id: Q6P050 gene_symbol: FBXL22 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXL22 (F-box and leucine-rich protein 22) is a cardiac-enriched member of the FBXL subfamily of F-box proteins, with an N-terminal F-box domain and a C-terminal leucine-rich repeat (LRR) region. It serves as the substrate-recognition subunit of a Cullin-RING (SCF; SKP1-CUL1-F-box) E3 ubiquitin ligase, docking onto SKP1/CUL1 through its F-box domain and recruiting substrates via its LRRs. FBXL22 is enriched in striated (cardiac and skeletal) muscle and localizes to the sarcomeric Z-disc, where it binds and promotes the proteasome-dependent polyubiquitination and degradation of the Z-disc sarcomeric proteins alpha-actinin-2 (ACTN2) and filamin-C (FLNC), thereby controlling sarcomeric/cytoskeletal protein turnover and quality control. Loss of FBXL22 (e.g. in zebrafish) causes accumulation of alpha-actinin and progressive reduction in cardiac contractility, and FBXL22 is essential for maintenance of normal contractile function in vivo. Beyond steady-state cardiac maintenance, FBXL22 participates in sarcomere remodeling programs: in skeletal muscle it is an atrogene-like factor strongly and transiently induced during neurogenic atrophy (denervation, ~15-fold within days) and during myogenic differentiation, with isoform-dependent effects on muscle mass and myopathic phenotypes upon overexpression; and in zebrafish heart regeneration its expression is regulated by AP-1-dependent chromatin accessibility and it promotes sarcomere disassembly. Most mechanistic substrate/localization/contractility evidence derives from model organisms (zebrafish, mouse) and reviews rather than direct human assays. alternative_products: - name: '1' id: Q6P050-1 - name: '2' id: Q6P050-2 sequence_note: VSP_062729 existing_annotations: - term: id: GO:0030018 label: Z disc evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of Z-disc localization from the UniProt subcellular location, which is itself experimentally supported by immunocolocalization in cardiomyocytes and heart tissue (PMID:22972877). The Z-disc is the functional site of FBXL22 action on sarcomeric substrates. action: ACCEPT reason: Correct, functionally central localization; FBXL22 localizes to the sarcomeric Z-disc where it acts on ACTN2/FLNC, supported experimentally. supported_by: - reference_id: file:human/FBXL22/FBXL22-uniprot.txt supporting_text: 'Cytoplasm, myofibril, sarcomere, Z line {ECO:0000269|PubMed:22972877}.' - reference_id: PMID:22972877 supporting_text: located Fbxl22 to the sarcomeric z-disc - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22972877 qualifier: enables review: summary: IntAct interactions (WITH/FROM) from the FBXL22 characterization study include the substrates ACTN2 (P35609) and FLNC (Q14315) and the SCF adaptor SKP1 (P63208). These are functionally meaningful, but the bare protein binding term is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally important FBXL22 interactions with its sarcomeric substrates (ACTN2, FLNC) and with SKP1, but bare protein binding is uninformative per curation guidelines; these relationships are captured by the substrate/SCF annotations. supported_by: - reference_id: file:human/FBXL22/FBXL22-uniprot.txt supporting_text: 'Q6P050; P35609: ACTN2; NbExp=3; IntAct=EBI-24224082, EBI-77797;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: IntAct interaction with SKP1 (WITH/FROM UniProtKB:P63208) captured by the binary-interactome reference map. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the FBXL22-SKP1 interaction underlying SCF assembly, but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL22/FBXL22-uniprot.txt supporting_text: 'Q6P050; P63208: SKP1; NbExp=7; IntAct=EBI-24224082, EBI-307486;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: IntAct interaction with SKP1 (WITH/FROM UniProtKB:P63208) captured by the BioPlex dual proteome-scale interactome. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the FBXL22-SKP1 interaction, but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL22/FBXL22-uniprot.txt supporting_text: 'Q6P050; P63208: SKP1; NbExp=7; IntAct=EBI-24224082, EBI-307486;' - term: id: GO:0016567 label: protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000041 qualifier: involved_in review: summary: UniPathway-derived general protein ubiquitination process. Correct but generic relative to the specific SCF-dependent proteasomal degradation FBXL22 mediates. action: KEEP_AS_NON_CORE reason: Correct but generic; the specific GO:0031146 (SCF-dependent proteasomal ubiquitin-dependent protein catabolic process) better captures FBXL22's role. supported_by: - reference_id: file:human/FBXL22/FBXL22-uniprot.txt supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.' - 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 FBXL22 acts in SCF-dependent proteasomal degradation. For FBXL22 this is experimentally grounded by the SCF-FBXL22-mediated, proteasome-dependent degradation of ACTN2 and FLNC; FBXL22-containing CRLs polyubiquitinate these Z-disc