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.