Existing Annotations Review

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 α-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 α-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.

Core Functions

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:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

Z disc

Supporting Evidence:

PMID:22972877
Fbxl22 promotes the proteasome-dependent degradation of key sarcomeric proteins, such as α-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**

References

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

PMID:22972877

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.

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.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33234069

The FBXL family of F-box proteins: variations on a theme.

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.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

file:human/FBXL22/FBXL22-deep-research-falcon.md

Falcon deep research report for human FBXL22

FBXL22 is a striated-muscle-enriched SCF (Cullin-1) substrate adaptor at the Z-disc that polyubiquitinates ACTN2 and FLNC for proteasome-mediated clearance.

"Fbxl22 **binds ACTN2 and FLNC** and that Fbxl22-containing CRLs **poly-ubiquitylate** these proteins, promoting **proteasome-mediated clearance**"
FBXL22 is a substrate-selection adaptor, not a small-molecule enzyme; it selects substrates for ubiquitylation by the SCF machinery.

"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"
Loss of fbxl22 in zebrafish causes ACTN2 accumulation and progressive reduction of cardiac contractility, consistent with impaired sarcomeric protein turnover.

"Fbxl22 loss-of-function in zebrafish leads to **ACTN2 accumulation** and **progressive reduction of cardiac contractility**, consistent with impaired sarcomeric protein turnover"
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).

"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"
In zebrafish heart regeneration fbxl22 expression is regulated by AP-1-dependent chromatin accessibility and it regulates sarcomere disassembly.

"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"

Reactome:R-HSA-8952618

AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-8952620

NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-8955241

CAND1 binds cytosolic CRL E3 ubiquitin ligases

Reactome:R-HSA-8955289

COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes

Reactome:R-HSA-8956040

COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes

Reactome:R-HSA-8956200

MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-983140

Transfer of Ub from E2 to substrate and release of E2

Reactome:R-HSA-983147

Release of E3 from polyubiquitinated substrate

Reactome:R-HSA-983156

Polyubiquitination of substrate

Reactome:R-HSA-983157

Interaction of E3 with substrate and E2-Ub complex

Suggested Experiments

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.

Deep Research

Falcon

(FBXL22-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 23 citations 2 artifacts 2026-06-13T06:29:17.587565

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000013 The requested information about Fbxl22 is found in Section 3.7 and Figure 3 of the document. 1. **SCF-Fbxl22 complex**: Figure 3A ( (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human FBXL22 (UniProt Q6P050) — functional annotation

0) Target verification (critical identity check)

The research target is human FBXL22 encoding F-box and leucine-rich protein 22, explicitly mapped in the FBXL-family review to UniProt Q6P050 (FXL22_HUMAN) (https://doi.org/10.1098/rsob.200319; published 2020-11) (mason2020thefbxlfamily pages 4-5). The defining architecture is consistent across sources: an F-box domain (Skp1-binding module) plus C-terminal leucine-rich repeats (LRRs) (substrate-binding) characteristic of the FBXL subfamily (mason2020thefbxlfamily pages 4-5, mason2020thefbxlfamily pages 2-3, mason2020thefbxlfamily pages 3-4). No conflicting gene/protein identity was detected in the retrieved literature set.

1) Key concepts and definitions (current understanding)

1.1 F-box proteins and SCF ubiquitin ligases

FBXL22 is best understood as a substrate-recruitment adaptor in a Cullin-RING E3 ubiquitin ligase of the SCF class (Skp1–Cullin1–F-box). In the canonical model, the F-box (~50 aa) binds Skp1, assembling the adaptor into the SCF complex, while the variable C-terminal domain (here, LRRs) contributes to substrate recognition (mason2020thefbxlfamily pages 2-3, mason2020thefbxlfamily pages 3-4).

1.2 What “function” means for FBXL22

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 (blondelle2020theroleof pages 13-15).

2) Molecular function, substrates, localization, and pathways

2.1 Molecular function and complex membership

Multiple muscle-focused reviews characterize Fbxl22/FBXL22 as a Cullin-1 (SCF) substrate adapter in striated muscle (blondelle2020theroleof pages 13-15). A key schematic of SCF architecture and the position of F-box adaptors (including Fbxl22 in the review context) is shown in a retrieved figure (blondelle2020theroleof media d9a83ddb).

