

3) Recent developments (emphasis 2023–2024)

3.1 Germline biology and infertility (2024 synthesis)

A 2024 review focusing on F-box proteins in spermatogenesis highlights FBXO43 as a meiosis-related factor and compiles genetic evidence linking biallelic FBXO43 variants (including truncating and missense alleles) to male infertility, alongside mouse model evidence of meiotic defects. (Xuan et al., 2024; https://doi.org/10.1186/s13619-024-00196-9) (xuan2024theemergingand pages 2-5)

3.2 Expansion beyond gametogenesis: multiciliated cell differentiation (2022 primary; still a “recent” conceptual expansion)

Although not 2023–2024, a notable recent mechanistic expansion is that emi2/fbxo43 can act in a post-mitotic somatic differentiation context. In multiciliated cell progenitors (Xenopus), emi2 is upregulated after cell-cycle exit and transiently inhibits APC/C^Cdh1, enabling Plk1 activation and multiple steps required for centriole amplification and basal body formation. This supports a broader interpretation of FBXO43 as an APC/C-modulating factor outside meiosis. (Kim et al., 2022; https://doi.org/10.1126/sciadv.abm7538) (kim2022emi2enablescentriole pages 1-2)

3.3 Cancer/bioinformatics associations (limited mechanistic depth in available evidence)

Available 2024 sources in this tool run provide association-level rather than mechanistic evidence for FBXO43 in cancer. For example, hepatocellular carcinoma (HCC) modeling studies include FBXO43 among gene sets with diagnostic/prognostic relevance, but these are primarily computational signatures. (sucularlı2025machinelearningbasedidentification pages 1-2)

4) Current applications and real-world implementations

4.1 Reproductive genetics and assisted reproduction

Human genetic studies support the use of FBXO43 as a candidate gene in infertility variant panels, particularly for severe male-factor phenotypes such as teratozoospermia and possibly for embryo developmental failure contexts (via its core role in meiotic/early embryonic cell-cycle control). Evidence includes segregation of rare homozygous variants with infertility phenotypes and adverse IVF/ICSI outcomes. (ma2019anovelhomozygous pages 1-2)

4.2 Oncology: candidate biomarker (IHC and transcriptomic signatures)

FBXO43/EMI2 has been proposed as a biomarker in cancer contexts.

  • In breast cancer, an immunohistochemistry study reported that 105/192 (54.7%) tumors had high EMI2 expression, which associated with adverse clinicopathologic features and worse survival, and reported hazard ratio = 3.93 for high EMI2 as a risk factor. (Vadhan et al., 2020; https://doi.org/10.1002/kjm2.12208) (vadhan2020emi2expressionas pages 1-3)
  • In HCC, machine-learning models identified FBXO43 among diagnostic gene sets with high AUC performance across datasets; however, these studies do not establish FBXO43 mechanism, only diagnostic separability at the expression level. (sucularlı2025machinelearningbasedidentification pages 1-2)

5) Expert opinions and analysis (authoritative synthesis)

  • The oocyte-meiosis literature frames EMI2/FBXO43 as a physiologically central APC/C inhibitor in CSF arrest, with regulation tightly coupled to phosphorylation-dependent degradation pathways that permit fertilization-induced release from arrest. (tang2010regulationofanaphase pages 57-65, tang2010regulationofanaphase pages 88-95)
  • Structural and biochemical studies strengthen the view that EMI2 inhibition involves direct interference with APC/C activation/coactivator engagement and ubiquitination chemistry, not solely competition for substrate binding. (shoji2014thezincbindingregion pages 1-2, shoji2014thezincbindingregion pages 13-14)
  • The 2024 spermatogenesis review characterizes FBXO43 as among the emerging F-box proteins with infertility relevance, while emphasizing that many germline F-box mechanisms remain incompletely defined and require further mechanistic work. (xuan2024theemergingand pages 2-5)

6) Recent statistics and data highlights

6.1 Human infertility genetics (primary clinical statistics)

In a consanguineous family study:

  • A homozygous FBXO43 variant p.G664D segregated with male infertility/teratozoospermia.
  • The homozygous variant was reported absent from 1000 Genomes and ExAC.
  • In 124 sporadic teratozoospermia cases, 4 additional heterozygous FBXO43 variants were found, while 0 were found in 200 fertile controls.
  • IVF/ICSI outcomes in two affected brothers showed poor embryo quality and no live birth, with one pregnancy ending in miscarriage at gestational week 9. (Ma et al., 2019; https://doi.org/10.1016/j.fertnstert.2019.01.007) (ma2019anovelhomozygous pages 1-2)

6.2 Breast cancer association (IHC cohort statistics)

  • 192 breast cancer patients: 105 (54.7%) high EMI2 expression.
  • High EMI2 associated with grade (P=0.006), tumor size (P<0.001), and lymph-node metastasis (P=0.008), and high EMI2 was reported as a risk factor with hazard ratio 3.93. (Vadhan et al., 2020; https://doi.org/10.1002/kjm2.12208; April 2020) (vadhan2020emi2expressionas pages 1-3)

6.3 HCC diagnostic modeling (dataset sizes and AUC)

An HCC machine-learning study (2025) reported:

  • TCGA LIHC: tumors n=371, normals n=50, with an SVM-RFE AUC of 1.0.
  • External datasets: GSE77509 AUC 0.95 (tumor n=20/normal n=20) and GSE144269 AUC 0.879 (tumor n=70/normal n=70).
  • FBXO43 was among nine genes with robust individual diagnostic performance (AUCs > 0.81). (Sucularlı, 2025; https://doi.org/10.1371/journal.pone.0331118) (sucularlı2025machinelearningbasedidentification pages 1-2)

