id: O94952
gene_symbol: FBXO21
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXO21 (FBX21, KIAA0875; also reported as SIP/FBXO3B) is a 628-residue F-box
  protein that serves as the substrate-recognition subunit of a multi-subunit
  SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Through its
  N-terminal F-box domain (residues 28-84) it binds SKP1, coupling to CUL1 and
  the catalytic RING subunit RBX1, while its central and C-terminal regions
  provide substrate specificity. The best-characterized substrate is EID1
  (EP300-interacting inhibitor of differentiation 1): FBXO21 binds the
  C-terminal region of EID1 and SCF(FBXO21) directly ubiquitylates EID1 to drive
  its proteasomal degradation predominantly in the cytoplasm (EID1 accumulates in
  both cytoplasm and nucleus upon FBXO21 loss), thereby influencing
  EID1-dependent transcriptional repression; a peptidic modular degron in EID1 is
  necessary and sufficient for SCF(FBXO21)-dependent polyubiquitylation. FBXO21
  operates in two mechanistic modes. In the canonical proteolytic mode it directs
  K48-type proteasomal degradation of substrates including EID1, the PI3K
  regulatory subunit p85alpha (PIK3R1; degradation in acute myeloid leukemia
  shapes PI3K/AKT versus ERK signaling and AML cell survival/differentiation), and
  the multidrug-resistance transporter ABCB1/P-glycoprotein (whose turnover is
  blocked by Ser291-phosphorylated CD44). In a non-proteolytic signaling mode,
  SCF(FBXO21) catalyzes Lys29-linked ubiquitination of the kinase ASK1 (MAP3K5)
  that promotes ASK1 activation rather than degradation, driving ASK1-JNK/p38 and
  IRF3-dependent antiviral innate immune signaling and type I interferon (IFN-beta)
  and IL-6 induction after viral or nucleic-acid challenge. As an SCF adaptor,
  FBXO21 thus acts in the ubiquitin-proteasome system to mediate
  ubiquitin-dependent, SCF-type protein catabolism and, via atypical chain
  linkages, ubiquitin-dependent signal transduction. It is broadly expressed
  (tissue-enhanced in fallopian tube).
alternative_products:
- name: '1'
  id: O94952-2
- name: '2'
  id: O94952-1
  sequence_note: VSP_035975
existing_annotations:
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro domain-based electronic assignment of DNA binding, propagated from a hemimethylated-DNA-binding-like (YccV-like) domain match; FBXO21 is an SCF substrate adaptor with no established DNA-binding function.
    action: REMOVE
    reason: >-
      This is an over-propagated IEA. FBXO21's UniProt-curated function is purely
      as the substrate-recognition subunit of an SCF E3 ubiquitin ligase, binding
      SKP1/CUL1 and substrates (EID1). The DNA binding term derives from an
      InterPro signature (IPR011722 hemimethylated-DNA-binding/YccV-like,
      TIGR02097 yccV) detected in the protein's C-terminal region; there is no
      experimental or curated evidence that FBXO21 binds DNA sequence-specifically
      or functions in DNA metabolism. The annotation conflates a remote
      domain-fold match with a molecular function and is biologically misleading
      for a cytoplasmic/nuclear ubiquitin-ligase adaptor.
    supported_by:
    - reference_id: file:human/FBXO21/FBXO21-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26085330
  qualifier: enables
  review:
    summary: IPI interaction underpinning the functionally meaningful FBXO21-EID1 substrate relationship (FBXO21 binds the C-terminal region of EID1 and targets it for ubiquitylation). The bare protein binding term is uninformative, but this records a real substrate interaction.
    action: KEEP_AS_NON_CORE
    reason: Records the substrate-recognition interaction with EID1, which is biologically central, but bare protein binding (GO:0005515) is uninformative per curation guidelines; the substrate relationship is better captured by the SCF/catabolism process annotations and core functions.