2.2 Substrate specificity (best-supported)

The most consistently cited candidate substrates in striated muscle systems are:
- α-actinin-2 (ACTN2)
- filamin-C (FLNC)

The striated-muscle CRL review reports biochemical evidence that Fbxl22 binds ACTN2 and FLNC and that Fbxl22-containing CRLs poly-ubiquitylate these proteins, promoting proteasome-mediated clearance (blondelle2020theroleof pages 13-15, blondelle2020theroleof media d9a83ddb). These reported targets align with the concept that FBXL22 contributes to sarcomeric/Z-disk protein turnover.

2.3 Subcellular localization

Fbxl22 is described as enriched in heart/striated muscle and localized to the sarcomeric Z-disk, consistent with its putative role in quality control/turnover of Z-disk structural components (blondelle2020theroleof pages 13-15).

2.4 Biological processes and phenotypes (mechanistic interpretation)

Cardiac contractility and sarcomere maintenance: Model-organism evidence summarized in reviews indicates that Fbxl22 loss-of-function in zebrafish leads to ACTN2 accumulation and progressive reduction of cardiac contractility, consistent with impaired sarcomeric protein turnover (blondelle2020theroleof pages 13-15). Independent cardiac-CRL work also explicitly summarizes FBXL22 as “cardiac-enriched” and “essential for maintenance of contractile function in vivo,” placing it in the mechanistic context of ubiquitin-dependent sarcomeric remodeling (https://doi.org/10.3389/fphys.2023.1134339; published 2023-03) (fischer2023identificationofhypertrophymodulating pages 10-10).

Skeletal muscle differentiation/atrophy: The muscle CRL review further notes two splice isoforms in murine skeletal muscle systems, induced during myogenic differentiation and upregulated during neurogenic atrophy/denervation; overexpression phenotypes include myopathic changes (cell infiltration, necrosis, degeneration, centralized nuclei) and altered cytoskeletal protein levels (including ACTN2), with isoform-dependent effects (blondelle2020theroleof pages 13-15).

Regulatory link to regeneration programs (AP-1): In zebrafish heart regeneration, 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 (https://doi.org/10.1161/circresaha.119.316167; published 2020-06) (beisaw2020ap1contributesto pages 1-4). Although this excerpt does not mechanistically connect FBXL22 to ubiquitin/proteasome action, it is consistent with the broader SCF-adaptor function described elsewhere.

3) Recent developments (prioritizing 2023–2024)

3.1 Quantitative regulation in denervation atrophy (2023)

A 2023 perspective on E3 ligases in muscle wasting highlights a 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 (https://doi.org/10.1152/ajpcell.00457.2023; published 2023-12) (hughes2023acriticaldiscussion pages 7-10). This supports FBXL22 as part of the acute transcriptional “atrogene-like” response program, though the same article cautions that E3-ligase mRNA does not always track with protein abundance or bulk protein degradation rates (hughes2023acriticaldiscussion pages 7-10).

3.2 Cardiac CRL context and remodeling screens (2023)

A 2023 cardiomyocyte CRL screen/review context highlights the importance of Cullin-RING ligases in hypertrophy and explicitly reiterates the functional framing of FBXL22 as a cardiac-enriched F-box protein regulating sarcomeric protein turnover and contractile function (fischer2023identificationofhypertrophymodulating pages 10-10). This supports continued interest in F-box adaptors as cardiac remodeling regulators.

