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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0030018 Z disc | IEA GO_REF:0000044 | ACCEPT | 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. Reason: Correct, functionally central localization; FBXL22 localizes to the sarcomeric Z-disc where it acts on ACTN2/FLNC, supported experimentally. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Cytoplasm, myofibril, sarcomere, Z line {ECO:0000269|PubMed:22972877}. PMID:22972877 located Fbxl22 to the sarcomeric z-disc |
| GO:0005515 protein binding | IPI PMID:22972877 F-box and leucine-rich repeat protein 22 is a cardiac-enrich... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Q6P050; P35609: ACTN2; NbExp=3; IntAct=EBI-24224082, EBI-77797; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: IntAct interaction with SKP1 (WITH/FROM UniProtKB:P63208) captured by the binary-interactome reference map. Bare protein binding is uninformative. Reason: Records the FBXL22-SKP1 interaction underlying SCF assembly, but bare protein binding is uninformative. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Q6P050; P63208: SKP1; NbExp=7; IntAct=EBI-24224082, EBI-307486; |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: IntAct interaction with SKP1 (WITH/FROM UniProtKB:P63208) captured by the BioPlex dual proteome-scale interactome. Bare protein binding is uninformative. Reason: Records the FBXL22-SKP1 interaction, but bare protein binding is uninformative. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Q6P050; P63208: SKP1; NbExp=7; IntAct=EBI-24224082, EBI-307486; |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-derived general protein ubiquitination process. Correct but generic relative to the specific SCF-dependent proteasomal degradation FBXL22 mediates. Reason: Correct but generic; the specific GO:0031146 (SCF-dependent proteasomal ubiquitin-dependent protein catabolic process) better captures FBXL22's role. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:33234069 The FBXL family of F-box proteins: variations on a theme. | ACCEPT | 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. 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. Supporting Evidence: PMID:22972877 Fbxl22 promotes the proteasome-dependent degradation of key sarcomeric proteins, such as Ξ±-actinin and filamin C file:human/FBXL22/FBXL22-deep-research-falcon.md Fbxl22 **binds ACTN2 and FLNC** and that Fbxl22-containing CRLs **poly-ubiquitylate** these proteins, promoting **proteasome-mediated clearance** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol annotation propagated across the generic CRL1/neddylation reaction set. Reason: Plausible localization for a cytoplasmic SCF component, but derived from generic CRL pathway membership; the functionally relevant compartment is the sarcomeric Z-disc. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol annotation from the generic CRL1 neddylation reaction set. Reason: Plausible but redundant generic-pathway localization; not FBXL22-specific. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol annotation from the generic CRL (CAND1) reaction set. Reason: Plausible but redundant generic-pathway localization; not FBXL22-specific. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol annotation from the generic CRL (COMMD/CAND1) reaction set. Reason: Plausible but redundant generic-pathway localization; not FBXL22-specific. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol annotation from the generic CRL deneddylation (COP9) reaction set. Reason: Plausible but redundant generic-pathway localization; not FBXL22-specific. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol annotation from the generic CRL1 (DCUN1D3) reaction set. Reason: Plausible but redundant generic-pathway localization; not FBXL22-specific. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (transfer of Ub from E2 to substrate). Reason: Plausible but redundant generic-pathway localization; not FBXL22-specific. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (release of E3 from substrate). Reason: Plausible but redundant generic-pathway localization; not FBXL22-specific. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (polyubiquitination of substrate). Reason: Plausible but redundant generic-pathway localization; not FBXL22-specific. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol annotation from the generic ubiquitination reaction set (interaction of E3 with substrate and E2-Ub). Reason: Plausible but redundant generic-pathway localization; not FBXL22-specific. Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:22972877 F-box and leucine-rich repeat protein 22 is a cardiac-enrich... | ACCEPT | 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. 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. Supporting Evidence: PMID:22972877 proteasome inhibition with MG-132 markedly attenuated degradation of both Ξ±-actinin and filamin C |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:22972877 F-box and leucine-rich repeat protein 22 is a cardiac-enrich... | MODIFY | 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. 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 replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXL22/FBXL22-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Q: 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?
Experiment: 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.
Experiment: 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.
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