    supported_by:
    - reference_id: PMID:26085330
      supporting_text: The central and COOH-terminal portion of FBXO21 was found to interact with the COOH-terminal region of EID1 in transfected cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: Interaction captured in a high-throughput affinity-purification map of the human Polycomb complexome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput AP-MS interaction; bare protein binding (GO:0005515) is uninformative and not a core function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Interaction captured in the BioPlex proteome-scale AP-MS interactome (cell-specific remodeling study). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput AP-MS interactome; bare protein binding (GO:0005515) is uninformative and not a core function.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: BioPlex 3.0, results from affinity purification of 10,128 human proteins-half the proteome-in 293T cells and includes 118,162 interactions among 14,586 proteins.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Interaction captured in a multimodal AP-MS/immunofluorescence cell map of U2OS cells. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput AP-MS interactome; bare protein binding (GO:0005515) is uninformative and not a core function.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins in U2OS osteosarcoma cells
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: FBXO21 is the variable F-box substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, binding SKP1 and CUL1. This is a core localization/complex-membership annotation.
    action: ACCEPT
    reason: >-
      Directly supported by UniProt curation (interacts with SKP1 and CUL1) and
      by a dedicated ComplexPortal entry (CPX-7930, SCF E3 ubiquitin ligase
      complex, FBXO21 variant). Core to FBXO21's molecular role.
    supported_by:
    - reference_id: file:human/FBXO21/FBXO21-uniprot.txt
      supporting_text: 'Directly interacts with SKP1 and CUL1.'
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: involved_in
  review:
    summary: As the substrate-recognition subunit of an SCF complex, FBXO21 drives SCF-dependent, proteasome-mediated degradation of its substrates (demonstrated for EID1). This is the core biological process.
    action: ACCEPT
    reason: >-
      Core biological process. SCF complexes target substrates with poly-ubiquitin
      chains for proteasomal degradation (PMID:34445249), and FBXO21 was shown to
      drive proteasomal degradation of EID1 (PMID:26085330). Specific and
      well-supported.
    supported_by:
    - reference_id: PMID:34445249
      supporting_text: encompasses a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome TAS localization to cytosol assigned via a generic CRL1 (cullin-RING ligase) neddylation/cycle reaction. Correct compartment but generic and inherited from pathway context.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization is consistent with FBXO21 acting in cytoplasmic SCF complexes (and EID1 is degraded in cytoplasm and nucleus), but this annotation is a generic CRL-cycle pathway assignment, redundant across many reactions; non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome TAS localization to cytosol from a generic CRL1 neddylation/cycle reaction.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL-cycle localization; correct but redundant and non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome TAS localization to cytosol from a generic cytosolic CRL E3 ligase (CAND1-binding) reaction.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL-cycle localization; correct but redundant and non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome TAS localization to cytosol from a generic cytosolic CRL E3 ligase (COMMD/CAND1) reaction.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL-cycle localization; correct but redundant and non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome TAS localization to cytosol from the COP9-signalosome deneddylation reaction on cytosolic CRL complexes.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL-cycle localization; correct but redundant and non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome TAS localization to cytosol from a generic CRL1 (DCUN1D3-binding) reaction.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL-cycle localization; correct but redundant and non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome TAS localization to cytosol from a generic ubiquitin-transfer (E2-to-substrate) reaction in the antigen-processing/proteasome pathway.
    action: KEEP_AS_NON_CORE
    reason: Generic ubiquitination-cycle localization; correct but redundant and non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome TAS localization to cytosol from a generic reaction (release of E3 from polyubiquitinated substrate).
    action: KEEP_AS_NON_CORE
    reason: Generic ubiquitination-cycle localization; correct but redundant and non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome TAS localization to cytosol from a generic polyubiquitination-of-substrate reaction.
    action: KEEP_AS_NON_CORE
    reason: Generic ubiquitination-cycle localization; correct but redundant and non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome TAS localization to cytosol from a generic reaction (interaction of E3 with substrate and E2-Ub complex).
    action: KEEP_AS_NON_CORE
    reason: Generic ubiquitination-cycle localization; correct but redundant and non-core.
