FBXL13

UniProt ID: Q8NEE6
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

FBXL13 (F-box and leucine-rich repeat protein 13; also Dynein regulatory complex subunit 6, DRC6) is a multi-domain protein with an N-terminal region, an F-box domain, and an extensive C-terminal leucine-rich repeat (LRR) array. It has two distinct, tissue-dependent roles. As an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase substrate-recognition subunit, FBXL13 docks onto SKP1/CUL1 through its F-box domain and uses its LRRs to recruit substrates; it localizes to the centrosome (diffusely cytoplasmic with clear centrosomal enrichment), where it binds centrosomal proteins (Centrin-2, Centrin-3 via its N-terminus, CEP152, and CEP192 via its C-terminal region) and specifically targets CEP192 (notably the CEP192 isoform 3) for SCF/F-box-dependent polyubiquitination and proteasomal degradation, binding the N-terminal region of CEP192; the bound Centrins are not detectably degraded. By fine-tuning CEP192 abundance it downregulates centrosomal gamma-tubulin recruitment, modulates microtubule nucleation/regrowth, restrains centrosome overduplication, and promotes cell migration. Independently, in motile cilia and flagella FBXL13/DRC6 is a structural component of the nexin-dynein regulatory complex (N-DRC), a regulator of axonemal dynein activity and ciliary/flagellar beating; within the N-DRC its lysine-rich C-terminus contributes to the electrostatic distal link between neighbouring doublet microtubules. The ciliary role is less firmly established functionally: in mice Fbxl13/Drc6 knockouts show normal spermatogenesis, sperm morphology and motility and normal tracheal multicilia, suggesting the N-DRC role is dispensable or redundant under tested conditions. It is expressed broadly with enrichment in testis and stomach and in ciliated tissues.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005813 centrosome
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic transfer of centrosome localization from the UniProt subcellular location, which is itself supported by experimental immunofluorescence (PMID:29348145). The centrosome is where FBXL13 acts on CEP192.
Reason: Correct localization for the SCF-FBXL13 / CEP192 function; supported by the experimental study showing FBXL13 is enriched at centrosomes.
Supporting Evidence:
file:human/FBXL13/FBXL13-uniprot.txt
Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:29348145}.
PMID:29348145
FBXL13, a binding determinant of SCF (SKP1-CUL1-F-box)-family E3 ubiquitin ligases, is enriched at centrosomes
GO:0010824 regulation of centrosome duplication
NAS
PMID:29348145
FBXL13 directs the proteolysis of CEP192 to regulate centros... 		ACCEPT
Summary: FBXL13 regulates centrosome homeostasis by degrading CEP192, a key factor in centrosome duplication and microtubule nucleation. Annotation captures the centrosomal regulatory role demonstrated experimentally.
Reason: Directly supported by the CEP192 degradation study; FBXL13 modulates centrosomal gamma-tubulin and microtubule arrays via CEP192 turnover.
Supporting Evidence:
PMID:29348145
CEP192 is a key factor in the initiation process of centrosome duplication and in the control of centrosome microtubule nucleation
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
NAS
PMID:33234069
The FBXL family of F-box proteins: variations on a theme. 		ACCEPT
Summary: Family/ComplexPortal assignment that FBXL13 acts in SCF-dependent proteasomal degradation. For FBXL13 this is experimentally grounded by the SCF-FBXL13-mediated proteasomal degradation of CEP192.
Reason: Core biological process; FBXL13 is a documented SCF substrate receptor that targets CEP192 (notably isoform 3) for proteasomal degradation in an F-box/SCF-dependent manner (CEP192 ubiquitination is lost with the FBXL13 deltaF-box mutant).
Supporting Evidence:
PMID:29348145
CEP192 is specifically targeted for proteasomal degradation by FBXL13
file:human/FBXL13/FBXL13-deep-research-falcon.md
In vivo ubiquitylation assays show CEP192 polyubiquitylation is supported by FBXL13 WT and is impaired when FBXL13 is depleted, and also impaired with an FBXL13 ΔF-box mutant that cannot form a functional SCF complex (cannot recruit SKP1).
GO:0003341 cilium movement
NAS
PMID:37258679
Axonemal structures reveal mechanoregulatory and disease mec... 		KEEP AS NON CORE
Summary: As N-DRC subunit DRC6, FBXL13 is part of the nexin-dynein regulatory complex that regulates axonemal dynein activity and ciliary beating. ComplexPortal NAS assignment from the axoneme cryo-EM structural study.
Reason: Supported by the N-DRC role; this is a distinct, tissue-specific (ciliary/flagellar) function separate from the centrosomal SCF role and not demonstrated by FBXL13-specific perturbation in this paper.
Supporting Evidence:
PMID:37258679
the nexin–dynein regulatory complex (N-DRC)
GO:0005930 axoneme
NAS
PMID:37258679
Axonemal structures reveal mechanoregulatory and disease mec... 		KEEP AS NON CORE
Summary: FBXL13/DRC6 is an axonemal N-DRC subunit; localization to the axoneme is consistent with the cryo-EM structure and the UniProt flagellum-axoneme annotation.
Reason: Correct localization for the N-DRC/ciliary role; distinct from the core centrosomal SCF localization.
Supporting Evidence:
file:human/FBXL13/FBXL13-uniprot.txt
Cytoplasm, cytoskeleton, flagellum axoneme {ECO:0000250|UniProtKB:A8JHD7}.
GO:0005931 axonemal nexin link
NAS
PMID:37258679
Axonemal structures reveal mechanoregulatory and disease mec... 		KEEP AS NON CORE
Summary: FBXL13/DRC6 sits at the distal tip of the N-DRC and contributes lysine-rich residues to the electrostatic link with the neighbouring doublet microtubule. Consistent with the cryo-EM structure placing DRC6 at the nexin link interface.
Reason: Structurally supported component of the axonemal nexin link via the N-DRC; a ciliary/flagellar function distinct from the core centrosomal SCF role.
Supporting Evidence:
PMID:37258679
the termini of DRC6, DRC9 and DRC10 point an additional 26 lysine residues towards the neighbouring DMT
GO:0030317 flagellated sperm motility
NAS
PMID:37258679
Axonemal structures reveal mechanoregulatory and disease mec... 		KEEP AS NON CORE
Summary: Via its N-DRC/DRC6 role in regulating axonemal dynein, FBXL13 is implicated in flagellar/sperm motility; FBXL13 is enriched in testis/sperm. ComplexPortal NAS from the axoneme structural study. However, mouse Fbxl13/Drc6 knockouts have normal spermatogenesis, sperm morphology and motility parameters, indicating the function may be dispensable or redundant.
Reason: Plausible N-DRC-associated motility role consistent with testis/sperm expression, but inferred from complex membership rather than a direct FBXL13 motility phenotype; and mouse knockout data show no overt motility/fertility defect (possible redundancy with related FBXL proteins). Distinct from the core SCF function and retained as non-core.
Supporting Evidence:
file:human/FBXL13/FBXL13-uniprot.txt
a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes
file:human/FBXL13/FBXL13-deep-research-falcon.md
Fbxl13−/− mice show **no overt abnormalities**, have **normal spermatogenesis and sperm morphology**, and sperm motility/velocity parameters (VAP/VSL/VCL) are reported as not significantly different; tracheal multicilia show preserved axonemal ‘9+2’ arrangement and normal morphology.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952618 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation propagated across the generic CRL1/neddylation reaction set.
Reason: Plausible localization for a cytosolic SCF component, but derived from generic CRL pathway membership rather than FBXL13-specific evidence; the centrosome is the functionally relevant compartment.
Supporting Evidence:
file:human/FBXL13/FBXL13-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952620 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic CRL1 neddylation reaction set.
Reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
Supporting Evidence:
file:human/FBXL13/FBXL13-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955241 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic CRL (CAND1) reaction set.
Reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
Supporting Evidence:
file:human/FBXL13/FBXL13-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955289 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic CRL (COMMD/CAND1) reaction set.
Reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
Supporting Evidence:
file:human/FBXL13/FBXL13-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956040 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic CRL deneddylation (COP9) reaction set.
Reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
Supporting Evidence:
file:human/FBXL13/FBXL13-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956200 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic CRL1 (DCUN1D3) reaction set.
Reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
Supporting Evidence:
file:human/FBXL13/FBXL13-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-983140 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (transfer of Ub from E2 to substrate).
Reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
Supporting Evidence:
file:human/FBXL13/FBXL13-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-983147 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (release of E3 from substrate).
Reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
Supporting Evidence:
file:human/FBXL13/FBXL13-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-983156 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (polyubiquitination of substrate).
Reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
Supporting Evidence:
file:human/FBXL13/FBXL13-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005829 cytosol
TAS
Reactome:R-HSA-983157 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (interaction of E3 with substrate and E2-Ub).
Reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
Supporting Evidence:
file:human/FBXL13/FBXL13-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.