7) Consolidated evidence summary table

Aspect Key findings Evidence type (review/primary; organism) Representative source(s) with year and URL Citation ID(s)
Identity/domains Human FBXO43 is the same protein as EMI2/Erp1/XERP1; it is an FBXO-class F-box protein and contains a C-terminal zinc-binding region (ZBR/IBR-like region) central to APC/C inhibition. Structural work maps distinct inhibitory surfaces within the ZBR and a post-ZBR segment that contacts APC/C. Primary biochemical/structural; vertebrate/human protein context Shoji et al., 2014, FEBS Open Bio, https://doi.org/10.1016/j.fob.2014.06.010; Vadhan et al., 2020, Kaohsiung J Med Sci, https://doi.org/10.1002/kjm2.12208 (shoji2014thezincbindingregion pages 1-2, shoji2014thezincbindingregion pages 13-14, vadhan2020emi2expressionas pages 1-3)
Mechanism FBXO43/EMI2 is the key APC/C inhibitor underlying cytostatic factor arrest in mature oocytes. The ZBR impairs Cdc20 association with the APC/C core and inhibits APC/C-mediated ubiquitylation, including UBE2C/Ube2S-dependent steps; Emi2 can act catalytically/substoichiometrically rather than as a simple pseudosubstrate. Primary mechanistic biochemistry; Xenopus/vertebrate oocyte systems Shoji et al., 2014, https://doi.org/10.1016/j.fob.2014.06.010; Sako et al., 2014, https://doi.org/10.1038/ncomms4667; Tang, 2010 review of primary literature (shoji2014thezincbindingregion pages 1-2, shoji2014thezincbindingregion pages 13-14, tang2010regulationofanaphase pages 105-113, tang2010regulationofanaphase pages 95-100, tang2010regulationofanaphase pages 88-95)
Regulation Emi2 activity/stability is controlled by multisite phosphorylation. Cdc2/Cdk1 phosphorylation destabilizes Emi2 around MI; CaMKII and Plx1 phosphorylation at fertilization promotes β-TrCP recognition, ubiquitination, and degradation, relieving APC/C inhibition for meiotic exit. PP2A antagonizes destabilizing phosphorylation and helps restabilize APC/C binding. Primary + synthesis/review; Xenopus/vertebrate oocyte systems Ohe et al., 2010, Mol Biol Cell, https://doi.org/10.1091/mbc.e09-11-0974; Tang, 2010; Vadhan et al., 2020, https://doi.org/10.1002/kjm2.12208 (ohe2010emi2inhibitionof pages 1-2, tang2010regulationofanaphase pages 57-65, tang2010regulationofanaphase pages 88-95, vadhan2020emi2expressionas pages 1-3)
Localization Function is executed in the oocyte cytoplasm on/with the APC/C during meiotic metaphase II; docking requires a short C-terminal RL tail that mediates Emi2 association with APC/C, enabling D-box and ZBR inhibitory actions. Primary cell-cycle biochemistry; vertebrate oocyte systems Ohe et al., 2010, https://doi.org/10.1091/mbc.e09-11-0974 (ohe2010emi2inhibitionof pages 1-2)
Biological processes Canonical role is maintenance of metaphase II arrest and prevention of premature cyclin B destruction in oocytes, thereby preserving MPF/Cdk1 activity until fertilization-triggered Ca2+ signaling. Additional meiosis-related roles are reported in spermatogenesis, where loss causes meiotic failure and male infertility in mice. Review + primary genetics; vertebrates/mouse Madgwick & Jones, 2007, https://doi.org/10.1186/1747-1028-2-4; Gopinathan et al., 2017, https://doi.org/10.1016/j.celrep.2017.06.033; Xuan et al., 2024, https://doi.org/10.1186/s13619-024-00196-9 (xuan2024theemergingand pages 2-5, ma2019anovelhomozygous pages 1-2)
Human genetics In a consanguineous Chinese family, a homozygous FBXO43 missense variant p.G664D segregated with male infertility/teratozoospermia; the variant was absent from 1000 Genomes and ExAC. Among 124 sporadic teratozoospermia cases, 4 additional heterozygous FBXO43 variants were found, versus none in 200 fertile controls; IVF/ICSI outcomes in affected brothers showed poor embryo quality and no live birth. A 2024 review also cites homozygous p.Q583X and p.G664D variants associated with male infertility. Primary human genetics + review; human Ma et al., 2019, Fertil Steril, https://doi.org/10.1016/j.fertnstert.2019.01.007; Xuan et al., 2024, https://doi.org/10.1186/s13619-024-00196-9 (ma2019anovelhomozygous pages 1-2, xuan2024theemergingand pages 2-5)
Cancer associations FBXO43/EMI2 is emerging as a cancer-associated marker, but evidence is less mature than for reproductive biology. In breast cancer IHC, 105/192 tumors (54.7%) had high EMI2; high expression associated with higher grade, larger tumor size, lymph-node metastasis, and worse survival, with reported HR 3.93. Recent HCC transcriptomic models also include FBXO43 as part of poor-risk/diagnostic signatures, though these are primarily bioinformatic rather than mechanistic. Primary clinical association + bioinformatics; human Vadhan et al., 2020, https://doi.org/10.1002/kjm2.12208; Gao et al., 2024, https://doi.org/10.31083/j.fbl2905202; Sucularlı, 2025, https://doi.org/10.1371/journal.pone.0331118 (vadhan2020emi2expressionas pages 1-3, sucularlı2025machinelearningbasedidentification pages 1-2)
Other roles Beyond meiosis, emi2/fbxo43 is up-regulated in multiciliated cell progenitors and transiently inhibits APC/C^Cdh1 after cell-cycle exit, enabling Plk1 activation and centriole amplification/basal-body formation during ciliogenesis. This supports a broader APC/C-modulatory role outside gametogenesis. Primary developmental cell biology; Xenopus Kim et al., 2022, Science Advances, https://doi.org/10.1126/sciadv.abm7538 (kim2022emi2enablescentriole pages 1-2)
Structural/mechanistic visual evidence Figure-level evidence shows the Emi2 ZBR structure, sequence conservation, and a model in which the ZBR/post-ZBR region both disrupts APC/C-Cdc20 association and inhibits the APC/C catalytic module. Useful for mapping UniProt domain annotations to experimentally defined inhibitory functions. Image/structure from primary paper; vertebrate protein Shoji et al., 2014, Figure 7, https://doi.org/10.1016/j.fob.2014.06.010 (shoji2014thezincbindingregion media 5e46d904)