- term:
    id: GO:0000151
    label: ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:10531035
  qualifier: part_of
  review:
    summary: FBXO21 is a subunit of a ubiquitin ligase (SCF) complex, the general parent of the more specific SCF ubiquitin ligase complex annotation. Supported by the founding F-box protein family paper.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the more specific GO:0019005 (SCF ubiquitin ligase complex) better captures FBXO21's complex membership. F-box proteins are one of the four subunits of SCF ubiquitin ligases.
    supported_by:
    - reference_id: PMID:10531035
      supporting_text: F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs.
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: NAS
  original_reference_id: PMID:10531035
  qualifier: enables
  review:
    summary: NAS assignment of ubiquitin-protein transferase activity from the founding F-box family paper. However, within the SCF complex the catalytic ubiquitin-transfer activity resides in the RING subunit (RBX1); the F-box protein FBXO21 functions as the substrate-recruiting adaptor, not the catalytic transferase.
    action: MODIFY
    reason: >-
      F-box proteins do not themselves catalyse ubiquitin transfer; they are the
      substrate-recognition adaptors that recruit substrates to the SCF, whose
      catalytic activity is provided by the RING subunit RBX1 (with the E2). The
      NAS source (PMID:10531035) describes SCF complexes (not FBXO21 itself) as
      ubiquitin ligases. The more accurate molecular function for an F-box protein
      is ubiquitin-like ligase-substrate adaptor activity (GO:1990756).
    proposed_replacement_terms:
    - id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    supported_by:
    - reference_id: file:human/FBXO21/FBXO21-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: FBXO21, as an SCF substrate adaptor, mediates ubiquitin-dependent protein catabolism (directly demonstrated for EID1). General parent of the SCF-dependent catabolism term.
    action: KEEP_AS_NON_CORE
    reason: Correct and supported (FBXO21 drives ubiquitin-dependent proteasomal degradation of EID1), but the more specific GO:0031146 (SCF-dependent proteasomal ubiquitin-dependent protein catabolic process) better captures the role; retained as non-core to avoid redundancy.
    supported_by:
    - reference_id: PMID:26085330
      supporting_text: FBXO21 mediates the ubiquitylation and proteasomal degradation of EID1.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: PMID:10531035
  title: Identification of a family of human F-box proteins.
  findings:
  - statement: F-box proteins are one of the four subunits of SCF ubiquitin protein ligases (with SKP1, a cullin, and ROC1/RBX1); FBXO21 (FBX21) was identified among 26 human F-box proteins using SKP1 as bait.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Founding paper identifying the human F-box protein family including FBXO21/FBX21; establishes the SCF four-subunit
      architecture. Supports SCF complex membership but describes the SCF (not the F-box protein itself) as the ligase,
      so it does not establish intrinsic transferase activity for FBXO21.
- id: PMID:26085330
  title: FBXO21 mediates the ubiquitylation and proteasomal degradation of EID1.
  findings:
  - statement: FBXO21 is the substrate-recognition subunit of an SCF-type E3; its central/C-terminal region binds the C-terminal region of EID1, and SCF(FBXO21) directly ubiquitylates EID1 to drive its proteasomal degradation in cytoplasm and nucleus.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache (full_text_available:false) but the abstract directly and specifically establishes the
      EID1 substrate relationship and FBXO21's role as an SCF substrate adaptor via an in vitro ubiquitylation assay
      and CRISPR knockout. The key functional reference for this gene.
- id: PMID:27705803
  title: A High-Density Map for Navigating the Human Polycomb Complexome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput AP-MS Polycomb complexome map; source of a bare protein binding (GO:0005515) annotation, not informative about FBXO21's specific function.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex 3.0 proteome-scale AP-MS interactome; source of a bare protein binding (GO:0005515) annotation.