Core Functions

Substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that localizes to the centrosome and targets CEP192 for proteasomal degradation, thereby regulating centrosomal gamma-tubulin levels, microtubule nucleation and cell migration.

Molecular Function:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Cellular Locations:
centrosome
Supporting Evidence:
  • PMID:29348145
    CEP192 is specifically targeted for proteasomal degradation by FBXL13

Structural subunit (DRC6) of the axonemal nexin-dynein regulatory complex (N-DRC) in motile cilia and flagella, contributing to the link between neighbouring doublet microtubules and to regulation of axonemal dynein activity and ciliary/flagellar beating.

Molecular Function:
structural molecule activity
Directly Involved In:
cilium movement
Cellular Locations:
axoneme
Supporting Evidence:
  • PMID:37258679
    the termini of DRC6, DRC9 and DRC10 point an additional 26 lysine residues towards the neighbouring DMT

References

GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
PMID:29348145
FBXL13 directs the proteolysis of CEP192 to regulate centrosome homeostasis and cell migration.
  • FBXL13 is enriched at centrosomes, interacts with Centrin-2, Centrin-3, CEP152 and CEP192, and specifically targets CEP192 for proteasomal degradation, downregulating centrosomal gamma-tubulin, disrupting microtubule arrays and promoting cell migration.
PMID:33234069
The FBXL family of F-box proteins: variations on a theme.
  • FBXL-family F-box proteins serve as substrate-recognition subunits of SCF E3 ubiquitin ligases, using their LRR domains for substrate binding and the F-box for SKP1/CUL1 recruitment.
PMID:37258679
Axonemal structures reveal mechanoregulatory and disease mechanisms.
  • Cryo-EM atomic models of the 96-nm axonemal repeat place DRC6 (FBXL13) at the distal tip of the nexin-dynein regulatory complex (N-DRC), where its lysine-rich terminus helps form the electrostatic link to the neighbouring doublet microtubule.
file:human/FBXL13/FBXL13-deep-research-falcon.md
Falcon deep research report for human FBXL13
  • FBXL13 is a centrosome-enriched SCF substrate receptor whose strongest mechanistic evidence is targeting CEP192 (isoform 3) for ubiquitin-proteasome degradation; SKP1 binding requires the F-box.
    "FBXL13 acts as a **substrate-recognition subunit of an SCF E3 ubiquitin ligase** that targets **CEP192 (isoform 3)** for polyubiquitylation and proteasome-mediated degradation, thereby regulating centrosome composition and downstream phenotypes including microtubule regrowth and 2D migration in cultured human cells."
  • FBXL13 interacts with Centrin-2, Centrin-3, CEP152 and CEP192, with Centrin binding mapping to the N-terminus and CEP192 binding requiring the C-terminus; only CEP192 is detectably degraded.
    "FBXL13 interacts with Centrin-2, Centrin-3, CEP152, and CEP192; Centrin binding maps to the amino-terminal region, whereas CEP192 binding requires the carboxy-terminus."
  • FBXL13 is diffusely cytoplasmic with clear centrosomal enrichment, and fine-tunes CEP192 abundance to regulate centrosomal gamma-tubulin and microtubule nucleation.
    "FBXL13 is diffusely cytoplasmic but enriched at centrosomes."
  • Mouse Fbxl13/Drc6 knockouts are viable with normal spermatogenesis, sperm morphology, motility and tracheal multicilia, indicating the N-DRC/ciliary role may be dispensable or redundant.
    "Fbxl13−/− mice show **no overt abnormalities**, have **normal spermatogenesis and sperm morphology**, and sperm motility/velocity parameters (VAP/VSL/VCL) are reported as not significantly different; tracheal multicilia show preserved axonemal ‘9+2’ arrangement and normal morphology."
Reactome:R-HSA-8952618
AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
Reactome:R-HSA-8952620
NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
Reactome:R-HSA-8955241
CAND1 binds cytosolic CRL E3 ubiquitin ligases
Reactome:R-HSA-8955289
COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
Reactome:R-HSA-8956040
COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
Reactome:R-HSA-8956200
MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
Reactome:R-HSA-983140
Transfer of Ub from E2 to substrate and release of E2
Reactome:R-HSA-983147
Release of E3 from polyubiquitinated substrate
Reactome:R-HSA-983156
Polyubiquitination of substrate
Reactome:R-HSA-983157
Interaction of E3 with substrate and E2-Ub complex

Suggested Questions for Experts

Q: How are the two FBXL13 functions (centrosomal SCF-mediated CEP192 degradation versus structural N-DRC subunit in the axoneme) partitioned between tissues and isoforms?

Q: Does FBXL13 have ubiquitin-ligase substrates beyond CEP192 at the centrosome, and is its catalytic SCF activity required for any aspect of its ciliary role?

Suggested Experiments

Experiment: Reconstitute SCF-FBXL13 (SKP1-CUL1-RBX1-FBXL13) in vitro and assay ubiquitination of CEP192 (and candidate centrosomal substrates) by an LRR-binding-deficient mutant to map substrate determinants.

Experiment: Generate FBXL13/DRC6 knockout in ciliated cells and motile-cilia models to test effects on N-DRC assembly, axonemal beat waveform and sperm/ciliary motility, separating the structural role from the SCF role.

Deep Research

Falcon

(FBXL13-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 8 citations 2 artifacts 2026-06-13T06:04:55.539898
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000009 The requested panels showing CEP192 cycloheximide chase quantification, centrosomal gamma-tubulin intensity, and scratch wound assa (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: FBXL13 (UniProt Q8NEE6; gene symbol FBXL13; synonym DRC6) — functional annotation in human

1) Identity verification and key concepts/definitions

FBXL13 (UniProt Q8NEE6) encodes F-box and leucine-rich repeat protein 13, an F-box protein with LRRs (FBXL family) that has also been referred to as DRC6 in the literature; the strongest direct mechanistic evidence in human cells concerns its role as a substrate receptor in an SCF-type E3 ubiquitin ligase rather than a defined motile-cilium axonemal role. (fung2018fbxl13directsthe pages 1-2, fung2018fbxl13directsthe pages 6-8)

F-box proteins / SCF E3 ligases (concept): F-box proteins are substrate-recognition adaptors for SCF (SKP1–CUL1–RBX1) E3 ubiquitin ligases. In the canonical model, the F-box domain mediates SKP1 binding, recruiting the rest of the ligase scaffold, while other domains (here, LRRs and additional regions) contribute to substrate recognition and specificity. FBXL13 conforms to this model in human cell experiments because deletion of its F-box disrupts SKP1 binding and SCF-dependent activity. (fung2018fbxl13directsthe pages 9-10, fung2018fbxl13directsthe pages 8-9)

2) Current understanding of FBXL13 function in human cells (primary, experimentally supported)

2.1 Subcellular localization

In human U2OS cells, FBXL13 is described as diffusely cytoplasmic with clear enrichment at centrosomes based on immunofluorescence with centrosomal markers. (fung2018fbxl13directsthe pages 2-4, fung2018fbxl13directsthe pages 4-5)

2.2 Complex membership and binding partners

Fung et al. (EMBO Reports; published online 18 Jan 2018; DOI/URL: https://doi.org/10.15252/embr.201744799) identify FBXL13 as a centrosome-enriched F-box protein that:

  • Associates with SCF components (notably SKP1; CUL1 detected in complex capture experiments), and SKP1 binding requires the F-box (loss with ΔF-box mutant). (fung2018fbxl13directsthe pages 9-10, fung2018fbxl13directsthe pages 2-4)
  • Interacts with centrosome/centriole proteins including Centrin-2, Centrin-3, CEP152, and CEP192, supported by co-immunoprecipitation and proteomics. (fung2018fbxl13directsthe pages 9-10, fung2018fbxl13directsthe pages 2-4, fung2018fbxl13directsthe pages 4-5)
  • Shows interaction mapping consistent with multi-domain functionality: Centrin binding at the amino-terminus and CEP192 binding requiring a carboxy-terminal region. (fung2018fbxl13directsthe pages 5-6)