Table: This table condenses the main experimentally supported functions, mechanisms, regulation, localization, and disease links for human FBXO43/EMI2. It is useful as a source-mapped annotation summary that distinguishes well-established meiotic APC/C inhibition from newer infertility and cancer associations.

8) Limitations of the current evidence set (important)

  • The strongest mechanistic evidence available here comes from vertebrate oocyte systems (frequently Xenopus and mouse), which are widely considered relevant for human biology but are not always direct human-cell experiments. (tang2010regulationofanaphase pages 57-65, tang2010regulationofanaphase pages 88-95)
  • Within this tool run, 2023–2024 primary mechanistic human-cell studies on FBXO43 in cancer (e.g., defined substrates, ubiquitination targets, structural biology of full-length protein) were not successfully retrieved as full-text evidence; thus, cancer-related statements are restricted to association-level evidence currently in context (IHC associations; bioinformatic signatures). (vadhan2020emi2expressionas pages 1-3, sucularlı2025machinelearningbasedidentification pages 1-2)

Key figure cited

Shoji et al. 2014 Figure 7 provides a structure-and-mechanism summary of how the EMI2 ZBR and post-ZBR segment inhibit APC/C function, supporting domain-to-function mapping for UniProt Q4G163 annotations. (shoji2014thezincbindingregion media 5e46d904)

References

  1. (vadhan2020emi2expressionas pages 1-3): Anupama Vadhan, Yen‐Yun Wang, Shyng‐Shiou F. Yuan, Yi‐Chen Lee, Stephen Chu‐Sung Hu, Jyun‐Yuan Huang, Takashi Ishikawa, and Ming‐Feng Hou. Emi2 expression as a poor prognostic factor in patients with breast cancer. The Kaohsiung Journal of Medical Sciences, 36:640-648, Apr 2020. URL: https://doi.org/10.1002/kjm2.12208, doi:10.1002/kjm2.12208. This article has 17 citations.

  2. (shoji2014thezincbindingregion pages 1-2): Shisako Shoji, Yutaka Muto, Mariko Ikeda, Fahu He, Kengo Tsuda, Noboru Ohsawa, Ryogo Akasaka, Takaho Terada, Motoaki Wakiyama, Mikako Shirouzu, and Shigeyuki Yokoyama. The zinc-binding region (zbr) fragment of emi2 can inhibit apc/c by targeting its association with the coactivator cdc20 and ube2c-mediated ubiquitylation. FEBS Open Bio, 4:689-703, Jul 2014. URL: https://doi.org/10.1016/j.fob.2014.06.010, doi:10.1016/j.fob.2014.06.010. This article has 28 citations and is from a peer-reviewed journal.

  3. (ohe2010emi2inhibitionof pages 1-2): Munemichi Ohe, Yoshiko Kawamura, Hiroyuki Ueno, Daigo Inoue, Yoshinori Kanemori, Chiharu Senoo, Michitaka Isoda, Nobushige Nakajo, and Noriyuki Sagata. Emi2 inhibition of the anaphase-promoting complex/cyclosome absolutely requires emi2 binding via the c-terminal rl tail. Mar 2010. URL: https://doi.org/10.1091/mbc.e09-11-0974, doi:10.1091/mbc.e09-11-0974. This article has 46 citations and is from a domain leading peer-reviewed journal.

  4. (tang2010regulationofanaphase pages 88-95): W Tang. Regulation of anaphase promoting complex/cyclosome to control m phase exit. Unknown journal, 2010.

  5. (tang2010regulationofanaphase pages 95-100): W Tang. Regulation of anaphase promoting complex/cyclosome to control m phase exit. Unknown journal, 2010.

  6. (shoji2014thezincbindingregion pages 13-14): Shisako Shoji, Yutaka Muto, Mariko Ikeda, Fahu He, Kengo Tsuda, Noboru Ohsawa, Ryogo Akasaka, Takaho Terada, Motoaki Wakiyama, Mikako Shirouzu, and Shigeyuki Yokoyama. The zinc-binding region (zbr) fragment of emi2 can inhibit apc/c by targeting its association with the coactivator cdc20 and ube2c-mediated ubiquitylation. FEBS Open Bio, 4:689-703, Jul 2014. URL: https://doi.org/10.1016/j.fob.2014.06.010, doi:10.1016/j.fob.2014.06.010. This article has 28 citations and is from a peer-reviewed journal.

  7. (shoji2014thezincbindingregion media 5e46d904): Shisako Shoji, Yutaka Muto, Mariko Ikeda, Fahu He, Kengo Tsuda, Noboru Ohsawa, Ryogo Akasaka, Takaho Terada, Motoaki Wakiyama, Mikako Shirouzu, and Shigeyuki Yokoyama. The zinc-binding region (zbr) fragment of emi2 can inhibit apc/c by targeting its association with the coactivator cdc20 and ube2c-mediated ubiquitylation. FEBS Open Bio, 4:689-703, Jul 2014. URL: https://doi.org/10.1016/j.fob.2014.06.010, doi:10.1016/j.fob.2014.06.010. This article has 28 citations and is from a peer-reviewed journal.