3.3 Human association resources and genetics (2023–2024)

Atrial fibrillation resource: A 2023 Heart Rhythm study used human left atrial appendage tissue (n=265) to create an eQTL/coexpression resource for AF risk-locus gene prioritization (GSE69890; paper published 2023-09; https://doi.org/10.1016/j.hrthm.2023.05.035) (wass2023novelfunctionalatrial pages 1-3). While the excerpted pages do not name FBXL22 explicitly, Open Targets links the AF association evidence to this paper’s PubMed ID in aggregated evidence (OpenTargets Search: -FBXL22).
Open Targets (genetic association aggregation): Open Targets reports association scores between FBXL22 and multiple diseases, including atrial fibrillation (score ~0.17) and neurodegeneration-related phenotypes (scores ~0.40–0.43), based largely on GWAS credible set evidence (Open Targets Platform; https://platform.opentargets.org; Open Targets platform paper cited in the tool output) (OpenTargets Search: -FBXL22). These are association-level results and do not establish mechanism.

4) Current applications and real-world implementations

4.1 Biomarker/target proposals (translational)

The retrieved 2023–2024 set contains mainly association resources rather than deployed clinical biomarkers. However, Open Targets association scores are actively used in drug discovery hypothesis generation workflows and thus represent a real-world implementation of aggregated genetics for target prioritization (OpenTargets Search: -FBXL22).

A later (non-priority-year) 2025 study explicitly frames FBXL22 as an immune biomarker with pan-cancer prognostic value and proposes therapeutic relevance (particularly in prostate cancer) using TCGA/GTEx and in vitro experiments (https://doi.org/10.3892/ol.2025.15316; published 2025-10) (liu2025fbxl22acircadian‑regulated pages 1-2, liu2025fbxl22acircadian‑regulated pages 14-15). Because this is outside the requested 2023–2024 window, it should be treated as supplemental context.

4.2 Experimental models and assays in current use

Across the evidence base summarized in reviews, FBXL22 function is interrogated through:
- Zebrafish knockdown/heart regeneration paradigms linked to sarcomere disassembly/regeneration programs (beisaw2020ap1contributesto pages 1-4)
- Striated muscle biochemical interaction and ubiquitination assays (ACTN2/FLNC binding; poly-ubiquitylation) and localization to sarcomeric structures (blondelle2020theroleof pages 13-15)
- Rodent denervation atrophy paradigms where Fbxl22 mRNA is strongly induced (hughes2023acriticaldiscussion pages 7-10)

5) Expert opinions / authoritative analysis (what experts think is most solid)

Authoritative reviews converge on a core model: FBXL22 is a striated-muscle-enriched SCF adaptor localized at the Z-disk, implicated in selective turnover of sarcomeric/cytoskeletal proteins (notably ACTN2 and FLNC), and thus in maintenance/remodeling of contractile structures (blondelle2020theroleof pages 13-15, fischer2023identificationofhypertrophymodulating pages 10-10). In the muscle-wasting field, expert commentary emphasizes that E3 ligase expression changes (including Fbxl22) must be interpreted cautiously: increased transcript abundance is not necessarily equivalent to increased protein abundance or increased bulk proteolysis (hughes2023acriticaldiscussion pages 7-10).

6) Relevant statistics and data (recent)

Denervation induction (mouse gastrocnemius): Fbxl22 mRNA ~15-fold up at day 3 post-denervation; baseline by day 7 (published 2023-12) (hughes2023acriticaldiscussion pages 7-10).
Open Targets disease association scores: atrial fibrillation 0.1696; neurodegenerative disease 0.4232; dementia 0.4264; Alzheimer disease 0.4003; type 2 diabetes mellitus 0.2811 (OpenTargets Search: -FBXL22).
AF eQTL/coexpression resource sample size: human left atrial appendage tissues n=265 (published 2023-09) (wass2023novelfunctionalatrial pages 1-3).

7) Evidence gaps and limitations (important for annotation quality)

Primary human mechanistic studies are limited in the retrieved corpus. Key mechanistic claims (ACTN2/FLNC substrates; Z-disk localization; contractility) are currently best supported via model-organism and review-summarized findings rather than extensive direct human tissue experiments in the accessible text set (blondelle2020theroleof pages 13-15).
Some foundational primary literature on FBXL22 cardiac function (2012) and skeletal muscle atrophy-promoting function (2020) was flagged as unobtainable in this run, limiting direct extraction of numeric effect sizes for contractility or muscle mass phenotypes.

8) Summary table

The following table consolidates the functional annotation into an evidence-graded view.

