Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000209 protein polyubiquitination	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of involvement in protein polyubiquitination, consistent with FBXO22's role as the substrate-recognition subunit of an SCF E3 ligase that directs polyubiquitination of substrates. Reason: Core biological role; FBXO22 mediates polyubiquitination of substrates such as KDM4A, KDM4B, methylated TP53, BACH1, nuclear PTEN, PD-L1, BAG3, MTOR and NSP5 through the SCF complex. Supporting Evidence: file:human/FBXO22/FBXO22-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex file:human/FBXO22/FBXO22-deep-research-falcon.md FBXO22 contains an N-terminal F-box domain mediating SCF assembly via SKP1, and a C-terminal FIST/FIST-C substrate-binding region (e.g., KDM4A binding mapped to the FBXO22 FIST-C domain).
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of a positive regulatory role in proteasomal ubiquitin-dependent catabolism, consistent with FBXO22 promoting proteasomal degradation of its substrates. Reason: Supported by multiple experimental studies in which FBXO22 promotes proteasome-dependent degradation of substrates (e.g. KDM4A, NSP5). Supporting Evidence: file:human/FBXO22/FBXO22-uniprot.txt Promotes the proteasome-dependent degradation of key sarcomeric proteins
GO:0048742 regulation of skeletal muscle fiber development	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Phylogenetic assignment of a role in skeletal muscle fiber development. FBXO22 is enriched in cardiac muscle and is reported to regulate sarcomeric protein turnover, but a specific role in skeletal muscle fiber development is thinly supported and likely propagated from family/ortholog context. Reason: FBXO22's documented muscle link is regulation of sarcomeric protein turnover (cardiac-enriched); a specific "skeletal muscle fiber development" process is not directly demonstrated for FBXO22 and appears to be an over-propagated IBA inference. Not a core function.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (ortholog-based) assignment of nuclear localization. Concordant with the experimentally supported nuclear localization of FBXO22, where it acts on nuclear substrates such as KDM4A, methylated TP53 and BACH1. Reason: Correct compartment; redundant with the EXP nucleus annotations. FBXO22 acts on chromatin-associated/nuclear substrates. Supporting Evidence: file:human/FBXO22/FBXO22-uniprot.txt Nucleus {ECO:0000269\|PubMed:37979583, ECO:0000269\|PubMed:39223933}
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (ortholog-based) assignment of cytoplasmic localization, concordant with the experimentally supported cytoplasmic pool of FBXO22. Reason: Correct compartment; redundant with the EXP cytoplasm annotations. FBXO22 accumulates in the cytoplasm upon amino-acid depletion to ubiquitinate MTOR. Supporting Evidence: file:human/FBXO22/FBXO22-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:37979583, ECO:0000269\|PubMed:39223933}
GO:0030018 Z disc	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic localization (UniProt subcellular-location mapping) to the Z disc/sarcomere, derived from a by-similarity (ECO:0000250) sarcomere annotation. This is an inferred, non-core localization tied to the proposed sarcomeric-protein-turnover role. Reason: The sarcomere/Z-line localization in UniProt is by-similarity (ECO:0000250), not experimentally demonstrated for human FBXO22; it reflects a peripheral, tissue-specific role rather than the core nuclear/cytoplasmic SCF function. Supporting Evidence: file:human/FBXO22/FBXO22-uniprot.txt Cytoplasm, myofibril, sarcomere, Z line
GO:0005515 protein binding	IPI PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by...	KEEP AS NON CORE	Summary: High-throughput quantitative proteomics of the cullin-RING ligase network; the recorded partner is CUL1 (Q13616), the SCF scaffold FBXO22 assembles with. Bare protein binding is uninformative. Reason: Records a real and expected SCF-scaffold interaction (CUL1), but bare protein binding is uninformative per curation guidelines; the SCF-complex membership is captured by GO:0019005. Supporting Evidence: file:human/FBXO22/FBXO22-uniprot.txt Directly interacts with SKP1 and CUL1
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	KEEP AS NON CORE	Summary: High-throughput quantitative interactome (stoichiometries and abundances); the recorded partner is SKP1 (P63208), the F-box-binding SCF adaptor. Bare protein binding is uninformative. Reason: Records the expected F-box-SKP1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005.