  8. (tang2010regulationofanaphase pages 57-65): W Tang. Regulation of anaphase promoting complex/cyclosome to control m phase exit. Unknown journal, 2010.

  9. (xuan2024theemergingand pages 2-5): 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.

  10. (kim2022emi2enablescentriole pages 1-2): Seongjae Kim, Yuan-Hung Chien, Amy Ryan, and Chris Kintner. Emi2 enables centriole amplification during multiciliated cell differentiation. Science Advances, Apr 2022. URL: https://doi.org/10.1126/sciadv.abm7538, doi:10.1126/sciadv.abm7538. This article has 18 citations and is from a highest quality peer-reviewed journal.

  11. (sucularlı2025machinelearningbasedidentification pages 1-2): Ceren Sucularlı. Machine learning-based identification of diagnostic and prognostic mitotic cell cycle genes in hepatocellular carcinoma. PLOS One, 20(8):e0331118, Aug 2025. URL: https://doi.org/10.1371/journal.pone.0331118, doi:10.1371/journal.pone.0331118. This article has 1 citations and is from a peer-reviewed journal.

  12. (ma2019anovelhomozygous pages 1-2): Ying Ma, Ning Xie, Dingxiong Xie, Litao Sun, Shuyan Li, Peiqiang Li, Yi Li, Jin Li, Zhilong Dong, and Xiaodong Xie. A novel homozygous fbxo43 mutation associated with male infertility and teratozoospermia in a consanguineous chinese family. Fertility and sterility, 111 5:909-917.e1, May 2019. URL: https://doi.org/10.1016/j.fertnstert.2019.01.007, doi:10.1016/j.fertnstert.2019.01.007. This article has 37 citations and is from a highest quality peer-reviewed journal.

  13. (tang2010regulationofanaphase pages 105-113): W Tang. Regulation of anaphase promoting complex/cyclosome to control m phase exit. Unknown journal, 2010.

Artifacts

Citations

  1. tang2010regulationofanaphase pages 57-65
  2. tang2010regulationofanaphase pages 88-95
  3. xuan2024theemergingand pages 2-5
  4. sucularlı2025machinelearningbasedidentification pages 1-2
  5. ma2019anovelhomozygous pages 1-2
  6. shoji2014thezincbindingregion pages 1-2
  7. tang2010regulationofanaphase pages 95-100
  8. shoji2014thezincbindingregion pages 13-14
  9. tang2010regulationofanaphase pages 105-113
  10. https://doi.org/10.1186/s13619-024-00196-9
  11. https://doi.org/10.1126/sciadv.abm7538
  12. https://doi.org/10.1002/kjm2.12208
  13. https://doi.org/10.1016/j.fertnstert.2019.01.007
  14. https://doi.org/10.1002/kjm2.12208;
  15. https://doi.org/10.1371/journal.pone.0331118
  16. https://doi.org/10.1016/j.fob.2014.06.010;
  17. https://doi.org/10.1038/ncomms4667;
  18. https://doi.org/10.1091/mbc.e09-11-0974;
  19. https://doi.org/10.1091/mbc.e09-11-0974
  20. https://doi.org/10.1186/1747-1028-2-4;
  21. https://doi.org/10.1016/j.celrep.2017.06.033;
  22. https://doi.org/10.1016/j.fertnstert.2019.01.007;
  23. https://doi.org/10.31083/j.fbl2905202;
  24. https://doi.org/10.1016/j.fob.2014.06.010
  25. https://doi.org/10.1002/kjm2.12208,
  26. https://doi.org/10.1016/j.fob.2014.06.010,
  27. https://doi.org/10.1091/mbc.e09-11-0974,
  28. https://doi.org/10.1186/s13619-024-00196-9,
  29. https://doi.org/10.1126/sciadv.abm7538,
  30. https://doi.org/10.1371/journal.pone.0331118,
  31. https://doi.org/10.1016/j.fertnstert.2019.01.007,

📚 Additional Documentation

Pn Notes

(FBXO43-pn-notes.md)

FBXO43 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q4G163
  • 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: FBXO43 (Endogenous meiotic inhibitor 2, EMI2/ERP1) is a meiotic cell-cycle regulator and the closest paralog of FBXO5/EMI1. Despite containing an F-box, its established function is as a direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase rather than as a canonical SCF substrate receptor. FBXO43 is the key component of cytostatic factor (CSF) activity that establishes and maintains the arrest of vertebrate oocytes at metaphase of the second meiotic division (MII) until fertilization, acting by binding and inhibiting the APC/C to stabilize cyclin B1 (CCNB1) and sustain CDK1 activity. Mechanistically, EMI2 docks onto the APC/C through a short C-terminal RL tail, and its C-terminal zinc-binding region (ZBR) both impairs association of the coactivator CDC20 with the APC/C core and inhibits APC/C catalytic activity (including UBE2C-dependent ubiquitin chain formation), so that inhibition reflects direct perturbation of APC/C rather than simple pseudosubstrate competition. Upon fertilization, a calcium signal triggers phosphorylation of FBXO43 (at residues including Ser76, Thr234 and Ser334 by kinases such as CaMKII and PLK1), generating a beta-TrCP-recognized phosphodegron that drives its ubiquitination and proteasomal degradation, relieving APC/C inhibition and allowing exit from MII and the metaphase-to-anaphase transition. FBXO43 binds directly to multiple APC/C subunits (ANAPC2, ANAPC4, CDC16, CDC23, ANAPC10, CDC26). It is expressed predominantly in the gonads (testis and oocyte), and loss-of-function variants cause human infertility: oocyte/embryo maturation arrest in females (OZEMA12) and spermatogenic failure/non-obstructive azoospermia with meiotic arrest in males (SPGF64).
  • Existing/core annotation action counts: ACCEPT: 5; KEEP_AS_NON_CORE: 4; MARK_AS_OVER_ANNOTATED: 5; NEW: 1; REMOVE: 1