substrates. action: ACCEPT reason: Core biological process; FBXL22 is a documented SCF (Cullin-1) substrate receptor that promotes proteasome-dependent degradation of sarcomeric substrates (MG-132-sensitive), contributing to sarcomeric protein turnover/quality control. additional_reference_ids: - file:human/FBXL22/FBXL22-deep-research-falcon.md supported_by: - reference_id: PMID:22972877 supporting_text: Fbxl22 promotes the proteasome-dependent degradation of key sarcomeric proteins, such as α-actinin and filamin C - reference_id: file:human/FBXL22/FBXL22-deep-research-falcon.md supporting_text: "Fbxl22 **binds ACTN2 and FLNC** and that Fbxl22-containing CRLs **poly-ubiquitylate** these proteins, promoting **proteasome-mediated clearance**" - 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 cytoplasmic SCF component, but derived from generic CRL pathway membership; the functionally relevant compartment is the sarcomeric Z-disc. supported_by: - reference_id: file:human/FBXL22/FBXL22-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 FBXL22-specific. supported_by: - reference_id: file:human/FBXL22/FBXL22-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 FBXL22-specific. supported_by: - reference_id: file:human/FBXL22/FBXL22-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 FBXL22-specific. supported_by: - reference_id: file:human/FBXL22/FBXL22-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 FBXL22-specific. supported_by: - reference_id: file:human/FBXL22/FBXL22-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 FBXL22-specific. supported_by: - reference_id: file:human/FBXL22/FBXL22-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 FBXL22-specific. supported_by: - reference_id: file:human/FBXL22/FBXL22-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 FBXL22-specific. supported_by: - reference_id: file:human/FBXL22/FBXL22-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 FBXL22-specific. supported_by: - reference_id: file:human/FBXL22/FBXL22-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 FBXL22-specific. supported_by: - reference_id: file:human/FBXL22/FBXL22-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:22972877 qualifier: acts_upstream_of_or_within review: summary: Direct experimental evidence (MGI IDA) that FBXL22 drives proteasome-dependent degradation of sarcomeric substrates; FBXL22 overexpression degrades ACTN2/FLNC dose-dependently and MG-132 attenuates this. action: ACCEPT reason: Directly supported core process; the more specific GO:0031146 (SCF-dependent) also applies, but this proteasome-mediated catabolic process annotation is correct and experimentally grounded. supported_by: - reference_id: PMID:22972877 supporting_text: proteasome inhibition with MG-132 markedly attenuated degradation of both α-actinin and filamin C - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IDA original_reference_id: PMID:22972877 qualifier: enables review: summary: MGI IDA annotation of ubiquitin protein ligase activity, based on FBXL22 promoting ubiquitination/degradation of ACTN2 and FLNC. However, FBXL22 is the SCF substrate-recognition subunit, not the catalytic RING; the ligase chemistry is contributed by RBX1/E2. The more accurate molecular function for the F-box receptor is ubiquitin-like ligase-substrate adaptor activity. action: MODIFY reason: FBXL22 is the substrate-recognition adaptor of the SCF complex, not the catalytic ubiquitin ligase; catalysis resides in RBX1/E2. The experimentally observed "ligase activity" reflects FBXL22 conferring substrate specificity on the SCF. Replace with the adaptor activity term. proposed_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXL22/FBXL22-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. references: - id: GO_REF:0000041 title: Gene Ontology annotation based on UniPathway vocabulary mapping 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: PMID:22972877 title: F-box and leucine-rich repeat protein 22 is a cardiac-enriched F-box protein that regulates sarcomeric protein turnover and is essential for maintenance of contractile function in vivo. findings: - statement: FBXL22 is a cardiac-enriched, Z-disc-localized F-box protein that interacts with SKP1 and CUL1 and promotes the proteasome-dependent degradation of the sarcomeric proteins alpha-actinin (ACTN2) and filamin C (FLNC); FBXL22 knockdown causes alpha-actinin accumulation, impaired contractile function and cardiomyopathy in vivo. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Establishes FBXL22 as a cardiac SCF substrate receptor with substrates ACTN2 and FLNC, Z-disc localization, SKP1/CUL1 interaction and an in vivo contractile-function requirement. Source of the Z-disc, substrate-interaction, ligase-activity (MGI IDA) and proteasomal-degradation annotations; abstract-only in cache but functional claims are explicit. - 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; FBXL22 IPI WITH/FROM is SKP1 (P63208). - 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:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: BioPlex interactome; FBXL22 IPI WITH/FROM is SKP1 (P63208). - id: file:human/FBXL22/FBXL22-deep-research-falcon.md title: Falcon deep research report for human FBXL22 findings: - statement: FBXL22 is a striated-muscle-enriched SCF (Cullin-1) substrate adaptor at the Z-disc that polyubiquitinates ACTN2 and FLNC for proteasome-mediated clearance. supporting_text: "Fbxl22 **binds ACTN2 and FLNC** and that Fbxl22-containing CRLs **poly-ubiquitylate** these proteins, promoting **proteasome-mediated clearance**" - statement: FBXL22 is a substrate-selection adaptor, not a small-molecule enzyme; it selects substrates for ubiquitylation by the SCF machinery. supporting_text: "FBXL22 is **not an enzyme that catalyzes a small-molecule reaction**; rather, its primary biochemical role is to **select specific protein substrates** for **ubiquitylation** (typically poly-ubiquitylation) by the SCF E3 ligase machinery, which can route substrates toward **proteasomal degradation** and/or alter their cellular behavior" - statement: Loss of fbxl22 in zebrafish causes ACTN2 accumulation and progressive reduction of cardiac contractility, consistent with impaired sarcomeric protein turnover. supporting_text: "Fbxl22 loss-of-function in zebrafish leads to **ACTN2 accumulation** and **progressive reduction of cardiac contractility**, consistent with impaired sarcomeric protein turnover" - statement: In skeletal muscle FBXL22 is an atrogene-like factor strongly and transiently induced after denervation (~15-fold at day 3, returning to baseline by day 7). supporting_text: "strong, stimulus-timed induction of Fbxl22 in neurogenic atrophy: **~15-fold mRNA increase at day 3 after denervation** in mouse gastrocnemius complex, returning to baseline by day 7" - statement: In zebrafish heart regeneration fbxl22 expression is regulated by AP-1-dependent chromatin accessibility and it regulates sarcomere disassembly. supporting_text: "AP-1 blockade decreases chromatin accessibility at the **fbxl22 locus**, and the study explicitly describes fbxl22 as regulating **sarcomere disassembly**, a key step for cardiomyocyte regenerative behavior" reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: Falcon (Edison Scientific) deep research synthesis. Corroborates the core cardiac SCF-FBXL22/ACTN2/FLNC/Z-disc biology (consistent with PMID:22972877) and adds the skeletal-muscle atrophy/denervation atrogene role (Hughes et al. 2023; Blondelle et al. 2020 review), the AP-1-regulated sarcomere-disassembly role in zebrafish heart regeneration (Beisaw et al. 2020), and the caveat that most substrate/contractility evidence is from model organisms and reviews rather than direct human assays. Primary leads cite DOIs not PMIDs and are largely reviews/model-organism studies not in the local cache; treated as enriching leads, not overriding the experimental curation. - 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: Cardiac-enriched substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that localizes to the sarcomeric Z-disc and promotes the proteasome-dependent ubiquitination and degradation of the Z-disc proteins alpha-actinin-2 (ACTN2) and filamin-C (FLNC), thereby controlling sarcomeric protein turnover and maintaining cardiac contractile function. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0030018 label: Z disc supported_by: - reference_id: PMID:22972877 supporting_text: Fbxl22 promotes the proteasome-dependent degradation of key sarcomeric proteins, such as α-actinin and filamin C - reference_id: file:human/FBXL22/FBXL22-deep-research-falcon.md supporting_text: "Fbxl22 **binds ACTN2 and FLNC** and that Fbxl22-containing CRLs **poly-ubiquitylate** these proteins, promoting **proteasome-mediated clearance**" directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process proposed_new_terms: [] suggested_questions: - question: Beyond ACTN2 and FLNC, what is the full FBXL22 substrate repertoire at the Z-disc, and how is its activity regulated during cardiac stress/remodeling versus skeletal-muscle atrophy? - question: Does the strong, transient induction of FBXL22 during denervation/neurogenic atrophy translate into increased sarcomeric protein degradation, given that E3-ligase mRNA does not always track protein abundance or bulk proteolysis? - question: How do human FBXL22 loss-of-function or regulatory variants relate to cardiomyopathy and atrial fibrillation, given the in vivo contractile phenotypes observed on FBXL22 depletion in model organisms? suggested_experiments: - description: Reconstitute SCF-FBXL22 (SKP1-CUL1-RBX1-FBXL22) in vitro and assay ubiquitination of ACTN2 and FLNC, mapping ubiquitin-acceptor sites and testing an F-box- or LRR-binding-deficient mutant. - description: Generate cardiac- and skeletal-muscle-specific FBXL22 knockout and gain-of-function models with quantitative ubiquitinome/proteome profiling of the Z-disc proteome, linking substrate accumulation to contractile dysfunction and to denervation-induced atrophy, and testing isoform-specific effects.