GO:0005515 protein binding	IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex...	KEEP AS NON CORE	Summary: High-throughput affinity-purification map of the human Polycomb complexome; the recorded partner is SKP1 (P63208). Bare protein binding is uninformative. Reason: High-throughput interaction (SKP1); bare protein binding is uninformative and not a core function.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: Binary protein interactome reference map; the recorded partner is SKP1 (P63208). Bare protein binding is uninformative. Reason: High-throughput binary interactome (SKP1); bare protein binding is uninformative.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: Proteome-scale BioPlex interactome; the recorded partner is SKP1 (P63208). Bare protein binding is uninformative. Reason: High-throughput interactome (SKP1); bare protein binding is uninformative.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: Multimodal cell-map interactome study; the recorded partner is SKP1 (P63208). Bare protein binding is uninformative. Reason: High-throughput interactome (SKP1); bare protein binding is uninformative.
GO:0005634 nucleus	EXP PMID:37979583 The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination sense...	ACCEPT	Summary: Experimental evidence for nuclear localization of FBXO22, consistent with its action on nuclear substrates and its regulated nuclear/cytoplasmic partitioning. Reason: Experimentally supported localization; FBXO22 partitions between nucleus and cytoplasm, with cytoplasmic accumulation triggered by amino-acid depletion. Supporting Evidence: file:human/FBXO22/FBXO22-uniprot.txt Nucleus {ECO:0000269\|PubMed:37979583, ECO:0000269\|PubMed:39223933}
GO:0005634 nucleus	EXP PMID:39223933 E3 ubiquitin ligase FBXO22 inhibits SARS-CoV-2 replication v...	ACCEPT	Summary: Experimental evidence for nuclear localization of FBXO22 from the NSP5-degradation study. Reason: Experimentally supported localization corroborating the nucleus annotation. Supporting Evidence: file:human/FBXO22/FBXO22-uniprot.txt Nucleus {ECO:0000269\|PubMed:37979583, ECO:0000269\|PubMed:39223933}
GO:0005737 cytoplasm	EXP PMID:37979583 The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination sense...	ACCEPT	Summary: Experimental evidence for cytoplasmic localization; FBXO22 accumulates in the cytoplasm upon amino-acid depletion (GCN2/EIF2AK4-dependent Thr-127 phosphorylation) to ubiquitinate MTOR. Reason: Experimentally supported localization directly tied to the mTORC1-regulatory function. Supporting Evidence: file:human/FBXO22/FBXO22-uniprot.txt Amino acid depletion lead to a time-dependent increase of FBXO22 in the cytoplasm
GO:0005737 cytoplasm	EXP PMID:39223933 E3 ubiquitin ligase FBXO22 inhibits SARS-CoV-2 replication v...	ACCEPT	Summary: Experimental evidence for cytoplasmic localization from the NSP5-degradation study. Reason: Experimentally supported localization corroborating the cytoplasm annotation. Supporting Evidence: file:human/FBXO22/FBXO22-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:37979583, ECO:0000269\|PubMed:39223933}
GO:0019005 SCF ubiquitin ligase complex	NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso...	ACCEPT	Summary: Membership in the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, the defining macromolecular assembly for FBXO22 as an F-box substrate receptor. ComplexPortal records an SCF FBXO22 variant complex. Reason: Core component; FBXO22 is the F-box substrate receptor of an SCF complex, directly interacting with SKP1 and CUL1. Supporting Evidence: file:human/FBXO22/FBXO22-uniprot.txt Directly interacts with SKP1 and CUL1
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso...	ACCEPT	Summary: Involvement in SCF-dependent proteasomal degradation, the core biological process executed by FBXO22 as an SCF substrate receptor. Reason: Core biological process; FBXO22-containing SCF targets substrates (e.g. KDM4A, methylated TP53, BACH1) for proteasomal degradation. Supporting Evidence: file:human/FBXO22/FBXO22-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-8952618	KEEP AS NON CORE	Summary: Reactome pathway-level cytosol localization within a generic CRL1 neddylation reaction (AcM-UBE2M transfers NEDD8 to CRL1). Generic compartment annotation propagated to all CRL1 members. Reason: Cytosol is consistent with the cytoplasmic pool of FBXO22, but this is a generic CRL-machinery Reactome annotation; the more informative compartment annotations are the EXP nucleus/cytoplasm terms.