PN Consistency Summary

  • Consistency: MAJOR PN-vs-review contradiction (the SPECIAL CASE). Deep research + review correctly establish FBXO43/EMI2 as a non-canonical F-box that does NOT bind SKP1 (PMID:34595750) and is NOT an SCF substrate receptor — it is a direct APC/C INHIBITOR (gonad-restricted meiotic CSF). But the PN node files FBXO43 under "Cul1 substrate receptor" and projects GO:1990756 adaptor activity, which directly conflicts with the review (which MARK_AS_OVER_ANNOTATED on GO:0019005 and GO:0031146, and gives core MF = GO:1990948 ubiquitin ligase inhibitor activity). Review internally consistent and well-evidenced (PMID:34052850 OZEMA12, PMID:34595750 SPGF64, both VERIFIED).
  • PN story / NEW pressure: Review adds NEW GO:1990948 "ubiquitin ligase inhibitor activity" (OLS-verified real; IMP from PMID:34595750) — the true core MF, absent from GOA. It also correctly REMOVEs the implausible ortholog-transfer IEA GO:1990090 "cellular response to NGF" (the flagged implausible IEA), and MARK_AS_OVER_ANNOTATED the mitotic-division IBA/IEA (paralog over-propagation from EMI1/FBXO5). Conclusion: PN over-reaches by projecting an adaptor MF onto an APC/C inhibitor; the defensible NEW term is GO:1990948, already in the review.
  • Evidence alignment: PN cites only "15340381 / rev" (generic F-box). Review carries the disease/mechanism primaries (PMID:34052850, PMID:34595750) and Falcon EMI2 synthesis — strong divergence; PN's generic citation does not support the substrate-receptor placement.
  • Verdict: Review correct; PN node mis-files FBXO43 and over-reaches with GO:1990756. Recommended edits: [MAP] exclude FBXO43/EMI2 from the GO:1990756 substrate-adaptor projection and flag as non-canonical F-box / APC/C inhibitor (core MF GO:1990948), mirroring FBXO5/EMI1.

Full Consistency Review

  • UniProt: Q4G163 (EMI2/ERP1) · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE
  • PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|ZBR-type ZnF ; PN-node mapping: F-box subtype/type = no_mapping; group "Cul1 substrate receptor" = mapped, ok_for_propagation_to_go, GO:1990756; class = context_only/too_broad (GO:0061630).
  • Consistency: MAJOR PN-vs-review contradiction (the SPECIAL CASE). Deep research + review correctly establish FBXO43/EMI2 as a non-canonical F-box that does NOT bind SKP1 (PMID:34595750) and is NOT an SCF substrate receptor — it is a direct APC/C INHIBITOR (gonad-restricted meiotic CSF). But the PN node files FBXO43 under "Cul1 substrate receptor" and projects GO:1990756 adaptor activity, which directly conflicts with the review (which MARK_AS_OVER_ANNOTATED on GO:0019005 and GO:0031146, and gives core MF = GO:1990948 ubiquitin ligase inhibitor activity). Review internally consistent and well-evidenced (PMID:34052850 OZEMA12, PMID:34595750 SPGF64, both VERIFIED).
  • PN story / NEW pressure: Review adds NEW GO:1990948 "ubiquitin ligase inhibitor activity" (OLS-verified real; IMP from PMID:34595750) — the true core MF, absent from GOA. It also correctly REMOVEs the implausible ortholog-transfer IEA GO:1990090 "cellular response to NGF" (the flagged implausible IEA), and MARK_AS_OVER_ANNOTATED the mitotic-division IBA/IEA (paralog over-propagation from EMI1/FBXO5). Conclusion: PN over-reaches by projecting an adaptor MF onto an APC/C inhibitor; the defensible NEW term is GO:1990948, already in the review.
  • Mapping strategy: This gene SHOULD change the node treatment. Per precedent (substrate-receptor MF rejected when the gene is not a receptor), GO:1990756 is wrong for FBXO43 — it is broader/incorrect, not narrower. FBXO43 should be excluded from the GO:1990756 projection / flagged as a non-canonical F-box (APC/C inhibitor), analogous to its paralog FBXO5/EMI1.
  • Evidence alignment: PN cites only "15340381 / rev" (generic F-box). Review carries the disease/mechanism primaries (PMID:34052850, PMID:34595750) and Falcon EMI2 synthesis — strong divergence; PN's generic citation does not support the substrate-receptor placement.
  • Verdict: Review correct; PN node mis-files FBXO43 and over-reaches with GO:1990756. Recommended edits: [MAP] exclude FBXO43/EMI2 from the GO:1990756 substrate-adaptor projection and flag as non-canonical F-box / APC/C inhibitor (core MF GO:1990948), mirroring FBXO5/EMI1.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/FBXO43/FBXO43-ai-review.yaml
  • PN workbook rows: 1

