id: Q8NEZ5 gene_symbol: FBXO22 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXO22 (F-box only protein 22, FBX22p44) is a 403-residue F-box protein that serves as the substrate-recognition receptor of a SCF (SKP1-CUL1-F-box)-type CUL1-RING E3 ubiquitin ligase complex. It binds the SCF core through an N-terminal F-box motif (residues ~21-67) that docks onto SKP1, while a C-terminal FIST-C/substrate-binding region engages target proteins; in the assembled SCF, the catalytic RING subunit RBX1 recruits the ubiquitin-charged E2, so FBXO22 itself contributes substrate selection rather than catalysis. Through this adaptor role FBXO22 directs polyubiquitination and proteasomal degradation of a defined set of substrates and thereby influences chromatin/transcriptional regulation, the DNA-damage and senescence response, oxidative-stress signaling, nutrient sensing, immune-checkpoint control, and antiviral defense. Documented substrates include the histone demethylases KDM4A/JMJD2A (controlling H3K9 and H3K36 methylation) and KDM4B (when KDM4B is complexed with tamoxifen-bound estrogen receptor, governing selective-estrogen-receptor- modulator pharmacology in breast cancer), methylated TP53 (in complex with KDM4A, at late senescence), the transcription factor BACH1 (upon oxidative-stress-induced exposure of its degron), nuclear (but not cytoplasmic) PTEN (ubiquitinated at Lys221), the immune-checkpoint ligand PD-L1 (CD274; degradation sensitizes cells to DNA-damaging therapy), the co-chaperone BAG3 (via an ERK-dependent phosphodegron, S377), the kinase MTOR (both K27-linked ubiquitination at Lys2066 upon amino-acid depletion to inhibit mTORC1, and degradation of the Ser2448-phosphorylated form), the transcription factor KLF4, and sarcomeric proteins; it also degrades the SARS-CoV-2 3C-like proteinase NSP5 via K48-linked chains to restrict viral replication. Many of these recognition events are post-translational-mark dependent (methylation marks, or phosphodegrons such as ERK-phosphorylated S377 of BAG3), consistent with a C-terminal substrate-binding region that reads modified degrons. A surface cysteine (Cys326) in the C-terminal domain can be covalently engaged by small molecules, making FBXO22 a recruitable E3 for targeted protein degradation. FBXO22 is broadly expressed with enrichment in liver and cardiac muscle and localizes to both the cytoplasm and nucleus, with its subcellular distribution modulated by EIF2AK4/GCN2-dependent phosphorylation at Thr-127. Biallelic loss-of-function causes Tayoun-Maawali syndrome (TYMAS), an autosomal-recessive multisystem developmental disorder. existing_annotations: - term: id: GO:0000209 label: protein polyubiquitination evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic assignment of involvement in protein polyubiquitination, consistent with FBXO22's role as the substrate-recognition subunit of an SCF E3 ligase that directs polyubiquitination of substrates. action: ACCEPT reason: Core biological role; FBXO22 mediates polyubiquitination of substrates such as KDM4A, KDM4B, methylated TP53, BACH1, nuclear PTEN, PD-L1, BAG3, MTOR and NSP5 through the SCF complex. supported_by: - reference_id: file:human/FBXO22/FBXO22-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - reference_id: file:human/FBXO22/FBXO22-deep-research-falcon.md supporting_text: FBXO22 contains an N-terminal **F-box domain** mediating SCF assembly via SKP1, and a C-terminal **FIST/FIST-C** substrate-binding region (e.g., KDM4A binding mapped to the FBXO22 FIST-C domain). - term: id: GO:0032436 label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic assignment of a positive regulatory role in proteasomal ubiquitin-dependent catabolism, consistent with FBXO22 promoting proteasomal degradation of its substrates. action: ACCEPT reason: Supported by multiple experimental studies in which FBXO22 promotes proteasome-dependent degradation of substrates (e.g. KDM4A, NSP5). supported_by: - reference_id: file:human/FBXO22/FBXO22-uniprot.txt supporting_text: Promotes the proteasome-dependent degradation of key sarcomeric proteins - term: id: GO:0048742 label: regulation of skeletal muscle fiber development evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic assignment of a role in skeletal muscle fiber development. FBXO22 is enriched in cardiac muscle and is reported to regulate sarcomeric protein turnover, but a specific role in skeletal muscle fiber development is thinly supported and likely propagated from family/ortholog context. action: MARK_AS_OVER_ANNOTATED reason: FBXO22's documented muscle link is regulation of sarcomeric protein