GO:0005829 cytosol	TAS Reactome:R-HSA-8952620	KEEP AS NON CORE	Summary: Reactome cytosol localization within a generic CRL1 neddylation reaction (NEDD8:AcM-UBE2M binds CRL1). Generic compartment annotation. Reason: Generic CRL-machinery Reactome localization; redundant with and less informative than the EXP compartment annotations.
GO:0005829 cytosol	TAS Reactome:R-HSA-8955241	KEEP AS NON CORE	Summary: Reactome cytosol localization within a generic CRL reaction (CAND1 binds cytosolic CRL E3 ligases). Generic compartment annotation. Reason: Generic CRL-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-8955289	KEEP AS NON CORE	Summary: Reactome cytosol localization within a generic CRL reaction (COMMDs displace CAND1 from cytosolic CRL complexes). Generic compartment annotation. Reason: Generic CRL-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-8956040	KEEP AS NON CORE	Summary: Reactome cytosol localization within a generic CRL reaction (COP9 signalosome deneddylates cytosolic CRL complexes). Generic compartment annotation. Reason: Generic CRL-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-8956200	KEEP AS NON CORE	Summary: Reactome cytosol localization within a generic CRL1 reaction (MyrG-DCUN1D3 binds CRL1). Generic compartment annotation. Reason: Generic CRL-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-983140	KEEP AS NON CORE	Summary: Reactome cytosol localization within a generic ubiquitination reaction (transfer of Ub from E2 to substrate). Generic compartment annotation. Reason: Generic ubiquitination-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-983147	KEEP AS NON CORE	Summary: Reactome cytosol localization within a generic ubiquitination reaction (release of E3 from polyubiquitinated substrate). Generic compartment annotation. Reason: Generic ubiquitination-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-983156	KEEP AS NON CORE	Summary: Reactome cytosol localization within a generic ubiquitination reaction (polyubiquitination of substrate). Generic compartment annotation. Reason: Generic ubiquitination-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-983157	KEEP AS NON CORE	Summary: Reactome cytosol localization within a generic ubiquitination reaction (interaction of E3 with substrate and E2-Ub complex). Generic compartment annotation. Reason: Generic ubiquitination-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
GO:0004842 ubiquitin-protein transferase activity	TAS PMID:10531037 A family of mammalian F-box proteins.	MODIFY	Summary: Legacy F-box-family TAS annotation of ubiquitin-protein transferase activity. As an F-box substrate receptor, FBXO22 is the substrate-specific adaptor of the SCF; the catalytic transferase activity resides in the RBX1-RING/E2 module, not in the F-box protein itself. Reason: FBXO22 is the substrate-recognition subunit of the SCF, not the catalytic transferase. The essence (participation in ubiquitin transfer) is sound, but the more accurate molecular function is the ubiquitin-like ligase-substrate adaptor activity; replace the catalytic transferase term with GO:1990756. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXO22/FBXO22-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0006511 ubiquitin-dependent protein catabolic process	TAS PMID:10531035 Identification of a family of human F-box proteins.	KEEP AS NON CORE	Summary: Legacy TAS annotation (F-box family identification paper) of involvement in ubiquitin-dependent protein catabolism. Correct but generic relative to the SCF-dependent catabolism term. Reason: Correct but a generic parent of GO:0031146 (SCF-dependent proteasomal catabolism), which more specifically captures FBXO22's role. Supporting Evidence: PMID:10531035 F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs
GO:0036211 protein modification process	TAS PMID:10531035 Identification of a family of human F-box proteins.	MARK AS OVER ANNOTATED	Summary: Legacy TAS annotation of involvement in protein modification, a very high-level parent term. Uninformative relative to the specific (poly)ubiquitination/SCF-catabolism annotations. Reason: Extremely generic parent term; the specific protein polyubiquitination and SCF-dependent catabolism annotations fully and more informatively capture FBXO22's role. Supporting Evidence: PMID:10531035 F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs

Core Functions

Substrate-recognition receptor of a SCF (SKP1-CUL1-F-box) CUL1-RING E3 ubiquitin ligase complex; binds SKP1 via its F-box motif and selects substrates via its C-terminal domain, directing their SCF-dependent polyubiquitination and proteasomal degradation.

Molecular Function:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

nucleus cytoplasm

Supporting Evidence:

file:human/FBXO22/FBXO22-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex

As the SCF(FBXO22) substrate receptor, targets the histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation, thereby regulating H3K9 and H3K36 methylation levels and, in complex with KDM4A, the abundance of methylated TP53 at late senescence.

Molecular Function:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

nucleus

Supporting Evidence:

file:human/FBXO22/FBXO22-uniprot.txt
Acts as a key regulator of histone methylation marks namely H3K9 and H3K36 methylation through the regulation of histone demethylase KDM4A protein levels

Upon amino-acid depletion, FBXO22 (after GCN2/EIF2AK4-dependent phosphorylation) accumulates in the cytoplasm and ubiquitinates MTOR at Lys2066 in a K27-linked manner, inhibiting mTORC1 substrate recruitment and linking nutrient stress to mTORC1 activity.

Molecular Function:

ubiquitin-like ligase-substrate adaptor activity

Cellular Locations:

cytoplasm

Supporting Evidence:

file:human/FBXO22/FBXO22-uniprot.txt
mediates 'Lys-27'-linked ubiquitination of MTOR and thereby inhibits substrate recruitment to mTORC1

As the SCF(FBXO22) substrate receptor, recognizes phospho- and modification-defined degrons on additional substrates (the oxidative-stress transcription factor BACH1, nuclear PTEN at Lys221, the immune-checkpoint ligand PD-L1/CD274, and the ERK-phosphorylated co-chaperone BAG3 at Ser377), directing their proteasomal degradation and thereby coupling SCF activity to oxidative-stress signaling, tumor-suppressor control, immune-checkpoint abundance, and proteostasis.

Molecular Function:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

nucleus cytoplasm

Supporting Evidence:

file:human/FBXO22/FBXO22-deep-research-falcon.md
A 2022 systems/biochemical study defined a **FBXO22-recognized phosphodegron motif** **XXPpSPXPXX** and validated **BAG3** as a bona fide FBXO22 substrate. BAG3 degradation requires **ERK-dependent phosphorylation at S377**, establishing an ERK→FBXO22→BAG3 axis linked to tumorigenesis phenotypes.
file:human/FBXO22/FBXO22-deep-research-falcon.md
FBXO22 **ubiquitylates nuclear (but not cytoplasmic) PTEN** at **lysine 221**, leading to proteasome-mediated degradation and nuclear PTEN depletion.

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

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

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10531035

Identification of a family of human F-box proteins.

FBXO22 (FBX22) was identified among a family of 26 human F-box proteins; F-box proteins are the substrate-recognition subunits of SCF ubiquitin protein ligases (together with Skp1, a cullin, and Roc1/Rbx1).

PMID:10531037

A family of mammalian F-box proteins.

F-box proteins contain a C-terminal substrate-binding domain and an F-box motif that binds Skp1, linking the F-box protein to a core ubiquitin ligase composed of Cul1, Rbx1 and an E2; the catalytic core is the cullin-RING module, not the F-box protein.

PMID:21145461

Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.

Quantitative proteomics of the cullin-RING ligase (CRL) network; a large fraction of cullins are assembled with substrate-adaptor modules. Recorded FBXO22 interaction partner is CUL1.

PMID:26496610

A human interactome in three quantitative dimensions organized by stoichiometries and abundances.

PMID:27705803

A High-Density Map for Navigating the Human Polycomb Complexome.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33961781

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

PMID:34445249

The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.

The SCF (SKP1-CUL1-F-box) complex comprises ~69 E3 ubiquitin ligases distinguished by variable F-box proteins that determine substrate specificity and modify substrates with poly-ubiquitin chains for proteasomal degradation.

PMID:37979583

The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency.

Upon amino-acid depletion, uncharged tRNAs stimulate GCN2 to phosphorylate FBXO22, which accumulates in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner, inhibiting mTORC1 by preventing substrate recruitment.

PMID:39223933

E3 ubiquitin ligase FBXO22 inhibits SARS-CoV-2 replication via promoting proteasome-dependent degradation of NSP5.

FBXO22 ubiquitinates SARS-CoV-2 NSP5 with K48-linked polyubiquitin chains at Lys5 and Lys90, promoting its proteasome-dependent degradation and restricting viral replication.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

file:human/FBXO22/FBXO22-deep-research-falcon.md

Falcon deep research report for human FBXO22

FBXO22 is the substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1/CRL1) E3 ligase; its N-terminal F-box binds SKP1 and its C-terminal FIST-C region binds substrates such as KDM4A.

"FBXO22 contains an N-terminal **F-box domain** mediating SCF assembly via SKP1, and a C-terminal **FIST/FIST-C** substrate-binding region (e.g., KDM4A binding mapped to the FBXO22 FIST-C domain)."
In ER-positive breast cancer, SCF(FBXO22) ubiquitylates and degrades KDM4B when KDM4B is complexed with tamoxifen-bound estrogen receptor, releasing steroid receptor coactivator and shaping SERM pharmacology.