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

  • UniProt: Q4G163
  • In branches: UPS
  • Signature domains: IPR001810
  • Auxiliary domains: IPR044064
  • 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|ZBR-type ZnF
      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: Q4G163
gene_symbol: FBXO43
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXO43 (Endogenous meiotic inhibitor 2, EMI2/ERP1) is a meiotic cell-cycle
  regulator and the closest paralog of FBXO5/EMI1. Despite containing an F-box,
  its established function is as a direct inhibitor of the
  anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase rather than as a
  canonical SCF substrate receptor. FBXO43 is the key component of cytostatic
  factor (CSF) activity that establishes and maintains the arrest of vertebrate
  oocytes at metaphase of the second meiotic division (MII) until fertilization,
  acting by binding and inhibiting the APC/C to stabilize cyclin B1 (CCNB1) and
  sustain CDK1 activity. Mechanistically, EMI2 docks onto the APC/C through a
  short C-terminal RL tail, and its C-terminal zinc-binding region (ZBR) both
  impairs association of the coactivator CDC20 with the APC/C core and inhibits
  APC/C catalytic activity (including UBE2C-dependent ubiquitin chain formation),
  so that inhibition reflects direct perturbation of APC/C rather than simple
  pseudosubstrate competition. Upon fertilization, a calcium signal triggers
  phosphorylation of FBXO43 (at residues including Ser76, Thr234 and Ser334 by
  kinases such as CaMKII and PLK1), generating a beta-TrCP-recognized
  phosphodegron that drives its ubiquitination and proteasomal degradation,
  relieving APC/C inhibition and allowing exit from MII and the
  metaphase-to-anaphase transition. FBXO43 binds directly to multiple APC/C
  subunits (ANAPC2, ANAPC4, CDC16, CDC23, ANAPC10, CDC26). It is expressed
  predominantly in the gonads (testis and oocyte), and
  loss-of-function variants cause human infertility: oocyte/embryo maturation
  arrest in females (OZEMA12) and spermatogenic failure/non-obstructive
  azoospermia with meiotic arrest in males (SPGF64).
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic assignment of nuclear localization, transferred across the EMI1/EMI2 family.
    action: KEEP_AS_NON_CORE
    reason: Plausible by family inference, but FBXO43 acts on the APC/C during meiotic divisions where the nuclear envelope has broken down; the localization is not experimentally established for human FBXO43 and is non-core.
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: Acts by inhibiting the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase
- term:
    id: GO:0007088
    label: regulation of mitotic nuclear division
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of regulation of mitotic nuclear division, transferred from the EMI1/EMI2 family.
    action: MARK_AS_OVER_ANNOTATED
    reason: FBXO43/EMI2 acts specifically in the meiotic cell cycle (oocyte MII arrest, spermatogenesis); a mitotic-division role is a family-level over-propagation from the mitotic paralog EMI1/FBXO5 and is not supported for FBXO43.
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: Required to establish and maintain the arrest of oocytes at the second meiotic metaphase until fertilization
- term:
    id: GO:0045835
    label: negative regulation of meiotic nuclear division
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of negative regulation of meiotic nuclear division, consistent with FBXO43's CSF-mediated MII arrest via APC/C inhibition. Core process.
    action: ACCEPT
    reason: Core biological process; FBXO43 inhibits APC/C to arrest oocytes at meiotic metaphase II, directly supported by functional and disease studies.
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: Required to establish and maintain the arrest of oocytes at the second meiotic metaphase until fertilization
- term:
    id: GO:0007088
    label: regulation of mitotic nuclear division
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic assignment of regulation of mitotic nuclear division.
    action: MARK_AS_OVER_ANNOTATED
    reason: FBXO43 is a meiotic regulator; the mitotic-division annotation is a family-level over-propagation from the FBX5_43 InterPro signature shared with mitotic EMI1.
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: Required to establish and maintain the arrest of oocytes at the second meiotic metaphase until fertilization
- term:
    id: GO:0045835
    label: negative regulation of meiotic nuclear division
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic assignment of negative regulation of meiotic nuclear division. Core process.
    action: ACCEPT
    reason: Core biological process; redundant with the IBA and experimental support for meiotic arrest via APC/C inhibition.
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: Required to establish and maintain the arrest of oocytes at the second meiotic metaphase until fertilization
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro/keyword-based assignment of zinc ion binding via the ZBR-type zinc-finger domain (residues 636-684) that coordinates two zinc ions.
    action: KEEP_AS_NON_CORE
    reason: Accurate structural feature of the ZBR domain (important for APC/C inhibition), but a structural attribute subsidiary to the core APC/C-inhibitor function rather than a standalone core function.
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: ZN_FING           636..684
- term:
    id: GO:0010948
    label: negative regulation of cell cycle process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of negative regulation of a cell-cycle process, consistent with FBXO43's APC/C inhibition arresting the meiotic cell cycle.
    action: ACCEPT
    reason: Correct (generic parent of the specific meiotic-arrest process); consistent with the IMP-supported negative regulation of the meiotic cell cycle.
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: Acts by inhibiting the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase
- term:
    id: GO:0045835
    label: negative regulation of meiotic nuclear division
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic assignment of negative regulation of meiotic nuclear division. Core process. (Second InterPro record.)
    action: ACCEPT
    reason: Core biological process; redundant with the IBA and experimental support for meiotic arrest via APC/C inhibition.
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: Required to establish and maintain the arrest of oocytes at the second meiotic metaphase until fertilization
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome reference map interaction (e.g. PPP2R1A/SKP1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: 'Q4G163; P30153: PPP2R1A; NbExp=3; IntAct=EBI-12053217, EBI-302388;'