Category	Key points	Evidence type (review/primary/model organism/database)	Key citations
Identity/domains	Human FBXL22 is the UniProt Q6P050/FXL22_HUMAN protein, a member of the FBXL subfamily with an N-terminal F-box domain and C-terminal leucine-rich repeats (LRRs); reviews describe a small FBXL protein with predicted ~3 LRRs and the canonical F-box/LRR architecture expected for substrate-binding adaptors.	Review/family annotation	(mason2020thefbxlfamily pages 4-5, mason2020thefbxlfamily pages 2-3, mason2020thefbxlfamily pages 3-4)
Complex	FBXL22 is inferred/assigned as a substrate-recruiting component of a Cullin-1/Skp1 SCF-type E3 ubiquitin ligase complex; FBXL family proteins use the F-box to bind Skp1 and recruit substrates through LRRs.	Review with primary/model-organism support	(mason2020thefbxlfamily pages 2-3, blondelle2020theroleof pages 13-15, blondelle2020theroleof media d9a83ddb)
Substrates	Best-supported reported substrates are sarcomeric α-actinin-2 (ACTN2) and filamin-C (FLNC); FBXL22-containing CRLs polyubiquitylate these proteins and promote proteasome-mediated degradation in striated-muscle systems.	Review summarizing primary/model-organism studies	(blondelle2020theroleof pages 13-15, blondelle2020theroleof media d9a83ddb)
Localization	FBXL22 is enriched in heart/striated muscle and localizes to the sarcomeric Z-disk, consistent with its proposed role in turnover of Z-disk/cytoskeletal proteins.	Review/model-organism evidence	(blondelle2020theroleof pages 13-15)
Regulation	In skeletal muscle atrophy models, Fbxl22 mRNA rises early after denervation (~15-fold at day 3) and returns toward baseline by day 7; reviews also note induction during myogenic differentiation and neurogenic atrophy. Zebrafish regeneration work links fbxl22 expression to AP-1–dependent chromatin accessibility; a 2024 preprint suggests FoxO regulation as a hypothesis under investigation.	Review; model-organism primary; preprint/hypothesis	(hughes2023acriticaldiscussion pages 7-10, blondelle2020theroleof pages 13-15, scalabrin2024alterationsinperoxisomalmitochondrial pages 1-3)
Biological roles/phenotypes	Core function is selective sarcomere/cytoskeletal protein quality control. Zebrafish loss of fbxl22 causes ACTN2 accumulation and progressive reduction in cardiac contractility. In murine skeletal muscle, overexpression causes transient muscle-mass increase but also myopathic changes (cell infiltration, necrosis, degeneration, centralized nuclei) and altered dystrophin, desmin, vimentin, and ACTN2; isoform-specific effects have been reported.	Review summarizing primary/model-organism studies	(blondelle2020theroleof pages 13-15)
Human genetic/disease association evidence	Direct human functional disease evidence is limited. Human left atrial transcriptomic/coexpression studies include FBXL22 among candidate AF-related genes/resources, and Open Targets lists low-to-moderate association evidence for atrial fibrillation, dementia/Alzheimer disease, neurodegenerative disease, and type 2 diabetes based on aggregated datasets; these are association-level, not mechanistic proof.	Human transcriptomic association/database	(wass2023novelfunctionalatrial pages 1-3, OpenTargets Search: -FBXL22)

Table: This table summarizes the currently supported functional annotation for human FBXL22 (UniProt Q6P050), separating well-supported molecular features from more tentative human disease associations. It is useful for distinguishing direct mechanistic evidence from broader association data.

