id: Q8IX29 gene_symbol: FBXO16 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXO16 (F-box only protein 16) is an F-box "other" (FBXO) family protein that serves as the substrate-recognition component of an SCF (SKP1-CUL1-F-box protein) / CRL1 Cullin-RING E3 ubiquitin-protein ligase complex. Through its F-box domain (residues 86-132) it docks onto SKP1 within the SCF scaffold, while its C-terminal region recruits specific substrate proteins for ubiquitination and subsequent proteasomal degradation; the catalytic transfer of ubiquitin is performed by the RING subunit RBX1 and an E2 enzyme, not by FBXO16 itself; consistently, its F-box domain is required for assembling a functional ligase complex while its C-terminal region mediates substrate recognition (e.g. binding the RRM3 domain of hnRNPL and the C-terminus being essential for beta-catenin binding). FBXO16 acts predominantly in the nucleus and drives K48-linked polyubiquitination of its targets. Reported substrates include the nuclear pool of beta-catenin/CTNNB1 (suppressing Wnt/TCF output such as c-Myc and Cyclin D1), the RNA-binding protein hnRNPL (whose degradation restrains MAPK/RAS/Wnt outputs), the autophagy-initiating kinase ULK1 (K48-linked polyubiquitination, suppressing autophagy), and the NF-kappa-B subunit RELA/p65 (as the substrate-recognition component of a PDLIM2-containing CRL1 complex that degrades nuclear p65). Through these targets FBXO16 has been implicated as a putative tumor suppressor (attenuating beta-catenin-driven epithelial-to-mesenchymal transition and ovarian/glioblastoma progression; in ovarian cancer it is down-regulated by MIR937 amplification, stabilizing ULK1) and as a negative regulator of NF-kappa-B inflammatory signaling. The protein is expressed in several tissues (heart, spleen, colon; tissue-enhanced in epididymis and pituitary) and exists as two alternatively spliced isoforms. alternative_products: - name: '1' id: Q8IX29-1 - name: '2' id: Q8IX29-2 sequence_note: VSP_045600 existing_annotations: - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: >- Binary interactome (Y2H) interactions of FBXO16 captured by IntAct, including LMO1, MORF4L1/MORF4L2, NXT1 and TRIM54. These are real interactions but the bare protein binding term is uninformative about molecular function. action: KEEP_AS_NON_CORE reason: >- Documents genuine physical interactions recorded by IntAct, but per curation guidelines bare protein binding is uninformative and not a core molecular function. The functionally meaningful substrate interactions (CTNNB1, HNRNPL, RELA, ULK1) come from dedicated studies, not this high-throughput screen. supported_by: - reference_id: file:human/FBXO16/FBXO16-uniprot.txt supporting_text: 'Q8IX29; P25800: LMO1; NbExp=3; IntAct=EBI-12063229, EBI-8639312;' - reference_id: file:human/FBXO16/FBXO16-uniprot.txt supporting_text: 'Q8IX29; Q9UKK6: NXT1; NbExp=5; IntAct=EBI-12063229, EBI-301889;' - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:34445249 qualifier: part_of review: summary: >- FBXO16 is the substrate-recognition (F-box) subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, as recorded by ComplexPortal (CPX-7926, "SCF E3 ubiquitin ligase complex, FBXO16 variant"). This is the core localization/complex membership of the protein. action: ACCEPT reason: >- Core complex membership. FBXO16 contains a bona fide F-box domain (residues 86-132) and is annotated by ComplexPortal as the variable F-box subunit of an SCF complex; UniProt explicitly states it is part of an SCF ligase complex. supported_by: - reference_id: file:human/FBXO16/FBXO16-uniprot.txt supporting_text: >- Substrate recognition component of an SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins. - reference_id: file:human/FBXO16/FBXO16-uniprot.txt supporting_text: 'Part of a SCF (SKP1-cullin-F-box) protein ligase complex.' - 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 receptor of an SCF complex, FBXO16 directs target proteins (e.g. nuclear beta-catenin, hnRNPL, RELA, ULK1) into SCF-dependent proteasomal degradation. This captures the core biological process FBXO16 participates in. action: ACCEPT reason: >- Core biological process. UniProt FUNCTION documents that FBXO16 mediates ubiquitination and subsequent proteasomal degradation of multiple substrates as the substrate-recognition component of an SCF complex, consistent with this SCF-dependent catabolic process term. Falcon-sourced primary literature grounds this with multiple validated K48-linked substrates (nuclear beta-catenin, hnRNPL, ULK1, nuclear p65/RELA), matching the functional placement of FBXO16 as an F-box/SCF (CRL1) substrate-recognition receptor. supported_by: - reference_id: file:human/FBXO16/FBXO16-uniprot.txt supporting_text: >- Substrate recognition component of an SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins. - reference_id: file:human/FBXO16/FBXO16-deep-research-falcon.md supporting_text: FBXO16 physically interacts with β-catenin and promotes **K48-linked polyubiquitination** and **proteasome-mediated degradation** of the **nuclear pool** of β-catenin, suppressing Wnt/TCF transcriptional output. core_functions: - description: >- Substrate-recognition (F-box) component of an SCF/CRL1 E3 ubiquitin ligase complex that binds specific substrate proteins (e.g. nuclear beta-catenin/CTNNB1, hnRNPL, RELA/p65, ULK1) and presents them, via SKP1 and the CUL1-RBX1 catalytic core, for polyubiquitination and proteasomal degradation. Acts as a ubiquitin-ligase substrate adaptor rather than the catalytic ligase. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity in_complex: id: GO:0019005 label: SCF ubiquitin ligase complex supported_by: - reference_id: file:human/FBXO16/FBXO16-uniprot.txt supporting_text: >- Substrate recognition component of an SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins. - reference_id: file:human/FBXO16/FBXO16-uniprot.txt supporting_text: 'Part of a SCF (SKP1-cullin-F-box) protein ligase complex.' directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process proposed_new_terms: [] suggested_questions: - question: >- Which E2 conjugating enzyme and ubiquitin-chain topology does the FBXO16-containing SCF complex use across its different substrates, and is the K48-linked chain reported for ULK1 a general feature of FBXO16-mediated degradation? - question: >- How is FBXO16 substrate selection regulated (e.g. by substrate phosphodegron, FBXO16 expression/MIR937 amplification, accessory partners such as PDLIM2, or subcellular localization such as the nuclear beta-catenin/p65 pools), and which substrate relationship is physiologically dominant in a given tissue? - question: >- Is FBXO16 a predominantly nuclear CRL1 substrate receptor as the functional studies suggest, and does its nuclear localization explain its preference for nuclear substrate pools (nuclear beta-catenin, hnRNPL, nuclear p65)? suggested_experiments: - description: >- Reconstitute the FBXO16-SKP1-CUL1-RBX1 SCF complex in vitro with a defined E2 panel and a candidate substrate (e.g. recombinant ULK1, CTNNB1, or hnRNPL) to confirm that FBXO16 functions as a substrate adaptor, map the C-terminal substrate-binding region, and determine the ubiquitin-chain linkage produced on each substrate. - description: >- Perform quantitative ubiquitinome/proteome profiling in FBXO16-knockout versus wild-type cells (and with F-box-domain deletion mutants that cannot bind SKP1) to define the endogenous substrate repertoire and confirm that substrate stabilization requires intact SCF assembly. - description: >- Determine FBXO16 subcellular localization (fractionation, immunofluorescence, tagged endogenous knock-in) and test whether nuclear targeting is required for degradation of nuclear substrates such as beta-catenin and p65, including the contribution of the PDLIM2-containing CRL1 complex. references: - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: - statement: >- High-throughput yeast two-hybrid binary interactome map that records FBXO16 interactions (e.g. LMO1, MORF4L1, MORF4L2, NXT1, TRIM54) deposited in IntAct. reference_section_type: ABSTRACT reference_review: relevance: LOW correctness: VERIFIED review_notes: >- Full text available. Source of the GO:0005515 bare protein binding annotations; high-throughput binary interactome, not FBXO16-specific functional characterization. - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: - statement: >- Review of SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complexes and their role in genome/chromosome stability; cited by ComplexPortal as supporting reference for SCF complex membership and SCF-dependent proteasomal degradation. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Abstract-only (full_text_available: false). General SCF review used by ComplexPortal as the NAS reference for FBXO16's SCF complex membership and SCF-dependent catabolic process annotations; supports the family-level mechanism rather than FBXO16-specific substrate claims. - id: file:human/FBXO16/FBXO16-deep-research-falcon.md title: Falcon deep research report for human FBXO16 findings: - statement: FBXO16 is a CRL1/SCF substrate-recognition protein that drives K48-linked polyubiquitination and proteasomal degradation of select substrates, with prominent nuclear activity. supporting_text: '**FBXO16 is a CRL1/SCF substrate-recognition protein that drives K48-linked polyubiquitination and proteasomal degradation of select substrates, with prominent nuclear activity.**' - statement: The FBXO16 F-box domain is required for ligase complex formation while its C-terminal region mediates substrate recognition (e.g. binding the hnRNPL RRM3 domain; C-terminus essential for beta-catenin binding). supporting_text: The **F-box domain** is required for **complex formation and ubiquitination function** (e.g., ΔF-box mutants fail to promote ubiquitination of targets or to form productive complexes). - statement: FBXO16 targets the nuclear pool of beta-catenin for K48-linked polyubiquitination, suppressing Wnt/TCF transcriptional output. supporting_text: FBXO16 physically interacts with β-catenin and promotes **K48-linked polyubiquitination** and **proteasome-mediated degradation** of the **nuclear pool** of β-catenin, suppressing Wnt/TCF transcriptional output. - statement: FBXO16 acts as the substrate-recognition component of a PDLIM2-containing CRL1 complex that promotes nuclear p65/RELA polyubiquitination and degradation, limiting NF-kappa-B activation. supporting_text: Fbxo16 was identified as a substrate-recognition component in a **PDLIM2-containing CRL1 complex** that promotes p65 polyubiquitination and degradation in nuclear compartments, suppressing NF-κB activation. reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: >- Falcon synthesis anchored on real primary studies: Khan et al. 2019 (beta-catenin/glioblastoma), Ji et al. 2021 (hnRNPL/ovarian cancer), Zhang et al. 2024 (MIR937/ULK1/autophagy, Cell Death Dis), and Sugimoto-Ishige et al. 2025 (p65/PDLIM2-CRL1). These corroborate and extend the substrate set already in this review and add a nuclear-localization theme and C-terminal substrate-binding domain logic. Falcon cites author-year/DOIs not PMIDs and the papers are not in the local cache, so substrate and localization claims are treated as strong leads (UNVERIFIED) pending curator confirmation; no substrate-specific or nuclear-location GO terms are added on this basis alone.