"In ER-positive breast cancer models, **SCF^FBXO22^ ubiquitylates and degrades KDM4B** when KDM4B is **complexed with tamoxifen-bound ER**, which in turn **releases steroid receptor coactivator (SRC)** from ER and shapes SERM pharmacology."
FBXO22 ubiquitinates nuclear, but not cytoplasmic, PTEN at Lys221 for proteasomal degradation.

"FBXO22 **ubiquitylates nuclear (but not cytoplasmic) PTEN** at **lysine 221**, leading to proteasome-mediated degradation and nuclear PTEN depletion."
FBXO22 recognizes a phosphodegron motif XXPpSPXPXX and degrades BAG3 in an ERK-S377-phosphorylation-dependent manner, defining an ERK-FBXO22-BAG3 axis.

"A 2022 systems/biochemical study defined a **FBXO22-recognized phosphodegron motif** **XXPpSPXPXX** and validated **BAG3** as a bona fide FBXO22 substrate. BAG3 degradation requires **ERK-dependent phosphorylation at S377**, establishing an ERK→FBXO22→BAG3 axis linked to tumorigenesis phenotypes."
FBXO22 is a recruitable E3 ligase for targeted protein degradation; an aldehyde metabolite of alkylamine-tethered degraders covalently adducts Cys326 in its C-terminal domain to drive ternary-complex formation and degradation.

"Alkylamine-tethered degraders can be metabolized to an **active aldehyde** that **covalently adduces Cys326** in the FBXO22 C-terminal domain."

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(FBXO22) ubiquitination in vitro with purified SKP1-CUL1-RBX1, an E2, and candidate substrates to confirm direct, adaptor-dependent substrate selection and to map lysine sites and chain linkages for each substrate.

Experiment: Perform quantitative ubiquitinome and proteome profiling in FBXO22-knockout versus wild-type cells under basal, amino-acid-starved, and oxidative-stress conditions to define the endogenous, context-dependent FBXO22 substrate repertoire.

Experiment: Dissect the regulated nuclear/cytoplasmic partitioning of FBXO22 by mutating the EIF2AK4/GCN2 phosphosite (Thr-127) and quantifying the effect on substrate-specific degradation (e.g. nuclear KDM4A vs cytoplasmic MTOR).

Deep Research

Falcon

(FBXO22-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 32 citations 2 artifacts 2026-06-13T06:40:09.723852

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000022 The requested Figure 4 panels and legend have been extracted. Specifically: - Panel B shows the interaction between FBXO22 and pS24 (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 FBXO22 (UniProt Q8NEZ5) — functional annotation, mechanisms, and applications

0) Target identity verification (mandatory)

FBXO22 (F-box only protein 22; UniProt Q8NEZ5) is consistently described in the primary literature as an F-box substrate-receptor that assembles with SKP1–CUL1–RBX1 (ROC1) to form an SCF (CRL1) E3 ubiquitin ligase. SCF composition and FBXO22’s role as the substrate-recognition subunit are explicitly stated in mechanistic and review sources, matching the UniProt description. (johmura2020fbxo22anepigenetic pages 1-2, tan2011scffbxo22regulateshistone pages 4-5, cheng2020emergingroleof pages 1-2)

Domain/function mapping in experimental work aligns with UniProt’s F-box and FIST_C annotations: FBXO22 contains an N-terminal F-box domain mediating SCF assembly via SKP1, and a C-terminal FIST/FIST-C substrate-binding region (e.g., KDM4A binding mapped to the FBXO22 FIST-C domain). (tan2011scffbxo22regulateshistone pages 4-5)

1) Key concepts and definitions (current understanding)

1.1 SCF E3 ubiquitin ligases and F-box proteins

SCF (SKP1–CUL1–RBX1–F-box) complexes are Cullin–RING E3 ligases in which F-box proteins select substrates for ubiquitination. FBXO22 is an “FBXO” class F-box protein that specifies substrate selection for a particular SCF complex (SCF^FBXO22^). (cheng2020emergingroleof pages 1-2, johmura2020fbxo22anepigenetic pages 1-2)

1.2 What FBXO22 “does” at the molecular level

Across studies, FBXO22’s primary biochemical function is best defined as:
- Substrate recognition (often phosphorylation- or modification-dependent) and recruitment to SCF,
- followed by ubiquitination that can lead to proteasomal degradation (frequently K48-linked) or sometimes altered function depending on ubiquitin linkage/context.