References

(mason2020thefbxlfamily pages 4-5): Bethany Mason and Heike Laman. The fbxl family of f-box proteins: variations on a theme. Nov 2020. URL: https://doi.org/10.1098/rsob.200319, doi:10.1098/rsob.200319. This article has 51 citations and is from a peer-reviewed journal.
(mason2020thefbxlfamily pages 2-3): Bethany Mason and Heike Laman. The fbxl family of f-box proteins: variations on a theme. Nov 2020. URL: https://doi.org/10.1098/rsob.200319, doi:10.1098/rsob.200319. This article has 51 citations and is from a peer-reviewed journal.
(mason2020thefbxlfamily pages 3-4): Bethany Mason and Heike Laman. The fbxl family of f-box proteins: variations on a theme. Nov 2020. URL: https://doi.org/10.1098/rsob.200319, doi:10.1098/rsob.200319. This article has 51 citations and is from a peer-reviewed journal.
(blondelle2020theroleof pages 13-15): Jordan Blondelle, Andrea Biju, and Stephan Lange. The role of cullin-ring ligases in striated muscle development, function, and disease. International Journal of Molecular Sciences, 21:7936, Oct 2020. URL: https://doi.org/10.3390/ijms21217936, doi:10.3390/ijms21217936. This article has 27 citations.
(blondelle2020theroleof media d9a83ddb): Jordan Blondelle, Andrea Biju, and Stephan Lange. The role of cullin-ring ligases in striated muscle development, function, and disease. International Journal of Molecular Sciences, 21:7936, Oct 2020. URL: https://doi.org/10.3390/ijms21217936, doi:10.3390/ijms21217936. This article has 27 citations.
(fischer2023identificationofhypertrophymodulating pages 10-10): Maximillian Fischer, Moritz Jakab, Marc N. Hirt, Tessa R. Werner, Stefan Engelhardt, and Antonio Sarikas. Identification of hypertrophy-modulating cullin-ring ubiquitin ligases in primary cardiomyocytes. Frontiers in Physiology, Mar 2023. URL: https://doi.org/10.3389/fphys.2023.1134339, doi:10.3389/fphys.2023.1134339. This article has 5 citations.
(beisaw2020ap1contributesto pages 1-4): Arica Beisaw, Carsten Kuenne, Stefan Guenther, Julia Dallmann, Chi-Chung Wu, Mette Bentsen, Mario Looso, and Didier Y.R. Stainier. Ap-1 contributes to chromatin accessibility to promote sarcomere disassembly and cardiomyocyte protrusion during zebrafish heart regeneration. Circulation Research, 126:1760-1778, Jun 2020. URL: https://doi.org/10.1161/circresaha.119.316167, doi:10.1161/circresaha.119.316167. This article has 167 citations and is from a highest quality peer-reviewed journal.
(hughes2023acriticaldiscussion pages 7-10): David C. Hughes, Craig A. Goodman, Leslie M. Baehr, Paul Gregorevic, and Sue C. Bodine. A critical discussion on the relationship between e3 ubiquitin ligases, protein degradation, and skeletal muscle wasting: it’s not that simple. Dec 2023. URL: https://doi.org/10.1152/ajpcell.00457.2023, doi:10.1152/ajpcell.00457.2023. This article has 41 citations.
(wass2023novelfunctionalatrial pages 1-3): Sojin Youn Wass, Erik J. Offerman, Han Sun, Jeffrey Hsu, Julie H. Rennison, Catherine C. Cantlay, Meghan L. McHale, A. Marc Gillinov, Christine Moravec, Jonathan D. Smith, David R. Van Wagoner, John Barnard, and Mina K. Chung. Novel functional atrial fibrillation risk genes and pathways identified from coexpression analyses in human left atria. Heart Rhythm, 20:1219-1226, Sep 2023. URL: https://doi.org/10.1016/j.hrthm.2023.05.035, doi:10.1016/j.hrthm.2023.05.035. This article has 14 citations and is from a peer-reviewed journal.
(OpenTargets Search: -FBXL22): Open Targets Query (-FBXL22, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(liu2025fbxl22acircadian‑regulated pages 1-2): Jin Liu, Maoyuan Feng, Jian Zhou, Shijie Yang, Yue Shi, and Wenping Li. Fbxl22, a circadian‑regulated immune biomarker with pan‑cancer prognostic value and therapeutic potential in prostate cancer. Oncology Letters, 30:1-16, Oct 2025. URL: https://doi.org/10.3892/ol.2025.15316, doi:10.3892/ol.2025.15316. This article has 0 citations and is from a peer-reviewed journal.
(liu2025fbxl22acircadian‑regulated pages 14-15): Jin Liu, Maoyuan Feng, Jian Zhou, Shijie Yang, Yue Shi, and Wenping Li. Fbxl22, a circadian‑regulated immune biomarker with pan‑cancer prognostic value and therapeutic potential in prostate cancer. Oncology Letters, 30:1-16, Oct 2025. URL: https://doi.org/10.3892/ol.2025.15316, doi:10.3892/ol.2025.15316. This article has 0 citations and is from a peer-reviewed journal.
(scalabrin2024alterationsinperoxisomalmitochondrial pages 1-3): Marco Scalabrin, Eloisa Turco, Leonardo Nogara, Gaia Gherardi, Giulia Trani, Samuele Negro, Anais Franco Romero, Yorrick Jaspers, Elisa Baschiera, Rossella De Cegli, Eugenio Del Prete, Tito Cali, Bert Blaauw, Leonardo Salviati, Michela Rigoni, Cristina Mammucari, Sylvie Caspar-Bauguil, Cedric Moro, Marco Sandri, Stephan Kemp, and Vanina Romanello. Alterations in peroxisomal-mitochondrial interplay in skeletal muscle accelerates muscle dysfunction. bioRxiv, Apr 2024. URL: https://doi.org/10.1101/2024.04.25.591056, doi:10.1101/2024.04.25.591056. This article has 4 citations.

