id: Q8NEA4 gene_symbol: FBXO36 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXO36 (F-box only protein 36) is a small (188 aa) F-box protein that serves as a substrate-recognition component of an SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex (a Cullin-RING ligase 1, CRL1). It contains a single F-box domain (residues 91-137) through which it docks onto the adaptor SKP1, which in turn bridges to the scaffold CUL1; the catalytic RING subunit RBX1 recruits the ubiquitin-charged E2 enzyme. Within such complexes, the F-box protein contributes substrate selectivity rather than catalytic activity, directing assembly of polyubiquitin chains on bound substrates to target them for proteasomal degradation. FBXO36 belongs to the "FBXO" (F-box only, lacking recognizable C-terminal substrate-binding domains such as WD40 or LRR) class and remains very poorly characterized: no endogenous substrate, catalytic context, or subcellular localization has been experimentally validated. The strongest direct functional data come from a high-content siRNA screen of ubiquitin-pathway regulators of TNF signaling, in which FBXO36 depletion increased TNF-induced nuclear NF-kappa-B accumulation, prolonged late-stage I-kappa-B and JNK phosphorylation, sensitized cells to TNF+cycloheximide apoptosis, and raised steady-state beta-catenin levels; these phenotypes were interpreted as FBXO36 being a candidate modifier of SCF-dependent (e.g. SCF-betaTrCP) ubiquitin signaling, although no direct FBXO36 substrate was established. FBXO36 has also been noted among F-box genes with testis-enriched expression and appears in lower-confidence human genetic associations (a rare-variant lipoprotein-trait signal, lung-adenocarcinoma prognosis) that require replication. It is broadly but lowly expressed and has two annotated splice isoforms. alternative_products: - name: '1' id: Q8NEA4-1 - name: '2' id: Q8NEA4-3 sequence_note: VSP_054336 existing_annotations: - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:34445249 qualifier: part_of review: summary: FBXO36 is the variable F-box (substrate-recognition) subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, docking onto SKP1/CUL1 via its F-box domain. This is the core localization/complex membership for an F-box protein. action: ACCEPT reason: Directly supported by the UniProt FUNCTION/SUBUNIT records (substrate-recognition component of SCF; interacts with SKP1 and CUL1) and by a dedicated SCF complex entry in ComplexPortal (CPX-7976, SCF E3 ubiquitin ligase complex, FBXO36 variant). Correct core complex membership. supported_by: - reference_id: file:human/FBXO36/FBXO36-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - reference_id: file:human/FBXO36/FBXO36-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 E3 ligase, FBXO36 contributes to SCF-dependent ubiquitination of substrates that targets them for proteasomal degradation. This is the core biological process for an SCF F-box protein. action: ACCEPT reason: Consistent with the canonical role of SCF complexes (poly-ubiquitination of substrates for proteasomal degradation, with the F-box protein determining substrate specificity) as described in the cited review and the UniProt annotation, and with the functional placement of FBXO36 as an F-box/SCF (CRL1) substrate-recognition receptor. The specific endogenous substrate(s) of FBXO36 are not yet established (Falcon-sourced literature confirms no validated substrate, though FBXO36 perturbation alters SCF-dependent TNF/NF-kappa-B signaling outputs), but membership in an SCF ligase directly entails this process. supported_by: - reference_id: file:human/FBXO36/FBXO36-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - reference_id: PMID:34445249 supporting_text: primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation. These SCF complexes are distinguishable by variable F-box proteins, which determine substrate specificity. - reference_id: file:human/FBXO36/FBXO36-deep-research-falcon.md supporting_text: although **no endogenous FBXO36 substrate has been directly validated** in the retrieved literature references: - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: - statement: SCF complexes modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation; the variable F-box protein determines substrate specificity, but the function of most individual SCF complexes (including F-box-only proteins like FBXO36) remains largely unknown. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- PubMed-verified (Int J Mol Sci 2021;22(16):8544, PMC8395177). This is a general review of SCF complex biology, not an FBXO36-specific study, and is abstract-only in the cache (full_text_available: false). It is the NAS reference attached by ComplexPortal to the two FBXO36 annotations and supports the generic F-box/SCF framing (substrate specificity, proteasomal degradation). It does not establish a specific FBXO36 substrate or biological role; FBXO36 remains poorly characterized. - id: file:human/FBXO36/FBXO36-uniprot.txt title: UniProtKB entry Q8NEA4 (FBX36_HUMAN), F-box only protein 36 findings: - statement: FBXO36 is the substrate-recognition component of an SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex and directly interacts with SKP1 and CUL1; it carries a single F-box domain (residues 91-137). reference_section_type: OTHER reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Primary record for the gene. FUNCTION and SUBUNIT lines are by similarity (ECO:0000250) but reflect the conserved, well-established F-box/SCF architecture. ComplexPortal CPX-7976 documents the FBXO36-variant SCF complex. - id: file:human/FBXO36/FBXO36-deep-research-falcon.md title: Falcon deep research report for human FBXO36 findings: - statement: FBXO36 is inferred to be an F-box substrate-recognition adaptor of an SCF/CRL1 complex, but no endogenous FBXO36 substrate has been directly validated in the literature. supporting_text: although **no endogenous FBXO36 substrate has been directly validated** in the retrieved literature - statement: The strongest direct functional evidence is from a TNF/NF-kappa-B RNAi screen in which FBXO36 depletion increased TNF-induced nuclear NF-kappa-B accumulation and altered I-kappa-B/JNK phosphorylation, consistent with FBXO36 modulating SCF-dependent ubiquitin signaling. supporting_text: '**FBXO36 is likely an F-box adaptor protein that can modulate SCF-dependent ubiquitin signaling, with experimental evidence that FBXO36 depletion alters TNF pathway signaling outputs (NF-κB nuclear accumulation kinetics, I-κB and JNK phosphorylation dynamics, and TNF+CHX apoptosis sensitivity) in human cell lines.**' - statement: FBXO36 depletion increased steady-state beta-catenin, interpreted as a possible modifier of the SCF-betaTrCP axis, but this does not establish beta-catenin as a direct FBXO36 substrate. supporting_text: depletion of FBXO36 increased steady-state **β-catenin** levels. They interpreted this as supportive of a possible role as a modifier of the **SCF–βTrCP** axis reference_review: relevance: MEDIUM correctness: UNVERIFIED review_notes: >- Falcon synthesis anchored on Fraser et al. 2014 (Front Immunol, doi:10.3389/fimmu.2014.00322; TNF/NF-kappaB RNAi screen — the only direct functional dataset), Riveros-McKay et al. 2020 (PLoS Genet, doi:10.1371/journal.pgen.1008605; rare-variant lipid association), Fu et al. 2021 (Transl Cancer Res; LUAD prognosis), and Xuan et al. 2024 (Cell Regen, doi:10.1186/s13619-024-00196-9; testis expression). The functional evidence is perturbation-level and indirect; no validated substrate or localization exists. Falcon cites author-year/DOIs not PMIDs and the papers are not in the local cache, so these are treated as leads (UNVERIFIED) and not promoted to new GO terms. core_functions: - description: Substrate-recognition (F-box) subunit of an SCF/CRL1 (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex; FBXO36 binds SKP1/CUL1 through its F-box domain and contributes substrate selectivity, directing SCF-dependent ubiquitination of substrates for proteasomal degradation. Specific endogenous substrates are not yet defined. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/FBXO36/FBXO36-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - reference_id: file:human/FBXO36/FBXO36-uniprot.txt supporting_text: 'Directly interacts with SKP1 and CUL1.' proposed_new_terms: [] suggested_questions: - question: What are the physiological substrate(s) of the FBXO36-containing SCF complex, and in which tissues or cellular contexts does FBXO36 act as the substrate receptor? Is the TNF/NF-kappa-B and beta-catenin phenotype of FBXO36 depletion due to a direct SCF(FBXO36) substrate or an indirect effect on the SCF-betaTrCP axis? - question: Does FBXO36 substrate recognition depend on a post-translational degron (e.g. phosphodegron) on its targets, as is typical for F-box proteins, and what determines its specificity given it lacks a recognizable C-terminal substrate-binding domain? - question: Where does FBXO36 localize, and does its testis-enriched expression reflect a specific role in spermatogenesis? suggested_experiments: - description: Affinity-purify epitope-tagged FBXO36 (and an F-box-deletion mutant that cannot assemble into SCF) followed by quantitative mass spectrometry, optionally combined with proteasome/neddylation inhibition, to identify candidate substrates that accumulate specifically with the assembly-competent receptor. - description: Reconstitute the FBXO36 SCF complex in vitro (SKP1-CUL1-RBX1-FBXO36 with an E1, E2, ubiquitin and ATP) and perform ubiquitination assays on candidate substrates to confirm that FBXO36 confers substrate-dependent ubiquitin-chain assembly. - description: Test in TNF-responsive cells whether the NF-kappa-B/JNK/beta-catenin phenotypes of FBXO36 depletion reflect a direct SCF(FBXO36) substrate (via ubiquitin-proteomics after FBXO36 perturbation) versus an indirect effect on SCF-betaTrCP-dependent I-kappa-B/beta-catenin turnover.