A canonical example is KDM4A turnover: KDM4A requires K48-linked ubiquitin for normal turnover and displays a ~2 h half-life, extended to ~5 h upon proteasome inhibition (MG132), consistent with FBXO22-driven proteasomal control. (tan2011scffbxo22regulateshistone pages 4-5)

2) Core functional annotation of FBXO22: mechanisms, substrates, pathways, and localization

2.1 SCF complex assembly and subcellular distribution

FBXO22 forms an SCF complex with SKP1 and CUL1; this is supported by proteomics and co-immunoprecipitation experiments recovering SKP1/CUL1 with FBXO22 or FBXO22-associated substrate complexes. (tan2011scffbxo22regulateshistone pages 4-5, li2024fbxo22inhibitscolitis pages 5-6)

Cell fractionation studies (HeLa) indicate KDM4A is nuclear, while FBXO22 is primarily cytoplasmic with detectable nuclear presence, supporting the idea that FBXO22 can regulate both cytoplasmic and nuclear targets depending on context and substrate access. (tan2011scffbxo22regulateshistone pages 4-5)

2.2 Established substrate mechanisms (selected high-confidence examples)

(A) Epigenetic regulators: KDM4A and KDM4B

KDM4A (histone demethylase)
- FBXO22 associates with KDM4A and SCF components and promotes K48-dependent ubiquitin–proteasome degradation of KDM4A. (tan2011scffbxo22regulateshistone pages 4-5)
- Binding is mediated by the FBXO22 FIST-C domain to the KDM4A catalytic JmjN/JmjC region, linking FBXO22 domain architecture to substrate selection. (tan2011scffbxo22regulateshistone pages 4-5)

KDM4B (histone demethylase) and endocrine response
- In ER-positive breast cancer models, SCF^FBXO22^ ubiquitylates and degrades KDM4B when KDM4B is complexed with tamoxifen-bound ER, which in turn releases steroid receptor coactivator (SRC) from ER and shapes SERM pharmacology. (johmura2018fbxo22mediatedkdm4bdegradation pages 1-2)
- Proteasome inhibition (MG132) interferes with these tamoxifen-driven cofactor dynamics and maintains expression of ER target transcripts (e.g., GREB1/EBAG9 kinetics described). (johmura2018fbxo22mediatedkdm4bdegradation pages 1-2)

(B) p53 network and senescence control

FBXO22 is transcriptionally induced in a p53-dependent manner in senescence settings, and SCF^FBXO22^-KDM4A targets methylated p53 for degradation as part of a negative-feedback loop needed for late senescence programs (including p16 and SASP regulation). (johmura2016scffbxo22kdm4atargetsmethylated pages 1-2, johmura2020fbxo22anepigenetic pages 1-2)

(C) Nuclear tumor suppressor PTEN

A key compartment-specific mechanism is nuclear PTEN degradation:
- FBXO22 ubiquitylates nuclear (but not cytoplasmic) PTEN at lysine 221, leading to proteasome-mediated degradation and nuclear PTEN depletion. (ge2020fbxo22degradesnuclear pages 1-2)
- Proteasome inhibitors (MG132; bortezomib) preferentially accumulate nuclear PTEN in tested systems, supporting a proteasome-dependent regulatory axis. (ge2020fbxo22degradesnuclear pages 1-2)

(D) Immune checkpoint regulation: PD-L1

In NSCLC cells, FBXO22 promotes PD-L1 ubiquitination and degradation, increasing sensitivity to DNA-damaging therapies (ionizing radiation and cisplatin). (de2021theubiquitine3 pages 1-2)

Upstream regulation in this context includes CDK5, reported to regulate FBXO22 such that inhibiting or reducing CDK5 increases FBXO22, decreases PD-L1, and sensitizes to DNA damage—providing a mechanistic rationale for combination strategies. (de2021theubiquitine3 pages 1-2)

(E) Phosphodegron logic and the ERK–FBXO22–BAG3 axis

A 2022 systems/biochemical study defined a FBXO22-recognized phosphodegron motif XXPpSPXPXX and validated BAG3 as a bona fide FBXO22 substrate. BAG3 degradation requires ERK-dependent phosphorylation at S377, establishing an ERK→FBXO22→BAG3 axis linked to tumorigenesis phenotypes. (liu2022globalidentificationof pages 1-2)