turnover (cardiac-enriched); a specific "skeletal muscle fiber development" process is not directly demonstrated for FBXO22 and appears to be an over-propagated IBA inference. Not a core function. - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Electronic (ortholog-based) assignment of nuclear localization. Concordant with the experimentally supported nuclear localization of FBXO22, where it acts on nuclear substrates such as KDM4A, methylated TP53 and BACH1. action: ACCEPT reason: Correct compartment; redundant with the EXP nucleus annotations. FBXO22 acts on chromatin-associated/nuclear substrates. supported_by: - reference_id: file:human/FBXO22/FBXO22-uniprot.txt supporting_text: 'Nucleus {ECO:0000269|PubMed:37979583, ECO:0000269|PubMed:39223933}' - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Electronic (ortholog-based) assignment of cytoplasmic localization, concordant with the experimentally supported cytoplasmic pool of FBXO22. action: ACCEPT reason: Correct compartment; redundant with the EXP cytoplasm annotations. FBXO22 accumulates in the cytoplasm upon amino-acid depletion to ubiquitinate MTOR. supported_by: - reference_id: file:human/FBXO22/FBXO22-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:37979583, ECO:0000269|PubMed:39223933}' - term: id: GO:0030018 label: Z disc evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic localization (UniProt subcellular-location mapping) to the Z disc/sarcomere, derived from a by-similarity (ECO:0000250) sarcomere annotation. This is an inferred, non-core localization tied to the proposed sarcomeric-protein-turnover role. action: KEEP_AS_NON_CORE reason: The sarcomere/Z-line localization in UniProt is by-similarity (ECO:0000250), not experimentally demonstrated for human FBXO22; it reflects a peripheral, tissue-specific role rather than the core nuclear/cytoplasmic SCF function. supported_by: - reference_id: file:human/FBXO22/FBXO22-uniprot.txt supporting_text: Cytoplasm, myofibril, sarcomere, Z line - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21145461 qualifier: enables review: summary: High-throughput quantitative proteomics of the cullin-RING ligase network; the recorded partner is CUL1 (Q13616), the SCF scaffold FBXO22 assembles with. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real and expected SCF-scaffold interaction (CUL1), but bare protein binding is uninformative per curation guidelines; the SCF-complex membership is captured by GO:0019005. supported_by: - reference_id: file:human/FBXO22/FBXO22-uniprot.txt supporting_text: Directly interacts with SKP1 and CUL1 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26496610 qualifier: enables review: summary: High-throughput quantitative interactome (stoichiometries and abundances); the recorded partner is SKP1 (P63208), the F-box-binding SCF adaptor. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the expected F-box-SKP1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27705803 qualifier: enables review: summary: High-throughput affinity-purification map of the human Polycomb complexome; the recorded partner is SKP1 (P63208). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interaction (SKP1); bare protein binding is uninformative and not a core function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Binary protein interactome reference map; the recorded partner is SKP1 (P63208). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput binary interactome (SKP1); bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Proteome-scale BioPlex interactome; the recorded partner is SKP1 (P63208). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome (SKP1); bare protein binding is uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Multimodal cell-map interactome study; the recorded partner is SKP1 (P63208). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome (SKP1); bare protein binding is uninformative. - term: id: GO:0005634 label: nucleus evidence_type: EXP original_reference_id: PMID:37979583 qualifier: located_in review: summary: Experimental evidence for nuclear localization of FBXO22, consistent with its action on nuclear substrates and its regulated nuclear/cytoplasmic partitioning. action: ACCEPT reason: Experimentally supported localization; FBXO22 partitions between nucleus and cytoplasm, with cytoplasmic accumulation triggered by amino-acid depletion. supported_by: - reference_id: file:human/FBXO22/FBXO22-uniprot.txt supporting_text: 'Nucleus {ECO:0000269|PubMed:37979583, ECO:0000269|PubMed:39223933}' - term: id: GO:0005634 label: nucleus evidence_type: EXP original_reference_id: PMID:39223933 qualifier: located_in review: summary: Experimental evidence for nuclear localization of FBXO22 from the NSP5-degradation study. action: ACCEPT reason: Experimentally supported localization corroborating the nucleus annotation. supported_by: - reference_id: file:human/FBXO22/FBXO22-uniprot.txt supporting_text: 'Nucleus {ECO:0000269|PubMed:37979583, ECO:0000269|PubMed:39223933}' - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:37979583 qualifier: located_in review: summary: Experimental evidence for cytoplasmic localization; FBXO22 accumulates in the cytoplasm upon amino-acid depletion (GCN2/EIF2AK4-dependent Thr-127 phosphorylation) to ubiquitinate MTOR. action: ACCEPT reason: Experimentally supported localization directly tied to the mTORC1-regulatory function. supported_by: - reference_id: file:human/FBXO22/FBXO22-uniprot.txt supporting_text: Amino acid depletion lead to a time-dependent increase of FBXO22 in the cytoplasm - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:39223933 qualifier: located_in review: summary: Experimental evidence for cytoplasmic localization from the NSP5-degradation study. action: ACCEPT reason: Experimentally supported localization corroborating the cytoplasm annotation. supported_by: - reference_id: file:human/FBXO22/FBXO22-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:37979583, ECO:0000269|PubMed:39223933}' - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:34445249 qualifier: part_of review: summary: Membership in the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, the defining macromolecular assembly for FBXO22 as an F-box substrate receptor. ComplexPortal records an SCF FBXO22 variant complex. action: ACCEPT reason: Core component; FBXO22 is the F-box substrate receptor of an SCF complex, directly interacting with SKP1 and CUL1. supported_by: - reference_id: file:human/FBXO22/FBXO22-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: Involvement in SCF-dependent proteasomal degradation, the core biological process executed by FBXO22 as an SCF substrate receptor. action: ACCEPT reason: Core biological process; FBXO22-containing SCF targets substrates (e.g. KDM4A, methylated TP53, BACH1) for proteasomal degradation. supported_by: - reference_id: file:human/FBXO22/FBXO22-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-8952618 qualifier: located_in review: summary: Reactome pathway-level cytosol localization within a generic CRL1 neddylation reaction (AcM-UBE2M transfers NEDD8 to CRL1). Generic compartment annotation propagated to all CRL1 members. action: KEEP_AS_NON_CORE reason: Cytosol is consistent with the cytoplasmic pool of FBXO22, but this is a generic CRL-machinery Reactome annotation; the more informative compartment annotations are the EXP nucleus/cytoplasm terms. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome cytosol localization within a generic CRL1 neddylation reaction (NEDD8:AcM-UBE2M binds CRL1). Generic compartment annotation. action: KEEP_AS_NON_CORE reason: Generic CRL-machinery Reactome localization; redundant with and less informative than the EXP compartment annotations. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome cytosol localization within a generic CRL reaction (CAND1 binds cytosolic CRL E3 ligases). Generic compartment annotation. action: KEEP_AS_NON_CORE reason: Generic CRL-machinery Reactome localization; not a core, FBXO22-specific compartment annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome cytosol localization within a generic CRL reaction (COMMDs displace CAND1 from cytosolic CRL complexes). Generic compartment annotation. action: KEEP_AS_NON_CORE reason: Generic CRL-machinery Reactome localization; not a core, FBXO22-specific compartment annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome cytosol localization within a generic CRL reaction (COP9 signalosome deneddylates cytosolic CRL complexes). Generic compartment annotation. action: KEEP_AS_NON_CORE reason: Generic CRL-machinery Reactome localization; not a core, FBXO22-specific compartment annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome cytosol localization within a generic CRL1 reaction (MyrG-DCUN1D3 binds CRL1). Generic compartment annotation. action: KEEP_AS_NON_CORE reason: Generic CRL-machinery Reactome localization; not a core, FBXO22-specific compartment annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome cytosol localization within a generic ubiquitination reaction (transfer of Ub from E2 to substrate). Generic compartment annotation. action: KEEP_AS_NON_CORE reason: Generic ubiquitination-machinery Reactome localization; not