Artifacts

Edison artifact artifact-00

Citations

mason2020thefbxlfamily pages 4-5
blondelle2020theroleof pages 13-15
fischer2023identificationofhypertrophymodulating pages 10-10
hughes2023acriticaldiscussion pages 7-10
wass2023novelfunctionalatrial pages 1-3
mason2020thefbxlfamily pages 2-3
mason2020thefbxlfamily pages 3-4
scalabrin2024alterationsinperoxisomalmitochondrial pages 1-3
https://doi.org/10.1098/rsob.200319;
https://doi.org/10.3389/fphys.2023.1134339;
https://doi.org/10.1161/circresaha.119.316167;
https://doi.org/10.1152/ajpcell.00457.2023;
https://doi.org/10.1016/j.hrthm.2023.05.035
https://platform.opentargets.org;
https://doi.org/10.3892/ol.2025.15316;
https://doi.org/10.1098/rsob.200319,
https://doi.org/10.3390/ijms21217936,
https://doi.org/10.3389/fphys.2023.1134339,
https://doi.org/10.1161/circresaha.119.316167,
https://doi.org/10.1152/ajpcell.00457.2023,
https://doi.org/10.1016/j.hrthm.2023.05.035,
https://doi.org/10.3892/ol.2025.15316,
https://doi.org/10.1101/2024.04.25.591056,

📚 Additional Documentation

Pn Notes

(FBXL22-pn-notes.md)

FBXL22 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q6P050
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FBXL22/FBXL22-ai-review.yaml
AIGR review HTML: missing - genes/human/FBXL22/FBXL22-ai-review.html
Gene notes: missing - genes/human/FBXL22/FBXL22-notes.md
GOA TSV: present - genes/human/FBXL22/FBXL22-goa.tsv
UniProt record: present - genes/human/FBXL22/FBXL22-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FBXL22.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FBXL22.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/FBXL22/FBXL22-deep-research-falcon.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 3; KEEP_AS_NON_CORE: 14; MODIFY: 1

PN Consistency Summary

Consistency: Fully consistent. Falcon DR (cardiac Z-disc adaptor; ACTN2/FLNC substrates; zebrafish contractility; denervation atrogene), review YAML, the PN F-box LRR receptor placement, and the GO:1990756 group mapping all converge. No contradictions.
PN story / NEW pressure: PN projects GO:1990756 (verified real) as new_to_goa. Review does not add it as NEW but reaches the same endpoint via action: MODIFY of the existing GO:0061630 ubiquitin protein ligase activity (IDA, PMID:22972877) → proposed_replacement GO:1990756 — the canonical F-box correction (catalysis is in RBX1, not the receptor). Net effect = adaptor MF present, matching PN. Conclude: already addressed by review via MODIFY; concordant with PN projection.
Evidence alignment: PN reference is only "15340381 / rev"; review anchors on the gene-defining PMID:22972877 (HIGH/VERIFIED — Z-disc, ACTN2/FLNC, SKP1/CUL1, in vivo contractility) plus FBXL review PMID:33234069 and Falcon DR. Divergence benign — PN generic family review vs review's primary cardiac study.
Verdict: Consistent; adaptor MF (GO:1990756) supplied via MODIFY of the mis-attributed catalytic term, matching PN. No over-reach.