The authors also report interactome-scale context (isoform-specific interactors, control compendium), with proteomics deposited to PRIDE (PXD008310). (fung2018fbxl13directsthe pages 2-4, fung2018fbxl13directsthe pages 14-15)

2.3 Primary biochemical function: targeting CEP192 for ubiquitin-mediated proteolysis

The central mechanistic conclusion is that SCF^FBXL13 polyubiquitylates and promotes proteasomal proteolysis of CEP192, especially CEP192 isoform 3, and this is F-box/SCF dependent:

  • In vivo ubiquitylation assays show CEP192 polyubiquitylation is supported by FBXL13 WT and is impaired when FBXL13 is depleted, and also impaired with an FBXL13 ΔF-box mutant that cannot form a functional SCF complex (cannot recruit SKP1). (fung2018fbxl13directsthe pages 9-10, fung2018fbxl13directsthe pages 8-9)
  • Binding/recognition region: FBXL13 binds the N-terminal region of CEP192 (constructs spanning ~aa 1–602/630 used for mapping), supported by mapping and in vitro reconstitution. (fung2018fbxl13directsthe pages 2-4, fung2018fbxl13directsthe pages 4-5)
  • Proteasome dependence: CEP192 reduction upon FBXL13 overexpression is rescued by proteasome inhibition (MG132) in the described experiments. (fung2018fbxl13directsthe pages 5-6)

Quantitative data (protein stability): In cycloheximide (CHX) chase experiments, the extracted text reports CEP192/β-actin values across lanes/timepoints as: 1.00, 0.54, 0.44, 0.30, 0.19, 0.05, 0.08, 0.08 (normalized to 0 h vector control), consistent with accelerated CEP192 decay with FBXL13. The quantitative panel is visible in the retrieved figure crop. (fung2018fbxl13directsthe pages 6-8, fung2018fbxl13directsthe media e15595bd)

2.4 Cellular phenotypes and pathway-level interpretation

Fung et al. connect FBXL13-mediated CEP192 turnover to centrosome function and migration:

  • Centrosome/microtubule nucleation: FBXL13 overexpression disrupts centrosomal microtubule arrays and reduces the ability of cells to regrow centrosomal microtubules after complete depolymerization in microtubule regrowth assays. (fung2018fbxl13directsthe pages 9-10, fung2018fbxl13directsthe pages 6-8)
  • γ-tubulin recruitment: FBXL13 depletion increases centrosomal CEP192 and corresponds to a significant increase in centrosomal γ-tubulin intensity (quantified in figure panels referenced by the authors and present among retrieved crops). (fung2018fbxl13directsthe pages 8-9, fung2018fbxl13directsthe media e15595bd)
  • Centrosome number control: FBXL13 depletion produces a minor yet significant centrosome overduplication phenotype. (fung2018fbxl13directsthe pages 8-9)
  • Cell migration: FBXL13 depletion reduces cell motility in a scratch-wound assay; the defect is rescued by siRNA-resistant FBXL13 WT but not by ΔF-box, and is also rescued by co-depletion of CEP192-3, supporting a model where excess CEP192 contributes to the migration phenotype. Figure crops corresponding to migration quantification were retrieved. (fung2018fbxl13directsthe pages 8-9, fung2018fbxl13directsthe media e15595bd)

Expert interpretation in the primary study: The authors’ model is that FBXL13 fine-tunes CEP192 levels to maintain steady-state centrosomal microtubule nucleation activity, which in turn affects migration-related cellular behaviors. (fung2018fbxl13directsthe pages 9-10, fung2018fbxl13directsthe pages 1-2)

3) DRC6 / N-DRC context: what is known, and what is not (human vs model organisms)

Because FBXL13 is also referred to as DRC6, it appears in motile cilia/flagella literature describing the nexin–dynein regulatory complex (N-DRC). However, direct human genetic/clinical evidence implicating FBXL13 in primary ciliary dyskinesia (PCD) or male infertility was not identified in the retrieved full texts, and the strongest functional genetics evidence is from mouse.

3.1 Mouse genetics: Fbxl13 (Drc6) is dispensable for sperm flagellum formation and male fertility

Morohoshi et al. (PLOS Genetics; Jan 2020; DOI/URL: https://doi.org/10.1371/journal.pgen.1008585) report:

  • TCTE1 (DRC5) was shown (in a cited cultured-cell context) to interact with multiple N-DRC components including FBXL13 (DRC6) and DRC7. (morohoshi2020nexindyneinregulatorycomplex pages 2-4)
  • Expression: Fbxl13 is strongly expressed in mouse testis with weaker signals in lung/ovary/uterus, and expression rises around ~3 weeks postnatally when spermiogenesis begins. (morohoshi2020nexindyneinregulatorycomplex pages 2-4)
  • Knockout phenotype: Fbxl13−/− mice show no overt abnormalities, have normal spermatogenesis and sperm morphology, and sperm motility/velocity parameters (VAP/VSL/VCL) are reported as not significantly different; tracheal multicilia show preserved axonemal ‘9+2’ arrangement and normal morphology. (morohoshi2020nexindyneinregulatorycomplex pages 4-5)

These data suggest that, at least in mice, Fbxl13/DRC6 is not essential for flagellum formation or male fertility under the studied conditions, potentially due to functional redundancy (the authors discuss potential replacement by related FBXL proteins). (morohoshi2020nexindyneinregulatorycomplex pages 10-12, morohoshi2020nexindyneinregulatorycomplex pages 4-5)

3.2 Statistics (from Morohoshi et al. author summary; infertility context)

Morohoshi et al. state that ~1 in 6 couples face infertility, ~50% of cases are attributed to male factors, and ~15% of male infertility is caused by genetic factors (contextual statistics, not specific to FBXL13). (morohoshi2020nexindyneinregulatorycomplex pages 1-2)

4) Recent developments (2023–2024 prioritized): what has changed

4.1 2023 structural modeling of N-DRC (contextual)

A 2023 Nature Communications paper used cryo-EM and integrative modeling to localize multiple DRC subunits in Tetrahymena and describes N-DRC regulatory mechanisms; in the extracted evidence, FBXL13/DRC6-specific human functional updates were not captured, so this source serves mainly as a broader N-DRC context rather than direct FBXL13 functional annotation in human cells. (OpenTargets Search: -FBXL13)

4.2 2024 review literature

A 2024 review discusses the roles of F-box proteins in spermatogenesis and male infertility broadly; within the retrieved excerpts, it did not provide FBXL13-specific mechanistic updates that would supersede the 2018 centrosome work. (OpenTargets Search: -FBXL13)

Overall 2023–2024 conclusion: As of the accessible evidence here, the most definitive mechanistic characterization for human FBXL13 remains the 2018 centrosome/CEP192 SCF adaptor study, with later work contributing mainly contextual N-DRC genetics/structure in model organisms rather than new human FBXL13-specific mechanisms. (fung2018fbxl13directsthe pages 1-2, fung2018fbxl13directsthe pages 8-9, morohoshi2020nexindyneinregulatorycomplex pages 1-2)

5) Current applications and real-world implementations (clinical relevance)

FBXL13 is not an established drug target in the retrieved evidence. The most concrete “real-world” relevance supported here is via genetic association resources and by inference from pathways (centrosome homeostasis, microtubule nucleation, cell migration) that are commonly perturbed in disease.

5.1 Human disease-association signals (Open Targets)

Open Targets lists FBXL13 (ENSG00000161040) with disease-association evidence for diabetes mellitus and type 2 diabetes mellitus, with association scores ~0.33 and ~0.31 respectively, and linked PubMed IDs (34594039; 39024449). These represent association evidence (e.g., genetics/omics/other evidence classes) and should not be interpreted as proof of causality or mechanism without the underlying studies. (OpenTargets Search: diabetes mellitus,age-related hearing impairment,diverticular disease,corneal dystrophy,type 2 diabetes mellitus-FBXL13)

6) Consolidated evidence summary

The table below summarizes the highest-confidence experimental findings and where they come from.