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings:
  - statement: The SCF complex is a family of ~69 E3 ubiquitin ligase complexes (SKP1-CUL1-F-box) that poly-ubiquitinate substrates for proteasomal degradation; variable F-box proteins determine substrate specificity.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Review establishing SCF complex architecture and function; supports the SCF complex-membership and SCF-dependent catabolism annotations for the F-box protein FBXO21.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput multimodal (AP-MS + immunofluorescence) cell map; source of a bare protein binding (GO:0005515) annotation.
- id: file:human/FBXO21/FBXO21-deep-research-falcon.md
  title: Falcon deep research report for human FBXO21
  findings:
  - statement: FBXO21 is an SCF (SKP1-CUL1-RBX1) substrate receptor with validated substrates EID1, ASK1, p85alpha/PIK3R1, and ABCB1/P-gp, operating in both proteolytic and non-proteolytic ubiquitination modes.
    supporting_text: >-
      The research target is **human FBXO21** (UniProt **O94952**; gene
      **FBXO21**, synonyms **FBX21**, **KIAA0875**), an **F-box only** protein
      that functions as a substrate-recognition subunit of an **SCF
      (SKP1–CUL1–RBX1) Cullin-RING E3 ubiquitin ligase** complex. This identity
      is consistent across primary literature describing **SCF^FBXO21** and its
      validated substrates (EID1, ASK1, p85α/PIK3R1, and ABCB1/P-gp).
  - statement: SCF(FBXO21) mediates non-proteolytic Lys29-linked ubiquitination of ASK1 (MAP3K5) that promotes ASK1 activation rather than degradation, driving antiviral innate signaling and type I interferon responses.
    supporting_text: >-
      SCF^FBXO21 mediates **Lys29-linked ubiquitination** of ASK1, demonstrated
      using ubiquitin mutants (K29-only ubiquitin), and this modification is
      **non-proteolytic** (ASK1 degradation not affected).
  - statement: FBXO21 deficiency impairs virus-induced ASK1-JNK/p38 and IRF3 signaling and reduces IL-6 and IFN-beta induction after viral or nucleic-acid challenge.
    supporting_text: >-
      FBXO21 deficiency impaired virus-induced signaling (reduced JNK/p38 and
      IRF3 activation; reduced nuclear c-Fos/IRF3) and reduced **IL-6 and IFNβ**
      induction after LPS, nucleic acid agonists, and VSV/HSV-1 infection,
      linking FBXO21→ASK1 ubiquitination to **ASK1–JNK/p38** antiviral signaling
      and type I interferon responses.
  - statement: In acute myeloid leukemia, FBXO21 ubiquitinates the PI3K regulatory subunit p85alpha (PIK3R1) for proteasomal degradation, shaping PI3K/AKT versus ERK signaling; silencing FBXO21 promotes differentiation and chemosensitization.
    supporting_text: >-
      Stabilization of p85α (via FBXO21 knockdown) is associated with reduced
      canonical PI3K signaling (decreased AKT activation) and increased ERK
      activation in the model, with p85α homodimerization proposed as a
      mechanistic intermediate; the paper’s model schematic is captured in
      retrieved figures.
  - statement: FBXO21 binds and ubiquitinates the multidrug-resistance transporter ABCB1/P-glycoprotein for proteasomal degradation, a turnover that Ser291-phosphorylated CD44 suppresses.
    supporting_text: >-
      CD44 physically associates with P-gp at the membrane, and a
      **Ser291-phosphorylated** form of CD44 inhibits FBXO21-directed
      degradation of P-gp (Ser291Ala loses protection).