a core, FBXO22-specific compartment annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome cytosol localization within a generic ubiquitination reaction (release of E3 from polyubiquitinated substrate). Generic compartment annotation. action: KEEP_AS_NON_CORE reason: Generic ubiquitination-machinery Reactome localization; not a core, FBXO22-specific compartment annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome cytosol localization within a generic ubiquitination reaction (polyubiquitination of substrate). Generic compartment annotation. action: KEEP_AS_NON_CORE reason: Generic ubiquitination-machinery Reactome localization; not a core, FBXO22-specific compartment annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome cytosol localization within a generic ubiquitination reaction (interaction of E3 with substrate and E2-Ub complex). Generic compartment annotation. action: KEEP_AS_NON_CORE reason: Generic ubiquitination-machinery Reactome localization; not a core, FBXO22-specific compartment annotation. - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: TAS original_reference_id: PMID:10531037 qualifier: enables review: summary: Legacy F-box-family TAS annotation of ubiquitin-protein transferase activity. As an F-box substrate receptor, FBXO22 is the substrate-specific adaptor of the SCF; the catalytic transferase activity resides in the RBX1-RING/E2 module, not in the F-box protein itself. action: MODIFY reason: FBXO22 is the substrate-recognition subunit of the SCF, not the catalytic transferase. The essence (participation in ubiquitin transfer) is sound, but the more accurate molecular function is the ubiquitin-like ligase-substrate adaptor activity; replace the catalytic transferase term with GO:1990756. proposed_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXO22/FBXO22-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: TAS original_reference_id: PMID:10531035 qualifier: involved_in review: summary: Legacy TAS annotation (F-box family identification paper) of involvement in ubiquitin-dependent protein catabolism. Correct but generic relative to the SCF-dependent catabolism term. action: KEEP_AS_NON_CORE reason: Correct but a generic parent of GO:0031146 (SCF-dependent proteasomal catabolism), which more specifically captures FBXO22's role. 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:0036211 label: protein modification process evidence_type: TAS original_reference_id: PMID:10531035 qualifier: involved_in review: summary: Legacy TAS annotation of involvement in protein modification, a very high-level parent term. Uninformative relative to the specific (poly)ubiquitination/SCF-catabolism annotations. action: MARK_AS_OVER_ANNOTATED reason: Extremely generic parent term; the specific protein polyubiquitination and SCF-dependent catabolism annotations fully and more informatively capture FBXO22's role. supported_by: - reference_id: PMID:10531035 supporting_text: F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - 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: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10531035 title: Identification of a family of human F-box proteins. findings: - statement: FBXO22 (FBX22) was identified among a family of 26 human F-box proteins; F-box proteins are the substrate-recognition subunits of SCF ubiquitin protein ligases (together with Skp1, a cullin, and Roc1/Rbx1). reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Original identification paper establishing FBXO22 as an F-box protein/SCF substrate receptor; source of the legacy TAS catabolism and protein-modification annotations. - id: PMID:10531037 title: A family of mammalian F-box proteins. findings: - statement: F-box proteins contain a C-terminal substrate-binding domain and an F-box motif that binds Skp1, linking the F-box protein to a core ubiquitin ligase composed of Cul1, Rbx1 and an E2; the catalytic core is the cullin-RING module, not the F-box protein. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Establishes the F-box/SCF architecture; supports MODIFY of the catalytic transferase annotation to the substrate-adaptor function. - id: PMID:21145461 title: Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. findings: - statement: Quantitative proteomics of the cullin-RING ligase (CRL) network; a large fraction of cullins are assembled with substrate-adaptor modules. Recorded FBXO22 interaction partner is CUL1. reference_section_type: ABSTRACT reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput CRL-network proteomics; source of a bare protein binding (CUL1) annotation. - id: PMID:26496610 title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput quantitative interactome; FBXO22 partner recorded is SKP1; source of a bare protein binding annotation. - 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; FBXO22 partner recorded is SKP1; source of a bare protein binding annotation. Abstract-only in cache. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Binary interactome reference map; FBXO22 partner recorded is SKP1; source of a bare protein binding annotation. - 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 proteome-scale interactome; FBXO22 partner recorded is SKP1; source of a bare protein binding annotation. - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: - statement: The SCF (SKP1-CUL1-F-box) complex comprises ~69 E3 ubiquitin ligases distinguished by variable F-box proteins that determine substrate specificity and modify substrates with poly-ubiquitin chains for proteasomal degradation. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Review/NAS source for SCF complex membership and SCF-dependent catabolism annotations; abstract supports the F-box-as-substrate-receptor framing. - id: PMID:37979583 title: The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency. findings: - statement: Upon amino-acid depletion, uncharged tRNAs stimulate GCN2 to phosphorylate FBXO22, which accumulates in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner, inhibiting mTORC1 by preventing substrate recruitment. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Establishes FBXO22 as an MTOR-ubiquitinating SCF receptor and its regulated cytoplasmic localization; source of the EXP nucleus/cytoplasm annotations. Abstract-only in cache (full_text_available false). - id: PMID:39223933 title: E3 ubiquitin ligase FBXO22 inhibits SARS-CoV-2 replication via promoting proteasome-dependent degradation of NSP5. findings: - statement: FBXO22 ubiquitinates SARS-CoV-2 NSP5 with K48-linked polyubiquitin chains at Lys5 and Lys90, promoting its proteasome-dependent degradation and restricting viral replication. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Establishes an antiviral substrate (NSP5) and the K48-linked degradative activity; source of the EXP nucleus/cytoplasm annotations. Abstract-only in cache (full_text_available false). - 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 cell-map interactome; FBXO22 partner recorded is SKP1; source of a bare protein binding annotation. - id: file:human/FBXO22/FBXO22-deep-research-falcon.md title: Falcon deep research report for human FBXO22 findings: - statement: FBXO22 is the substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1/CRL1) E3 ligase; its N-terminal F-box binds SKP1 and its C-terminal FIST-C region binds substrates such as KDM4A. supporting_text: FBXO22 contains an N-terminal **F-box domain** mediating SCF assembly via SKP1, and a C-terminal **FIST/FIST-C** substrate-binding region (e.g., KDM4A binding mapped to the FBXO22 FIST-C domain). - statement: In ER-positive breast cancer, SCF(FBXO22) ubiquitylates and degrades KDM4B when KDM4B is complexed with tamoxifen-bound estrogen receptor, releasing steroid receptor coactivator and shaping SERM pharmacology. supporting_text: In ER-positive breast cancer models, **SCF^FBXO22^ ubiquitylates and degrades KDM4B** when KDM4B is **complexed with tamoxifen-bound ER**, which in turn **releases steroid receptor coactivator (SRC)** from ER and shapes SERM pharmacology. - statement: FBXO22 ubiquitinates nuclear, but not cytoplasmic, PTEN at Lys221 for proteasomal degradation. supporting_text: FBXO22 **ubiquitylates nuclear (but not cytoplasmic) PTEN** at **lysine 221**, leading to proteasome-mediated degradation and nuclear PTEN depletion. - statement: FBXO22 recognizes a phosphodegron motif XXPpSPXPXX and degrades BAG3 in an ERK-S377-phosphorylation-dependent manner, defining an ERK-FBXO22-BAG3 axis. supporting_text: A 2022 systems/biochemical study defined a **FBXO22-recognized phosphodegron motif** **XXPpSPXPXX** and validated **BAG3** as a bona fide FBXO22 substrate. BAG3 degradation requires **ERK-dependent phosphorylation at S377**, establishing an ERK→FBXO22→BAG3 axis linked to tumorigenesis phenotypes. - statement: FBXO22 is a recruitable E3 ligase for targeted protein degradation; an aldehyde metabolite of alkylamine-tethered degraders covalently adducts Cys326 in its C-terminal domain to drive ternary-complex formation and degradation. supporting_text: Alkylamine-tethered degraders can be metabolized to an **active aldehyde** that **covalently adduces Cys326** in the FBXO22 C-terminal domain. reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: Falcon (Edison Scientific) deep-research synthesis. Cross-checked against the UniProt FUNCTION block (KDM4A, methylated TP53, BACH1, MTOR, NSP5) and used as leads for substrates not yet in UniProt (KDM4B/SERM, nuclear PTEN K221, PD-L1, BAG3 phosphodegron, pS2448-mTOR, Cys326 TPD handle); 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 receptor of a SCF (SKP1-CUL1-F-box) CUL1-RING E3 ubiquitin ligase complex; binds SKP1 via its F-box motif and selects substrates via its C-terminal domain, directing their SCF-dependent polyubiquitination and proteasomal degradation. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005634 label: nucleus - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/FBXO22/FBXO22-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: As the SCF(FBXO22) substrate receptor, targets the histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation, thereby regulating H3K9 and H3K36 methylation levels and, in complex with KDM4A, the abundance of methylated TP53 at late senescence. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005634 label: nucleus supported_by: - reference_id: file:human/FBXO22/FBXO22-uniprot.txt supporting_text: Acts as a key regulator of histone methylation marks namely H3K9 and H3K36 methylation through the regulation of histone demethylase KDM4A protein levels directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: Upon amino-acid depletion, FBXO22 (after GCN2/EIF2AK4-dependent phosphorylation) accumulates in the cytoplasm and ubiquitinates MTOR at Lys2066 in a K27-linked manner, inhibiting mTORC1 substrate recruitment and linking nutrient stress to mTORC1 activity. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/FBXO22/FBXO22-uniprot.txt supporting_text: mediates 'Lys-27'-linked ubiquitination of MTOR and thereby inhibits substrate recruitment to mTORC1 - description: As the SCF(FBXO22) substrate receptor, recognizes phospho- and modification-defined degrons on additional substrates (the oxidative-stress transcription factor BACH1, nuclear PTEN at Lys221, the immune-checkpoint ligand PD-L1/CD274, and the ERK-phosphorylated co-chaperone BAG3 at Ser377), directing their proteasomal degradation and thereby coupling SCF activity to oxidative-stress signaling, tumor-suppressor control, immune-checkpoint abundance, and proteostasis. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005634 label: nucleus - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/FBXO22/FBXO22-deep-research-falcon.md supporting_text: A 2022 systems/biochemical study defined a **FBXO22-recognized phosphodegron motif** **XXPpSPXPXX** and validated **BAG3** as a bona fide FBXO22 substrate. BAG3 degradation requires **ERK-dependent phosphorylation at S377**, establishing an ERK→FBXO22→BAG3 axis linked to tumorigenesis phenotypes. - reference_id: file:human/FBXO22/FBXO22-deep-research-falcon.md supporting_text: FBXO22 **ubiquitylates nuclear (but not cytoplasmic) PTEN** at **lysine 221**, leading to proteasome-mediated degradation and nuclear PTEN depletion. directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process proposed_new_terms: [] suggested_questions: - question: What structural determinants in the FBXO22 C-terminal FIST-C domain dictate its broad substrate repertoire (KDM4A, methylated TP53, BACH1, MTOR, KLF4, NSP5), and how are degrons such as the oxidation-exposed BACH1 bZIP region recognized? - question: How is FBXO22's choice of ubiquitin-chain linkage controlled (K48-linked degradative chains on NSP5/most substrates vs K27-linked chains on MTOR), given that chain topology is normally set by the E2/RBX1 module rather than the F-box adaptor? - question: To what extent do the diverse FBXO22 substrate-degradation activities each contribute to the Tayoun-Maawali syndrome phenotype caused by biallelic FBXO22 loss of function? suggested_experiments: - description: Reconstitute SCF(FBXO22) ubiquitination in vitro with purified SKP1-CUL1-RBX1, an E2, and candidate substrates to confirm direct, adaptor-dependent substrate selection and to map lysine sites and chain linkages for each substrate. - description: Perform quantitative ubiquitinome and proteome profiling in FBXO22-knockout versus wild-type cells under basal, amino-acid-starved, and oxidative-stress conditions to define the endogenous, context-dependent FBXO22 substrate repertoire. - description: Dissect the regulated nuclear/cytoplasmic partitioning of FBXO22 by mutating the EIF2AK4/GCN2 phosphosite (Thr-127) and quantifying the effect on substrate-specific degradation (e.g. nuclear KDM4A vs cytoplasmic MTOR).