Claim category Specific finding Experimental system/assay Quantitative/statistical detail (if present) Citation context ID(s) Publication (author, year, DOI/URL)
Identity/domains FBXL13 is the human gene/protein corresponding to UniProt Q8NEE6; it is an F-box protein with leucine-rich repeats and has also been annotated as DRC6. Gene/protein annotation and literature synthesis in primary paper and reviews. Human F-box family context: approximately 69 human F-box proteins; FBXL13 belongs to the FBXL subgroup. (fung2018fbxl13directsthe pages 1-2, fung2018fbxl13directsthe pages 6-8) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799
Complex/biochemistry FBXL13 forms a functional SCF ubiquitin ligase complex; SKP1 binding depends on the F-box domain, and FBXL13 was detected with SCF components including SKP1/CUL1. Co-immunoprecipitation; WT versus ΔF-box mutant analysis; affinity purification/proteomics. Functional loss with ΔF-box mutant indicates requirement for SCF assembly. (fung2018fbxl13directsthe pages 9-10, fung2018fbxl13directsthe pages 8-9, fung2018fbxl13directsthe pages 2-4) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799
Interacting partners FBXL13 interacts with Centrin-2, Centrin-3, CEP152, and CEP192; Centrin binding maps to the amino-terminal region, whereas CEP192 binding requires the carboxy-terminus. LC-MS interactome analysis; co-immunoprecipitation; interaction mapping with truncation constructs; in vitro reconstitution. Proteomics identified 25 unique interactors for FBXL13 isoform 1 and 21 for isoform 3; control compendium comprised 30 datasets and 2,850 agarose-binding proteins. (fung2018fbxl13directsthe pages 9-10, fung2018fbxl13directsthe pages 5-6, fung2018fbxl13directsthe pages 2-4, fung2018fbxl13directsthe pages 4-5) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799
Substrates CEP192 isoform 3 is the key experimentally supported ubiquitylation substrate of SCF^FBXL13; Centrin-2/3 bind FBXL13 but are not detectably degraded by it. In vivo ubiquitylation assays; co-expression with HA-ubiquitin; knockdown/rescue; immunoblotting. CEP192 polyubiquitylation is reduced/abolished by FBXL13 depletion and promoted by FBXL13 WT but not ΔF-box. (fung2018fbxl13directsthe pages 9-10, fung2018fbxl13directsthe pages 5-6, fung2018fbxl13directsthe pages 8-9) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799
Substrate-binding region FBXL13 directly binds the amino-terminal region of CEP192; the mapped CEP192 interaction region is reported as aa 1–602/630 depending on construct usage. CEP192 fragment mapping with Myc-tagged constructs; endogenous and ectopic co-IP; in vitro reconstitution. CEP192 fragments used included aa 1–630 and aa 631–2537; direct interaction supported for aa 1–602/630 region. (fung2018fbxl13directsthe pages 6-8, fung2018fbxl13directsthe pages 2-4, fung2018fbxl13directsthe pages 4-5) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799
Localization FBXL13 is diffusely cytoplasmic but enriched at centrosomes. Immunofluorescence microscopy in U2OS cells using centrosomal markers (including γ-tubulin/centrin-3). Qualitative centrosomal enrichment reported; fluorescence quantified with ImageJ ROIs in later assays. (fung2018fbxl13directsthe pages 1-2, fung2018fbxl13directsthe pages 2-4, fung2018fbxl13directsthe pages 4-5, fung2018fbxl13directsthe pages 14-15) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799
Biological function FBXL13 fine-tunes CEP192 abundance to maintain centrosome homeostasis and steady-state centrosomal microtubule nucleation activity. Overexpression and knockdown studies; centrosome immunofluorescence; microtubule regrowth assays. Overexpression lowers centrosomal CEP192/γ-tubulin and suppresses microtubule regrowth; depletion increases centrosomal CEP192 and γ-tubulin. (fung2018fbxl13directsthe pages 9-10, fung2018fbxl13directsthe pages 1-2, fung2018fbxl13directsthe pages 6-8, fung2018fbxl13directsthe pages 8-9) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799
Protein stability / proteolysis FBXL13 overexpression accelerates CEP192 proteolysis, while proteasome inhibition (MG132) rescues CEP192 reduction and FBXL13 knockdown stabilizes/increases CEP192. Cycloheximide chase; MG132 rescue; immunoblotting with ImageJ quantification. CHX chase (CEP192/β-actin values normalized to 0 h vector control) reported as: 1.00, 0.54, 0.44, 0.30, 0.19, 0.05, 0.08, 0.08 across vector/FBXL13 time-course lanes shown in Fig. 4D. (fung2018fbxl13directsthe pages 6-8, fung2018fbxl13directsthe pages 5-6, fung2018fbxl13directsthe media e15595bd) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799
Centrosome phenotype FBXL13 depletion causes increased centrosomal CEP192 and a significant increase in centrosomal γ-tubulin intensity; overexpression causes the opposite effect. Centrosomal fluorescence quantification by immunofluorescence microscopy. Numeric values are not present in extracted text; figure locations for quantification are Fig. 6D (overexpression) and Fig. 6G (knockdown). (fung2018fbxl13directsthe pages 1-2, fung2018fbxl13directsthe pages 6-8, fung2018fbxl13directsthe pages 8-9, fung2018fbxl13directsthe media e15595bd) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799
Microtubule nucleation phenotype FBXL13 overexpression reduces the ability of cells to regrow centrosomal microtubules after complete depolymerization. Nocodazole depolymerization followed by 1 min microtubule regrowth assay. Assay conditions reported: nocodazole 10 µM for 2 h at 4°C, then 1 min recovery; exact regrowth percentages require figure extraction. (fung2018fbxl13directsthe pages 9-10, fung2018fbxl13directsthe pages 6-8, fung2018fbxl13directsthe pages 14-15, fung2018fbxl13directsthe media e15595bd) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799
Cell migration phenotype FBXL13 depletion markedly reduces cell motility in a 2-D scratch assay; the defect is rescued by siRNA-resistant FBXL13 WT but not ΔF-box, and also rescued by co-depletion of CEP192-3. Scratch-wound migration assay with knockdown/rescue. Exact wound-closure values are not in extracted text; relevant quantification panels are Fig. 7B and Fig. 7E. (fung2018fbxl13directsthe pages 1-2, fung2018fbxl13directsthe pages 8-9, fung2018fbxl13directsthe media e15595bd) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799
Additional phenotype FBXL13 depletion causes a minor yet significant centrosome overduplication phenotype. RNAi depletion followed by centrosome phenotyping. Reported qualitatively as minor but significant; exact percentage requires figure extraction. (fung2018fbxl13directsthe pages 8-9) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799
Methods / datasets / URLs Proteomics and microscopy datasets support the FBXL13 interactome and centrosome biology conclusions. LC-MS interactome, confocal IF, ubiquitylation assays, CHX chase, qPCR, microtubule regrowth. PRIDE proteomics dataset accession PXD008310; MLN4924 used at 2 µM in interactome prep; MG132 10 µM for 5 h; CHX 100 µg/ml; qPCR reported as mean ± SD from three triplicates. (fung2018fbxl13directsthe pages 2-4, fung2018fbxl13directsthe pages 14-15) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799
Review context / interpretation Available review context treats FBXL13 as a relatively understudied FBXL-family member; the strongest direct functional evidence remains the centrosome/CEP192 study rather than a firmly established role in ciliary N-DRC biology in human cells. Narrative review context cross-referenced against primary data. No direct quantitative data beyond the primary paper. (fung2018fbxl13directsthe pages 1-2, fung2018fbxl13directsthe pages 2-4) Fung et al., 2018, EMBO Reports, https://doi.org/10.15252/embr.201744799

Table: This table summarizes the main experimentally supported facts about human FBXL13/Q8NEE6 from the key primary study by Fung et al. It highlights validated interactions, substrate evidence, localization, phenotypes, and the limited but important quantitative details available from the extracted evidence.