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: >-
      Falcon (Edison Scientific) deep-research synthesis. Cross-checked against
      the UniProt FUNCTION block and the EID1 primary paper (PMID:26085330)
      already in this review; used as leads for substrates/mechanisms not yet in
      UniProt (ASK1 K29-linked antiviral ubiquitination per Yu 2016, p85alpha/AML
      per Dobish 2023 Leukemia, ABCB1/P-gp per Ravindranath 2015). Cites
      author-year/DOIs rather than PMIDs, so individual primary claims remain
      UNVERIFIED here.
- 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 (F-box adaptor) of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex that binds SKP1/CUL1 via its F-box domain and recruits the substrate EID1, directing SCF(FBXO21)-mediated ubiquitylation and proteasomal degradation of EID1.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  supported_by:
  - reference_id: PMID:26085330
    supporting_text: An in vitro ubiquitylation assay showed that EID1 is a direct substrate of SCF(FBXO)(21).
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  in_complex:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
- description: As an SCF(FBXO21) substrate receptor, catalyzes non-proteolytic Lys29-linked ubiquitination of the kinase ASK1 (MAP3K5) that promotes ASK1 activation, driving ASK1-JNK/p38 and IRF3-dependent antiviral innate immune signaling and type I interferon induction; this signaling-activating ubiquitination is distinct from the canonical degradative SCF role.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  supported_by:
  - reference_id: file:human/FBXO21/FBXO21-deep-research-falcon.md
    supporting_text: >-
      SCF^FBXO21 mediates **Lys29-linked ubiquitination** of ASK1, demonstrated
      using ubiquitin mutants (K29-only ubiquitin), and this modification is
      **non-proteolytic** (ASK1 degradation not affected).
  directly_involved_in:
  - id: GO:0045087
    label: innate immune response
  in_complex:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
- description: As an SCF(FBXO21) substrate receptor, targets the PI3K regulatory subunit p85alpha (PIK3R1) for ubiquitin-dependent proteasomal degradation, thereby tuning PI3K/AKT versus ERK signaling; in acute myeloid leukemia this activity supports cell survival and blocks differentiation.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  supported_by:
  - reference_id: file:human/FBXO21/FBXO21-deep-research-falcon.md
    supporting_text: >-
      Dobish et al. used proteomics (TMT MS; K-ε-GG ubiquitin-remnant IP/MS) to
      identify candidate FBXO21-dependent substrates and nominated **p85α** as a
      ubiquitination target. They then provided biochemical evidence of p85α
      ubiquitination dependent on FBXO21 and its F-box domain (ΔF-box mutant
      inactive), including **in vitro ubiquitination** with immunopurified
      FBXO21.
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  in_complex:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
proposed_new_terms: []
suggested_questions:
- question: Beyond EID1, what is the full substrate repertoire of SCF(FBXO21), and which substrate-recognition surface (central vs C-terminal region) engages each substrate?
- question: Is the reported antiviral/innate-immune signalling role of FBXO21 dependent on its SCF ligase activity and substrate ubiquitylation, or does it act through a ligase-independent mechanism?
- question: What governs the subcellular partitioning of SCF(FBXO21) activity between cytoplasm and nucleus, given that EID1 accumulates in both compartments upon FBXO21 loss?
suggested_experiments:
- description: Perform DiPIUS or quantitative ubiquitinome/proteome profiling in FBXO21-knockout versus wild-type cells (with and without proteasome inhibition) to define the endogenous SCF(FBXO21) substrate repertoire.
- description: Reconstitute SCF(FBXO21)-mediated ubiquitylation of EID1 in vitro with purified SKP1, CUL1, RBX1, an E2, and an F-box-domain mutant of FBXO21 to confirm that adaptor (SKP1-binding) function is required and to map EID1 ubiquitylation sites and chain linkage.
- description: Test whether FBXO21's reported antiviral signalling function requires SCF assembly by comparing wild-type FBXO21 with an F-box-deletion (SKP1-binding-defective) mutant in interferon-pathway reporter and viral-challenge assays.