- term:
    id: GO:1990090
    label: cellular response to nerve growth factor stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic transfer of a cellular response to nerve growth factor. There is no biological support for FBXO43 acting in NGF signaling; FBXO43 is a gonad-restricted meiotic APC/C inhibitor.
    action: REMOVE
    reason: Biologically implausible electronic over-propagation. FBXO43 is expressed in testis/oocyte and functions in meiotic APC/C inhibition; an NGF-response role contradicts its tissue specificity and documented function, and rests only on Ensembl Compara ortholog transfer.
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: Expressed in the testis
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-derived generic protein ubiquitination annotation, propagated from the F-box/UPA00143 mapping.
    action: MARK_AS_OVER_ANNOTATED
    reason: FBXO43's established role is inhibition of the APC/C ubiquitin ligase, and it is itself a phosphodegron substrate; UniProt notes that SKP1 interaction does not occur (PMID:34595750). A generic productive-ubiquitination annotation overstates a catalytic role; the UniProt FUNCTION line about promoting ubiquitination is hedged ("probably") and not experimentally established.
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: According to PubMed:34595750 interaction with SKP1 does not occur
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: ComplexPortal author-statement assigning FBXO43 to an SCF ubiquitin ligase complex based on its F-box. However, UniProt records that FBXO43 does not interact with SKP1 (PMID:34595750), and FBXO43 instead binds directly to APC/C subunits.
    action: MARK_AS_OVER_ANNOTATED
    reason: The SCF assignment is a default F-box-family inference. The experimental record indicates FBXO43 does not bind SKP1 and acts as an APC/C inhibitor, not an SCF substrate receptor. Retaining it as part_of SCF over-states a complex membership not supported for FBXO43.
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: According to PubMed:34595750 interaction with SKP1 does not occur
- 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 author-statement assigning FBXO43 to SCF-dependent proteasomal protein catabolism. FBXO43 is itself degraded by the ubiquitin-proteasome system after calcium-triggered phosphorylation; no productive SCF substrate-receptor role is established and SKP1 interaction is reported not to occur.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-extension from the F-box-family default. FBXO43's documented ubiquitin/proteasome link is as a substrate, and its core activity is APC/C inhibition; an SCF-dependent catabolic involved_in annotation is not supported.
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: Ubiquitinated in response to calcium, which promotes proteasomal degradation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34595750
  qualifier: enables
  review:
    summary: Interactions demonstrated with APC/C subunits (ANAPC2, ANAPC4, CDC16, CDC23, ANAPC10, CDC26) during spermatogenesis. These direct contacts, together with the C-terminal RL-tail docking module and ZBR, underlie EMI2's inhibition of the APC/C. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally central direct interactions with APC/C subunits, but bare protein binding is uninformative; the inhibitory APC/C relationship is captured by the meiotic-division annotations. EMI2 docks via an RL tail and uses its ZBR to disrupt CDC20 association and UBE2C-dependent ubiquitylation.
    additional_reference_ids:
    - file:human/FBXO43/FBXO43-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/FBXO43/FBXO43-uniprot.txt
      supporting_text: Interacts with ANAPC2; the interaction is direct, ANAPC4, CDC16, CDC23; the interaction is direct, ANAPC10; the interaction is direct and CDC26, during spermatogenesis
    - reference_id: file:human/FBXO43/FBXO43-deep-research-falcon.md
      supporting_text: 'EMI2 requires a short **C-terminal RL tail** for physical docking to the APC/C; this docking is required for inhibitory activity, facilitating the functional engagement of other inhibitory regions (including ZBR).'
- term:
    id: GO:0010948
    label: negative regulation of cell cycle process
  evidence_type: IMP
  original_reference_id: PMID:34052850
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence (FBXO43 infertility variants; failure to upregulate CCNB1; failure to rescue mouse oocyte phenotype) that FBXO43 negatively regulates the meiotic cell-cycle by inhibiting APC/C. Core process.
    action: ACCEPT
    reason: Core biological process with direct mutant-phenotype support; FBXO43 restrains the meiotic cell cycle (MII arrest) via APC/C inhibition and CCNB1 stabilization.
    supported_by:
    - reference_id: PMID:34052850
      supporting_text: FBXO43, an inhibitor of the anaphase-promoting complex/cyclosome, mediates Metaphase II arrest as a component of the cytostatic factor in oocytes
- term:
    id: GO:1990948
    label: ubiquitin ligase inhibitor activity
  evidence_type: IMP
  original_reference_id: PMID:34595750
  qualifier: enables
  review:
    summary: Proposed molecular function annotation. FBXO43 acts as a direct inhibitor of the APC/C ubiquitin ligase; loss-of-function abolishes this inhibition, causing meiotic arrest. This captures the core molecular function not represented in the seeded GOA.
    action: NEW
    reason: FBXO43's core molecular function is inhibition of the APC/C E3 ligase (a ubiquitin ligase inhibitor activity, GO:1990948, consistent with its EMI1/FBXO5 paralog), directly supported by the disease loss-of-function study; this term is absent from the existing GOA and is added here. Mechanistically the ZBR impairs CDC20 coactivator association and inhibits UBE2C-dependent ubiquitin chain formation, so inhibition is a direct perturbation of APC/C activity.
    additional_reference_ids:
    - file:human/FBXO43/FBXO43-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:34595750
      supporting_text: FBXO43 is a direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C) E3 ligase
    - reference_id: file:human/FBXO43/FBXO43-deep-research-falcon.md
      supporting_text: 'the ZBR can (i) **impair association of the APC/C coactivator CDC20 with the APC/C core**, and (ii) **inhibit APC/C catalytic activity**, including UBE2C-dependent ubiquitin chain formation/elongation steps—implying EMI2 is not merely a stoichiometric blocker but directly perturbs APC/C function.'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput binary interactome; source of a bare protein binding annotation.
- id: PMID:34052850
  title: FBXO43 variants in patients with female infertility characterized by early embryonic arrest.