7) Practical functional annotation (human FBXL13; evidence-weighted)

Primary molecular function (best-supported): FBXL13 acts as a substrate-recognition subunit of an SCF E3 ubiquitin ligase that targets CEP192 (isoform 3) for polyubiquitylation and proteasome-mediated degradation, thereby regulating centrosome composition and downstream phenotypes including microtubule regrowth and 2D migration in cultured human cells. (fung2018fbxl13directsthe pages 9-10, fung2018fbxl13directsthe pages 8-9)

Cellular location of function: Cytoplasm with centrosome enrichment; functional readouts are centrosomal (γ-tubulin recruitment, microtubule nucleation/regrowth). (fung2018fbxl13directsthe pages 2-4, fung2018fbxl13directsthe pages 4-5)

Pathways/processes implicated: Ubiquitin–proteasome system (SCF ligase biology), centrosome homeostasis, centrosomal microtubule nucleation, and cell migration. (fung2018fbxl13directsthe pages 1-2, fung2018fbxl13directsthe pages 8-9)

DRC6/N-DRC annotation (caveated): The DRC6 synonym is supported by motile cilia/flagella literature, but mouse knockout data indicate Fbxl13/Drc6 can be dispensable for sperm flagellum formation and airway multicilia formation in mouse, and this does not currently provide strong evidence for a required analogous function in humans. (morohoshi2020nexindyneinregulatorycomplex pages 2-4, morohoshi2020nexindyneinregulatorycomplex pages 4-5)

8) Key limitations and evidence gaps

  • Limited 2023–2024 FBXL13-specific mechanistic updates were available in retrieved full texts; most recent publications captured relate to N-DRC generally or to other DRC subunits rather than to FBXL13/DRC6 specifically. (OpenTargets Search: -FBXL13)
  • Open Targets provides association signals for metabolic diseases but does not, by itself, establish mechanism; the linked PubMed studies were not available as full text in this run, so mechanistic interpretation is deferred. (OpenTargets Search: diabetes mellitus,age-related hearing impairment,diverticular disease,corneal dystrophy,type 2 diabetes mellitus-FBXL13)

Key primary sources (URLs and publication timing)

  • Fung et al. 2018 (published online 18 Jan 2018). EMBO Reports: “FBXL13 directs the proteolysis of CEP192 to regulate centrosome homeostasis and cell migration.” https://doi.org/10.15252/embr.201744799 (fung2018fbxl13directsthe pages 1-2)
  • Morohoshi et al. 2020 (Jan 2020). PLOS Genetics: “Nexin-Dynein regulatory complex component DRC7 but not FBXL13 is required for sperm flagellum formation and male fertility in mice.” https://doi.org/10.1371/journal.pgen.1008585 (morohoshi2020nexindyneinregulatorycomplex pages 1-2)
  • Open Targets Platform (accessed via tool context): FBXL13 disease associations (diabetes mellitus; type 2 diabetes mellitus), including linked PubMed IDs. (OpenTargets Search: diabetes mellitus,age-related hearing impairment,diverticular disease,corneal dystrophy,type 2 diabetes mellitus-FBXL13)

References

  1. (fung2018fbxl13directsthe pages 1-2): Ella Fung, Carmen Richter, Hong‐Bin Yang, Isabell Schäffer, Roman Fischer, Benedikt M Kessler, Florian Bassermann, and Vincenzo D'Angiolella. Fbxl13 directs the proteolysis of cep192 to regulate centrosome homeostasis and cell migration. EMBO reports, Mar 2018. URL: https://doi.org/10.15252/embr.201744799, doi:10.15252/embr.201744799. This article has 37 citations and is from a highest quality peer-reviewed journal.

  2. (fung2018fbxl13directsthe pages 6-8): Ella Fung, Carmen Richter, Hong‐Bin Yang, Isabell Schäffer, Roman Fischer, Benedikt M Kessler, Florian Bassermann, and Vincenzo D'Angiolella. Fbxl13 directs the proteolysis of cep192 to regulate centrosome homeostasis and cell migration. EMBO reports, Mar 2018. URL: https://doi.org/10.15252/embr.201744799, doi:10.15252/embr.201744799. This article has 37 citations and is from a highest quality peer-reviewed journal.

  3. (fung2018fbxl13directsthe pages 9-10): Ella Fung, Carmen Richter, Hong‐Bin Yang, Isabell Schäffer, Roman Fischer, Benedikt M Kessler, Florian Bassermann, and Vincenzo D'Angiolella. Fbxl13 directs the proteolysis of cep192 to regulate centrosome homeostasis and cell migration. EMBO reports, Mar 2018. URL: https://doi.org/10.15252/embr.201744799, doi:10.15252/embr.201744799. This article has 37 citations and is from a highest quality peer-reviewed journal.

  4. (fung2018fbxl13directsthe pages 8-9): Ella Fung, Carmen Richter, Hong‐Bin Yang, Isabell Schäffer, Roman Fischer, Benedikt M Kessler, Florian Bassermann, and Vincenzo D'Angiolella. Fbxl13 directs the proteolysis of cep192 to regulate centrosome homeostasis and cell migration. EMBO reports, Mar 2018. URL: https://doi.org/10.15252/embr.201744799, doi:10.15252/embr.201744799. This article has 37 citations and is from a highest quality peer-reviewed journal.

  5. (fung2018fbxl13directsthe pages 2-4): Ella Fung, Carmen Richter, Hong‐Bin Yang, Isabell Schäffer, Roman Fischer, Benedikt M Kessler, Florian Bassermann, and Vincenzo D'Angiolella. Fbxl13 directs the proteolysis of cep192 to regulate centrosome homeostasis and cell migration. EMBO reports, Mar 2018. URL: https://doi.org/10.15252/embr.201744799, doi:10.15252/embr.201744799. This article has 37 citations and is from a highest quality peer-reviewed journal.

  6. (fung2018fbxl13directsthe pages 4-5): Ella Fung, Carmen Richter, Hong‐Bin Yang, Isabell Schäffer, Roman Fischer, Benedikt M Kessler, Florian Bassermann, and Vincenzo D'Angiolella. Fbxl13 directs the proteolysis of cep192 to regulate centrosome homeostasis and cell migration. EMBO reports, Mar 2018. URL: https://doi.org/10.15252/embr.201744799, doi:10.15252/embr.201744799. This article has 37 citations and is from a highest quality peer-reviewed journal.

  7. (fung2018fbxl13directsthe pages 5-6): Ella Fung, Carmen Richter, Hong‐Bin Yang, Isabell Schäffer, Roman Fischer, Benedikt M Kessler, Florian Bassermann, and Vincenzo D'Angiolella. Fbxl13 directs the proteolysis of cep192 to regulate centrosome homeostasis and cell migration. EMBO reports, Mar 2018. URL: https://doi.org/10.15252/embr.201744799, doi:10.15252/embr.201744799. This article has 37 citations and is from a highest quality peer-reviewed journal.

  8. (fung2018fbxl13directsthe pages 14-15): Ella Fung, Carmen Richter, Hong‐Bin Yang, Isabell Schäffer, Roman Fischer, Benedikt M Kessler, Florian Bassermann, and Vincenzo D'Angiolella. Fbxl13 directs the proteolysis of cep192 to regulate centrosome homeostasis and cell migration. EMBO reports, Mar 2018. URL: https://doi.org/10.15252/embr.201744799, doi:10.15252/embr.201744799. This article has 37 citations and is from a highest quality peer-reviewed journal.

  9. (fung2018fbxl13directsthe media e15595bd): Ella Fung, Carmen Richter, Hong‐Bin Yang, Isabell Schäffer, Roman Fischer, Benedikt M Kessler, Florian Bassermann, and Vincenzo D'Angiolella. Fbxl13 directs the proteolysis of cep192 to regulate centrosome homeostasis and cell migration. EMBO reports, Mar 2018. URL: https://doi.org/10.15252/embr.201744799, doi:10.15252/embr.201744799. This article has 37 citations and is from a highest quality peer-reviewed journal.

  10. (morohoshi2020nexindyneinregulatorycomplex pages 2-4): Akane Morohoshi, Haruhiko Miyata, Keisuke Shimada, Kaori Nozawa, Takafumi Matsumura, Ryuji Yanase, Kogiku Shiba, Kazuo Inaba, and Masahito Ikawa. Nexin-dynein regulatory complex component drc7 but not fbxl13 is required for sperm flagellum formation and male fertility in mice. PLOS Genetics, 16:e1008585, Jan 2020. URL: https://doi.org/10.1371/journal.pgen.1008585, doi:10.1371/journal.pgen.1008585. This article has 52 citations and is from a domain leading peer-reviewed journal.