Full Consistency Review

UniProt: Q6P050 (FBXL22) · batch: proteostasis-batch-2026-06-13 (Falcon DR) · review status: COMPLETE
PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|LRR ; PN-node mapping: group Cul1 substrate receptor=mapped/ok_for_propagation→GO:1990756; F-box/LRR subtype+type=no_mapping; class=context_only/too_broad→GO:0061630.
Consistency: Fully consistent. Falcon DR (cardiac Z-disc adaptor; ACTN2/FLNC substrates; zebrafish contractility; denervation atrogene), review YAML, the PN F-box LRR receptor placement, and the GO:1990756 group mapping all converge. No contradictions.
PN story / NEW pressure: PN projects GO:1990756 (verified real) as new_to_goa. Review does not add it as NEW but reaches the same endpoint via action: MODIFY of the existing GO:0061630 ubiquitin protein ligase activity (IDA, PMID:22972877) → proposed_replacement GO:1990756 — the canonical F-box correction (catalysis is in RBX1, not the receptor). Net effect = adaptor MF present, matching PN. Conclude: already addressed by review via MODIFY; concordant with PN projection.
Mapping strategy: Gene supports the node. KEY PATTERN exemplary: review explicitly demotes the catalytic ligase MF (the MGI IDA "ligase activity," which over-attributes RBX1 chemistry to the receptor) to the GO:1990756 adaptor term. PN class-level GO:0061630 correctly flagged too_broad. No broader/narrower mismatch.
Evidence alignment: PN reference is only "15340381 / rev"; review anchors on the gene-defining PMID:22972877 (HIGH/VERIFIED — Z-disc, ACTN2/FLNC, SKP1/CUL1, in vivo contractility) plus FBXL review PMID:33234069 and Falcon DR. Divergence benign — PN generic family review vs review's primary cardiac study.
Verdict: Consistent; adaptor MF (GO:1990756) supplied via MODIFY of the mis-attributed catalytic term, matching PN. No over-reach.
Recommended edits: none to FBXL22-ai-review.yaml; PN mappings sound as-is.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/FBXL22/FBXL22-ai-review.yaml
PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | LRR

UniProt: Q6P050
In branches: UPS
Signature domains: IPR001810
Auxiliary domains: IPR006553
PN references (titles):
- 15340381 / rev
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|LRR
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
  status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
  rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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.

FBXL22

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human FBXL22 (UniProt Q6P050) — functional annotation

0) Target verification (critical identity check)

1) Key concepts and definitions (current understanding)

1.1 F-box proteins and SCF ubiquitin ligases

1.2 What “function” means for FBXL22

2) Molecular function, substrates, localization, and pathways

2.1 Molecular function and complex membership

2.2 Substrate specificity (best-supported)

2.3 Subcellular localization

2.4 Biological processes and phenotypes (mechanistic interpretation)

3) Recent developments (prioritizing 2023–2024)

3.1 Quantitative regulation in denervation atrophy (2023)

3.2 Cardiac CRL context and remodeling screens (2023)

3.3 Human association resources and genetics (2023–2024)

4) Current applications and real-world implementations

4.1 Biomarker/target proposals (translational)

4.2 Experimental models and assays in current use

5) Expert opinions / authoritative analysis (what experts think is most solid)

6) Relevant statistics and data (recent)

7) Evidence gaps and limitations (important for annotation quality)

8) Summary table

Artifacts

Citations

📚 Additional Documentation

Pn Notes

FBXL22 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | LRR

Projected GO annotations (1)

Note

📄 View Raw YAML