  findings:
  - statement: Homozygous FBXO43 variants cause female infertility with early embryonic arrest; FBXO43 inhibits the APC/C and mediates metaphase II arrest as a cytostatic-factor component, with the truncating variant failing to upregulate CCNB1 and failing to rescue the mouse oocyte phenotype.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the OZEMA12 disease link and the meiotic APC/C-inhibitor (CSF) function; abstract-only in cache but explicit on function.
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings:
  - statement: Review of the 69 SCF E3 ubiquitin ligase complexes in which variable F-box proteins determine substrate specificity.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Family-level review used as NAS basis for SCF-complex and SCF-catabolism annotations; does not establish a productive SCF role for FBXO43, which is reported not to bind SKP1.
- id: PMID:34595750
  title: A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia.
  findings:
  - statement: FBXO43 is a direct inhibitor of the APC/C E3 ligase; a homozygous nonsense mutation causes non-obstructive azoospermia with meiotic arrest at early diplotene; FBXO43 interacts directly with multiple APC/C subunits and does not interact with SKP1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the SPGF64 disease link, direct APC/C-subunit interactions, the absence of SKP1 binding, and the direct APC/C-inhibitor function; abstract-only in cache.
- id: file:human/FBXO43/FBXO43-deep-research-falcon.md
  title: Falcon deep research report for human FBXO43
  findings:
  - statement: FBXO43/EMI2 is the meiotic APC/C inhibitor underlying cytostatic-factor (CSF) metaphase-II arrest in vertebrate oocytes, suppressing APC/C-mediated cyclin B destruction to sustain MPF/CDK1 until fertilization.
    supporting_text: FBXO43/EMI2 is best understood functionally as a **meiotic inhibitor of the anaphase-promoting complex/cyclosome (APC/C)**—a multi-subunit E3 ubiquitin ligase controlling anaphase onset and exit from M phase. In vertebrate oocytes, APC/C inhibition is the core biochemical requirement for maintaining **metaphase II arrest** (cytostatic factor/CSF arrest) until fertilization.
  - statement: The EMI2 C-terminal zinc-binding region (ZBR) inhibits APC/C by both impairing CDC20 coactivator association with the APC/C core and inhibiting UBE2C-dependent ubiquitin chain formation, i.e. it directly perturbs APC/C catalytic activity rather than acting only as a stoichiometric/pseudosubstrate blocker.
    supporting_text: 'the ZBR can (i) **impair association of the APC/C coactivator CDC20 with the APC/C core**, and (ii) **inhibit APC/C catalytic activity**, including UBE2C-dependent ubiquitin chain formation/elongation steps—implying EMI2 is not merely a stoichiometric blocker but directly perturbs APC/C function.'
  - statement: EMI2 requires a short C-terminal RL tail for physical docking to the APC/C, and this docking is required for its inhibitory activity, enabling engagement of the D-box and ZBR inhibitory modules.
    supporting_text: 'EMI2 requires a short **C-terminal RL tail** for physical docking to the APC/C; this docking is required for inhibitory activity, facilitating the functional engagement of other inhibitory regions (including ZBR).'
  - statement: At fertilization, Ca2+/CaMKII and Plx1/PLK1 phosphorylation generate a beta-TrCP-recognized phosphodegron driving EMI2 ubiquitination and degradation, releasing APC/C inhibition for meiotic exit.
    supporting_text: 'Ca2+-activated signaling (via **CaMKII**) and **Plx1/Plk1** phosphorylation leads to **β-TrCP recognition**, ubiquitination, and degradation of EMI2, thereby releasing APC/C inhibition and allowing meiotic exit.'
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: Falcon deep-research synthesis; anchors FBXO43/EMI2 as the meiotic CSF APC/C inhibitor and adds the RL-tail docking requirement, ZBR-mediated disruption of CDC20 association and UBE2C ubiquitylation, and the beta-TrCP/CaMKII/PLK1 degradation switch. Treated as leads cross-checked against UniProt and the cached disease PMIDs; mechanistic detail rests largely on Xenopus/mouse oocyte systems.
core_functions:
- description: Direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase; binds directly to multiple APC/C subunits (ANAPC2, ANAPC4, CDC16, CDC23, ANAPC10, CDC26) to suppress its activity.
  molecular_function:
    id: GO:1990948
    label: ubiquitin ligase inhibitor activity
  supported_by:
  - reference_id: PMID:34595750
    supporting_text: FBXO43 is a direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C) E3 ligase
  directly_involved_in:
  - id: GO:0045835
    label: negative regulation of meiotic nuclear division
- description: Cytostatic-factor (CSF) component that establishes and maintains arrest of oocytes at metaphase of the second meiotic division until fertilization, by inhibiting APC/C to stabilize cyclin B1 and sustain CDK1 activity; calcium-triggered degradation at fertilization relieves the arrest.
  molecular_function:
    id: GO:1990948
    label: ubiquitin ligase inhibitor activity
  supported_by:
  - reference_id: PMID:34052850
    supporting_text: FBXO43, an inhibitor of the anaphase-promoting complex/cyclosome, mediates Metaphase II arrest as a component of the cytostatic factor in oocytes
  directly_involved_in:
  - id: GO:0045835
    label: negative regulation of meiotic nuclear division
proposed_new_terms: []
suggested_questions:
- question: Does human FBXO43/EMI2 ever assemble a functional SCF complex and target any substrate for ubiquitination, given that SKP1 interaction is reported not to occur and its dominant role is direct APC/C inhibition?
- question: How do the calcium-triggered phosphorylation events (CaMKII, PLK1) on FBXO43 quantitatively convert it from an APC/C inhibitor into a degradation substrate to time the metaphase-II-to-anaphase transition at fertilization?
- question: Does human FBXO43/EMI2 have a non-meiotic, post-mitotic role analogous to the reported Xenopus function in multiciliated-cell progenitors (transient APC/C^CDH1 inhibition enabling PLK1 activation and centriole amplification), and if so in which human tissues?
suggested_experiments:
- description: Reconstitute APC/C inhibition in vitro with purified human FBXO43 and APC/C(CDC20) and measure cyclin B1 ubiquitination, mapping which APC/C-subunit contacts (ANAPC2/ANAPC10/CDC23) are required for inhibition versus its proposed pseudosubstrate mode.
- description: In human or mouse oocytes, perform degron-tagged FBXO43 depletion/add-back with phosphosite mutants (Ser76, Thr234, Ser334) and live imaging of MII arrest and exit to test the requirement of each phosphorylation event for calcium-triggered destruction and anaphase onset.