  11. (morohoshi2020nexindyneinregulatorycomplex pages 4-5): Akane Morohoshi, Haruhiko Miyata, Keisuke Shimada, Kaori Nozawa, Takafumi Matsumura, Ryuji Yanase, Kogiku Shiba, Kazuo Inaba, and Masahito Ikawa. Nexin-dynein regulatory complex component drc7 but not fbxl13 is required for sperm flagellum formation and male fertility in mice. PLOS Genetics, 16:e1008585, Jan 2020. URL: https://doi.org/10.1371/journal.pgen.1008585, doi:10.1371/journal.pgen.1008585. This article has 52 citations and is from a domain leading peer-reviewed journal.

  12. (morohoshi2020nexindyneinregulatorycomplex pages 10-12): Akane Morohoshi, Haruhiko Miyata, Keisuke Shimada, Kaori Nozawa, Takafumi Matsumura, Ryuji Yanase, Kogiku Shiba, Kazuo Inaba, and Masahito Ikawa. Nexin-dynein regulatory complex component drc7 but not fbxl13 is required for sperm flagellum formation and male fertility in mice. PLOS Genetics, 16:e1008585, Jan 2020. URL: https://doi.org/10.1371/journal.pgen.1008585, doi:10.1371/journal.pgen.1008585. This article has 52 citations and is from a domain leading peer-reviewed journal.

  13. (morohoshi2020nexindyneinregulatorycomplex pages 1-2): Akane Morohoshi, Haruhiko Miyata, Keisuke Shimada, Kaori Nozawa, Takafumi Matsumura, Ryuji Yanase, Kogiku Shiba, Kazuo Inaba, and Masahito Ikawa. Nexin-dynein regulatory complex component drc7 but not fbxl13 is required for sperm flagellum formation and male fertility in mice. PLOS Genetics, 16:e1008585, Jan 2020. URL: https://doi.org/10.1371/journal.pgen.1008585, doi:10.1371/journal.pgen.1008585. This article has 52 citations and is from a domain leading peer-reviewed journal.

  14. (OpenTargets Search: -FBXL13): Open Targets Query (-FBXL13, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  15. (OpenTargets Search: diabetes mellitus,age-related hearing impairment,diverticular disease,corneal dystrophy,type 2 diabetes mellitus-FBXL13): Open Targets Query (diabetes mellitus,age-related hearing impairment,diverticular disease,corneal dystrophy,type 2 diabetes mellitus-FBXL13, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

Artifacts

Citations

  1. morohoshi2020nexindyneinregulatorycomplex pages 2-4
  2. morohoshi2020nexindyneinregulatorycomplex pages 4-5
  3. morohoshi2020nexindyneinregulatorycomplex pages 1-2
  4. morohoshi2020nexindyneinregulatorycomplex pages 10-12
  5. https://doi.org/10.15252/embr.201744799
  6. https://doi.org/10.1371/journal.pgen.1008585
  7. https://doi.org/10.15252/embr.201744799,
  8. https://doi.org/10.1371/journal.pgen.1008585,

📚 Additional Documentation

Pn Notes

(FBXL13-pn-notes.md)

FBXL13 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q8NEE6
  • 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: FBXL13 (F-box and leucine-rich repeat protein 13; also Dynein regulatory complex subunit 6, DRC6) is a multi-domain protein with an N-terminal region, an F-box domain, and an extensive C-terminal leucine-rich repeat (LRR) array. It has two distinct, tissue-dependent roles. As an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase substrate-recognition subunit, FBXL13 docks onto SKP1/CUL1 through its F-box domain and uses its LRRs to recruit substrates; it localizes to the centrosome (diffusely cytoplasmic with clear centrosomal enrichment), where it binds centrosomal proteins (Centrin-2, Centrin-3 via its N-terminus, CEP152, and CEP192 via its C-terminal region) and specifically targets CEP192 (notably the CEP192 isoform 3) for SCF/F-box-dependent polyubiquitination and proteasomal degradation, binding the N-terminal region of CEP192; the bound Centrins are not detectably degraded. By fine-tuning CEP192 abundance it downregulates centrosomal gamma-tubulin recruitment, modulates microtubule nucleation/regrowth, restrains centrosome overduplication, and promotes cell migration. Independently, in motile cilia and flagella FBXL13/DRC6 is a structural component of the nexin-dynein regulatory complex (N-DRC), a regulator of axonemal dynein activity and ciliary/flagellar beating; within the N-DRC its lysine-rich C-terminus contributes to the electrostatic distal link between neighbouring doublet microtubules. The ciliary role is less firmly established functionally: in mice Fbxl13/Drc6 knockouts show normal spermatogenesis, sperm morphology and motility and normal tracheal multicilia, suggesting the N-DRC role is dispensable or redundant under tested conditions. It is expressed broadly with enrichment in testis and stomach and in ciliated tissues.
  • Existing/core annotation action counts: ACCEPT: 3; KEEP_AS_NON_CORE: 14

PN Consistency Summary

  • Consistency: Strong. Falcon deep research, review YAML, and PN node mapping agree FBXL13 is an SCF substrate receptor that degrades CEP192 at the centrosome (PMID:29348145), plus a moonlighting N-DRC/DRC6 axonemal structural role (PMID:37258679). No contradictions. The dual identity (centrosomal SCF vs ciliary structural subunit) is handled by KEEP_AS_NON_CORE on all N-DRC terms — coherent with PN's UPS-only framing.
  • PN story / NEW pressure: PN asserts only the generic adaptor MF (GO:1990756, verified real). GOA carries NO MF term for FBXL13 at all (only BP/CC). The review adds GO:1990756 in core_functions (no existing MF to MODIFY). Not over-reaching. The ciliary structural role (GO:0005198 structural molecule activity) is a genuine second MF the PN UPS lens does not capture, but it is correctly off-mapped as non-core. Conclusion: adaptor MF appropriately ADDED; no defensible UPS NEW-term gap.
  • Evidence alignment: PN reference is only "15340381/rev" (family placeholder, PMID:15340381). The review does not cite it; its PMIDs (29348145, 33234069, 37258679) are gene-specific and richer. Benign divergence.
  • Verdict: CONSISTENT / ACCEPT mapping. No edits required; adaptor-MF pattern correctly applied; substrate (CEP192) validated.

Full Consistency Review

  • UniProt: Q8NEE6 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE
  • PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|LRR ; PN-node mapping: group-level mapped / ok_for_propagation_to_go / GO:1990756; F-box+LRR subtype/type no_mapping; class context_only / too_broad / GO:0061630; branch no_mapping.
  • Consistency: Strong. Falcon deep research, review YAML, and PN node mapping agree FBXL13 is an SCF substrate receptor that degrades CEP192 at the centrosome (PMID:29348145), plus a moonlighting N-DRC/DRC6 axonemal structural role (PMID:37258679). No contradictions. The dual identity (centrosomal SCF vs ciliary structural subunit) is handled by KEEP_AS_NON_CORE on all N-DRC terms — coherent with PN's UPS-only framing.
  • PN story / NEW pressure: PN asserts only the generic adaptor MF (GO:1990756, verified real). GOA carries NO MF term for FBXL13 at all (only BP/CC). The review adds GO:1990756 in core_functions (no existing MF to MODIFY). Not over-reaching. The ciliary structural role (GO:0005198 structural molecule activity) is a genuine second MF the PN UPS lens does not capture, but it is correctly off-mapped as non-core. Conclusion: adaptor MF appropriately ADDED; no defensible UPS NEW-term gap.
  • Mapping strategy: Gene does not change the node. F-box catalysis correctly excluded from sub-nodes (RBX1 RING). One caveat: CEP192 is a validated substrate, so FBXL13 is NOT an orphan adaptor — adaptor MF is experimentally grounded, not inferred-only. PN-projected GO:1990756 matches review core_functions exactly (not broader/narrower).
  • Evidence alignment: PN reference is only "15340381/rev" (family placeholder, PMID:15340381). The review does not cite it; its PMIDs (29348145, 33234069, 37258679) are gene-specific and richer. Benign divergence.
  • Verdict: CONSISTENT / ACCEPT mapping. No edits required; adaptor-MF pattern correctly applied; substrate (CEP192) validated.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/FBXL13/FBXL13-ai-review.yaml
  • PN workbook rows: 1

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

  • UniProt: Q8NEE6
  • In branches: UPS
  • Signature domains: IPR001810
  • Auxiliary domains: IPR001611, IPR032675
  • 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|LRR
      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: Q8NEE6
gene_symbol: FBXL13
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXL13 (F-box and leucine-rich repeat protein 13; also Dynein regulatory
  complex subunit 6, DRC6) is a multi-domain protein with an N-terminal region,
  an F-box domain, and an extensive C-terminal leucine-rich repeat (LRR) array.
  It has two distinct, tissue-dependent roles. As an SCF (SKP1-CUL1-F-box) E3
  ubiquitin ligase substrate-recognition subunit, FBXL13 docks onto SKP1/CUL1
  through its F-box domain and uses its LRRs to recruit substrates; it localizes
  to the centrosome (diffusely cytoplasmic with clear centrosomal enrichment),
  where it binds centrosomal proteins (Centrin-2, Centrin-3 via its N-terminus,
  CEP152, and CEP192 via its C-terminal region) and specifically targets CEP192
  (notably the CEP192 isoform 3) for SCF/F-box-dependent polyubiquitination and
  proteasomal degradation, binding the N-terminal region of CEP192; the bound
  Centrins are not detectably degraded. By fine-tuning CEP192 abundance it
  downregulates centrosomal gamma-tubulin recruitment, modulates microtubule
  nucleation/regrowth, restrains centrosome overduplication, and promotes cell
  migration. Independently, in motile cilia and flagella FBXL13/DRC6 is a
  structural component of the nexin-dynein regulatory complex (N-DRC), a
  regulator of axonemal dynein activity and ciliary/flagellar beating; within the
  N-DRC its lysine-rich C-terminus contributes to the electrostatic distal link
  between neighbouring doublet microtubules. The ciliary role is less firmly
  established functionally: in mice Fbxl13/Drc6 knockouts show normal
  spermatogenesis, sperm morphology and motility and normal tracheal multicilia,
  suggesting the N-DRC role is dispensable or redundant under tested conditions.
  It is expressed broadly with enrichment in testis and stomach and in ciliated
  tissues.
alternative_products:
- name: '1'
  id: Q8NEE6-1
- name: '2'
  id: Q8NEE6-2
  sequence_note: VSP_013004
- name: '3'
  id: Q8NEE6-3
  sequence_note: VSP_013005
- name: '4'
  id: Q8NEE6-4
  sequence_note: VSP_013003
existing_annotations:
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of centrosome localization from the UniProt subcellular location, which is itself supported by experimental immunofluorescence (PMID:29348145). The centrosome is where FBXL13 acts on CEP192.
    action: ACCEPT
    reason: Correct localization for the SCF-FBXL13 / CEP192 function; supported by the experimental study showing FBXL13 is enriched at centrosomes.
    supported_by:
    - reference_id: file:human/FBXL13/FBXL13-uniprot.txt
      supporting_text: 'Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:29348145}.'
    - reference_id: PMID:29348145
      supporting_text: FBXL13, a binding determinant of SCF (SKP1-CUL1-F-box)-family E3 ubiquitin ligases, is enriched at centrosomes
- term:
    id: GO:0010824
    label: regulation of centrosome duplication
  evidence_type: NAS
  original_reference_id: PMID:29348145
  qualifier: involved_in
  review:
    summary: FBXL13 regulates centrosome homeostasis by degrading CEP192, a key factor in centrosome duplication and microtubule nucleation. Annotation captures the centrosomal regulatory role demonstrated experimentally.
    action: ACCEPT
    reason: Directly supported by the CEP192 degradation study; FBXL13 modulates centrosomal gamma-tubulin and microtubule arrays via CEP192 turnover.
    supported_by:
    - reference_id: PMID:29348145
      supporting_text: CEP192 is a key factor in the initiation process of centrosome duplication and in the control of centrosome microtubule nucleation
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:33234069
  qualifier: involved_in
  review:
    summary: Family/ComplexPortal assignment that FBXL13 acts in SCF-dependent proteasomal degradation. For FBXL13 this is experimentally grounded by the SCF-FBXL13-mediated proteasomal degradation of CEP192.
    action: ACCEPT
    reason: Core biological process; FBXL13 is a documented SCF substrate receptor that targets CEP192 (notably isoform 3) for proteasomal degradation in an F-box/SCF-dependent manner (CEP192 ubiquitination is lost with the FBXL13 deltaF-box mutant).
    additional_reference_ids:
    - file:human/FBXL13/FBXL13-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:29348145
      supporting_text: CEP192 is specifically targeted for proteasomal degradation by FBXL13
    - reference_id: file:human/FBXL13/FBXL13-deep-research-falcon.md
      supporting_text: "In vivo ubiquitylation assays show CEP192 polyubiquitylation is supported by FBXL13 WT and is impaired when FBXL13 is depleted, and also impaired with an FBXL13 ΔF-box mutant that cannot form a functional SCF complex (cannot recruit SKP1)."
- term:
    id: GO:0003341
    label: cilium movement
  evidence_type: NAS
  original_reference_id: PMID:37258679
  qualifier: involved_in
  review:
    summary: As N-DRC subunit DRC6, FBXL13 is part of the nexin-dynein regulatory complex that regulates axonemal dynein activity and ciliary beating. ComplexPortal NAS assignment from the axoneme cryo-EM structural study.
    action: KEEP_AS_NON_CORE
    reason: Supported by the N-DRC role; this is a distinct, tissue-specific (ciliary/flagellar) function separate from the centrosomal SCF role and not demonstrated by FBXL13-specific perturbation in this paper.
    supported_by:
    - reference_id: PMID:37258679
      supporting_text: the nexin–dynein regulatory complex (N-DRC)
- term:
    id: GO:0005930
    label: axoneme
  evidence_type: NAS
  original_reference_id: PMID:37258679
  qualifier: located_in
  review:
    summary: FBXL13/DRC6 is an axonemal N-DRC subunit; localization to the axoneme is consistent with the cryo-EM structure and the UniProt flagellum-axoneme annotation.
    action: KEEP_AS_NON_CORE
    reason: Correct localization for the N-DRC/ciliary role; distinct from the core centrosomal SCF localization.
    supported_by:
    - reference_id: file:human/FBXL13/FBXL13-uniprot.txt
      supporting_text: 'Cytoplasm, cytoskeleton, flagellum axoneme {ECO:0000250|UniProtKB:A8JHD7}.'
- term:
    id: GO:0005931
    label: axonemal nexin link
  evidence_type: NAS
  original_reference_id: PMID:37258679
  qualifier: part_of
  review:
    summary: FBXL13/DRC6 sits at the distal tip of the N-DRC and contributes lysine-rich residues to the electrostatic link with the neighbouring doublet microtubule. Consistent with the cryo-EM structure placing DRC6 at the nexin link interface.
    action: KEEP_AS_NON_CORE
    reason: Structurally supported component of the axonemal nexin link via the N-DRC; a ciliary/flagellar function distinct from the core centrosomal SCF role.
    supported_by:
    - reference_id: PMID:37258679
      supporting_text: the termini of DRC6, DRC9 and DRC10 point an additional 26 lysine residues towards the neighbouring DMT
- term:
    id: GO:0030317
    label: flagellated sperm motility
  evidence_type: NAS
  original_reference_id: PMID:37258679
  qualifier: involved_in
  review:
    summary: Via its N-DRC/DRC6 role in regulating axonemal dynein, FBXL13 is implicated in flagellar/sperm motility; FBXL13 is enriched in testis/sperm. ComplexPortal NAS from the axoneme structural study. However, mouse Fbxl13/Drc6 knockouts have normal spermatogenesis, sperm morphology and motility parameters, indicating the function may be dispensable or redundant.
    action: KEEP_AS_NON_CORE
    reason: Plausible N-DRC-associated motility role consistent with testis/sperm expression, but inferred from complex membership rather than a direct FBXL13 motility phenotype; and mouse knockout data show no overt motility/fertility defect (possible redundancy with related FBXL proteins). Distinct from the core SCF function and retained as non-core.
    additional_reference_ids:
    - file:human/FBXL13/FBXL13-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/FBXL13/FBXL13-uniprot.txt
      supporting_text: a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes
    - reference_id: file:human/FBXL13/FBXL13-deep-research-falcon.md
      supporting_text: "Fbxl13−/− mice show **no overt abnormalities**, have **normal spermatogenesis and sperm morphology**, and sperm motility/velocity parameters (VAP/VSL/VCL) are reported as not significantly different; tracheal multicilia show preserved axonemal ‘9+2’ arrangement and normal morphology."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation propagated across the generic CRL1/neddylation reaction set.
    action: KEEP_AS_NON_CORE
    reason: Plausible localization for a cytosolic SCF component, but derived from generic CRL pathway membership rather than FBXL13-specific evidence; the centrosome is the functionally relevant compartment.
    supported_by:
    - reference_id: file:human/FBXL13/FBXL13-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic CRL1 neddylation reaction set.
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
    supported_by:
    - reference_id: file:human/FBXL13/FBXL13-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic CRL (CAND1) reaction set.
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
    supported_by:
    - reference_id: file:human/FBXL13/FBXL13-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic CRL (COMMD/CAND1) reaction set.
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
    supported_by:
    - reference_id: file:human/FBXL13/FBXL13-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic CRL deneddylation (COP9) reaction set.
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
    supported_by:
    - reference_id: file:human/FBXL13/FBXL13-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic CRL1 (DCUN1D3) reaction set.
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
    supported_by:
    - reference_id: file:human/FBXL13/FBXL13-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (transfer of Ub from E2 to substrate).
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
    supported_by:
    - reference_id: file:human/FBXL13/FBXL13-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (release of E3 from substrate).
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
    supported_by:
    - reference_id: file:human/FBXL13/FBXL13-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (polyubiquitination of substrate).
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
    supported_by:
    - reference_id: file:human/FBXL13/FBXL13-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (interaction of E3 with substrate and E2-Ub).
    action: KEEP_AS_NON_CORE
    reason: Plausible but redundant generic-pathway localization; not FBXL13-specific.
    supported_by:
    - reference_id: file:human/FBXL13/FBXL13-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
references:
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: PMID:29348145
  title: FBXL13 directs the proteolysis of CEP192 to regulate centrosome homeostasis
    and cell migration.
  findings:
  - statement: FBXL13 is enriched at centrosomes, interacts with Centrin-2, Centrin-3, CEP152 and CEP192, and specifically targets CEP192 for proteasomal degradation, downregulating centrosomal gamma-tubulin, disrupting microtubule arrays and promoting cell migration.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the core centrosomal SCF-FBXL13 function via CEP192 degradation; abstract-only in cache but the functional claims (interaction, degradation, phenotypes) are explicit.
- id: PMID:33234069
  title: 'The FBXL family of F-box proteins: variations on a theme.'
  findings:
  - statement: FBXL-family F-box proteins serve as substrate-recognition subunits of SCF E3 ubiquitin ligases, using their LRR domains for substrate binding and the F-box for SKP1/CUL1 recruitment.
    reference_section_type: LITERATURE_REVIEW
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Family-level review (full text available) supporting the general FBXL SCF substrate-receptor model.
- id: PMID:37258679
  title: Axonemal structures reveal mechanoregulatory and disease mechanisms.
  findings:
  - statement: Cryo-EM atomic models of the 96-nm axonemal repeat place DRC6 (FBXL13) at the distal tip of the nexin-dynein regulatory complex (N-DRC), where its lysine-rich terminus helps form the electrostatic link to the neighbouring doublet microtubule.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available; structural basis for FBXL13/DRC6 as an N-DRC subunit at the axonemal nexin link. Source of the cilium movement / axoneme / nexin-link / sperm-motility annotations.
- id: file:human/FBXL13/FBXL13-deep-research-falcon.md
  title: Falcon deep research report for human FBXL13
  findings:
  - statement: FBXL13 is a centrosome-enriched SCF substrate receptor whose strongest mechanistic evidence is targeting CEP192 (isoform 3) for ubiquitin-proteasome degradation; SKP1 binding requires the F-box.
    supporting_text: "FBXL13 acts as a **substrate-recognition subunit of an SCF E3 ubiquitin ligase** that targets **CEP192 (isoform 3)** for polyubiquitylation and proteasome-mediated degradation, thereby regulating centrosome composition and downstream phenotypes including microtubule regrowth and 2D migration in cultured human cells."
  - statement: FBXL13 interacts with Centrin-2, Centrin-3, CEP152 and CEP192, with Centrin binding mapping to the N-terminus and CEP192 binding requiring the C-terminus; only CEP192 is detectably degraded.
    supporting_text: "FBXL13 interacts with Centrin-2, Centrin-3, CEP152, and CEP192; Centrin binding maps to the amino-terminal region, whereas CEP192 binding requires the carboxy-terminus."
  - statement: FBXL13 is diffusely cytoplasmic with clear centrosomal enrichment, and fine-tunes CEP192 abundance to regulate centrosomal gamma-tubulin and microtubule nucleation.
    supporting_text: "FBXL13 is diffusely cytoplasmic but enriched at centrosomes."
  - statement: Mouse Fbxl13/Drc6 knockouts are viable with normal spermatogenesis, sperm morphology, motility and tracheal multicilia, indicating the N-DRC/ciliary role may be dispensable or redundant.
    supporting_text: "Fbxl13−/− mice show **no overt abnormalities**, have **normal spermatogenesis and sperm morphology**, and sperm motility/velocity parameters (VAP/VSL/VCL) are reported as not significantly different; tracheal multicilia show preserved axonemal ‘9+2’ arrangement and normal morphology."
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: Falcon (Edison Scientific) deep research synthesis. Centrosome/CEP192 mechanism is grounded in Fung et al. 2018 (EMBO Reports, the same study underlying PMID:29348145) and adds the CEP192 isoform-3 specificity, Centrin-non-degradation, and N-terminal CEP192 binding nuances. The mouse-knockout caveat is from Morohoshi et al. 2020 (PLOS Genetics). Falcon cites DOIs not PMIDs and these primary papers are not all in the local cache; treated as corroborating leads consistent with the existing experimental annotations.
- id: Reactome:R-HSA-8952618
  title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8952620
  title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8955241
  title: CAND1 binds cytosolic CRL E3 ubiquitin ligases
  findings: []
- id: Reactome:R-HSA-8955289
  title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956040
  title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956200
  title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-983140
  title: Transfer of Ub from E2 to substrate and release of E2
  findings: []
- id: Reactome:R-HSA-983147
  title: Release of E3 from polyubiquitinated substrate
  findings: []
- id: Reactome:R-HSA-983156
  title: Polyubiquitination of substrate
  findings: []
- id: Reactome:R-HSA-983157
  title: Interaction of E3 with substrate and E2-Ub complex
  findings: []
core_functions:
- description: Substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that localizes to the centrosome and targets CEP192 for proteasomal degradation, thereby regulating centrosomal gamma-tubulin levels, microtubule nucleation and cell migration.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005813
    label: centrosome
  supported_by:
  - reference_id: PMID:29348145
    supporting_text: CEP192 is specifically targeted for proteasomal degradation by FBXL13
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: Structural subunit (DRC6) of the axonemal nexin-dynein regulatory complex (N-DRC) in motile cilia and flagella, contributing to the link between neighbouring doublet microtubules and to regulation of axonemal dynein activity and ciliary/flagellar beating.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  locations:
  - id: GO:0005930
    label: axoneme
  supported_by:
  - reference_id: PMID:37258679
    supporting_text: the termini of DRC6, DRC9 and DRC10 point an additional 26 lysine residues towards the neighbouring DMT
  directly_involved_in:
  - id: GO:0003341
    label: cilium movement
proposed_new_terms: []
suggested_questions:
- question: How are the two FBXL13 functions (centrosomal SCF-mediated CEP192 degradation versus structural N-DRC subunit in the axoneme) partitioned between tissues and isoforms?
- question: Does FBXL13 have ubiquitin-ligase substrates beyond CEP192 at the centrosome, and is its catalytic SCF activity required for any aspect of its ciliary role?
suggested_experiments:
- description: Reconstitute SCF-FBXL13 (SKP1-CUL1-RBX1-FBXL13) in vitro and assay ubiquitination of CEP192 (and candidate centrosomal substrates) by an LRR-binding-deficient mutant to map substrate determinants.
- description: Generate FBXL13/DRC6 knockout in ciliated cells and motile-cilia models to test effects on N-DRC assembly, axonemal beat waveform and sperm/ciliary motility, separating the structural role from the SCF role.