(F) 2024 advance: phospho-specific degradation of pS2448-mTOR in colitis/CRC

A major 2024 development is identification of a phospho-state selective mTOR mechanism:
- FBXO22 targets the S2448-phosphorylated form of mTOR (pS2448-mTOR) for ubiquitination and proteasomal degradation, supported by co-IP/colocalization and phosphopeptide binding/competition assays. (li2024fbxo22inhibitscolitis pages 5-6)
- A biotinylated phosphopeptide (BT-PS2448) binds FBXO22 more effectively than the unphosphorylated peptide (BT-S2448), and BT-PS2448 competes with endogenous pS2448-mTOR for FBXO22 binding—evidence for phospho-specific recognition. (li2024fbxo22inhibitscolitis pages 5-6, li2024fbxo22inhibitscolitis media c1302dda)
- Statistical testing is explicitly indicated for multiple immunoblot quantifications (P < 0.05, P < 0.01, **P < 0.001). (li2024fbxo22inhibitscolitis pages 5-6)

Visual evidence: cropped Figure 4 panels supporting the phospho-specific FBXO22–pS2448-mTOR interaction and peptide competition are available. (li2024fbxo22inhibitscolitis media c1302dda)

3) Recent developments and latest research (prioritizing 2023–2024)

3.1 FBXO22 as a recruitable E3 ligase for targeted protein degradation (TPD)

Two complementary 2024 lines of work position FBXO22 as an “actionable” E3 ligase beyond CRBN/VHL:

(i) Covalent recruitment via Cys326 (Nature Communications, 18 Jun 2024; accepted 18 June 2024)
- Alkylamine-tethered degraders can be metabolized to an active aldehyde that covalently adduces Cys326 in the FBXO22 C-terminal domain.
- This Cys326 engagement is described as critical for ternary complex formation, ubiquitylation and degradation, establishing a generalizable strategy for hijacking SCF^FBXO22^. (kagiou2024alkylaminetetheredmoleculesrecruit pages 1-2)

(ii) CRISPR activation screen identifies FBXO22 as enabling PROTAC-like degradation (bioRxiv 15 Sep 2023; Nature Chemical Biology Jul 2024)
- A pooled CRISPRa screen used 3,520 sgRNAs targeting 680 E3 ligases (5 sgRNAs/gene) and identified FBXO22 as enabling FKBP12 degradation by a heterobifunctional electrophilic compound. (basu2023acrispractivation pages 3-5)
- Mechanistic dependencies: degradation was rescued by MG132 (proteasome), MLN4924 (cullin neddylation/CRL activity), and competition with the FKBP12 ligand (SLF), and was rapid (near complete within ~2 h). (basu2023acrispractivation pages 3-5)

Together these studies represent a 2023–2024 shift in viewing FBXO22 not only as a cancer-/stress-related E3 adaptor but also as a drug-development handle for induced proximity/TPD. (kagiou2024alkylaminetetheredmoleculesrecruit pages 1-2, basu2023acrispractivation pages 3-5)

3.2 Human genetics: FBXO22 deficiency syndrome (2024 preprint)

A 2024 medRxiv report proposes that biallelic loss-of-function FBXO22 variants cause a pleiotropic developmental syndrome (growth restriction, neurodevelopmental delay, multisystem anomalies). Patient-derived fibroblasts lacked FBXO22 protein and showed increased KDM4B, consistent with KDM4B as an FBXO22 substrate and supporting a chromatin-centered pathogenesis model. (ramakrishna2024fbxo22deficiencydefines pages 1-4)

This genetics report is also reflected in curated disease-target associations (OpenTargets) for neurodevelopmental phenotypes including a named syndrome association in their output. (OpenTargets Search: -FBXO22)

4) Current applications and real-world implementations

4.1 Biomarkers and therapy response: ER+ breast cancer endocrine treatment

FBXO22 is implicated as a determinant of tamoxifen/SERM response through KDM4B degradation dynamics. The JCI 2018 study reports clinical associations where low FBXO22 in tumors predicts poorer outcome in ER-positive/HER2-negative breast cancer, independent of some established markers. (johmura2018fbxo22mediatedkdm4bdegradation pages 1-2)

The same paper provides clinically relevant context statistics for endocrine therapy: ~70% of breast cancers are ER-positive, and up to 25% of early-stage tamoxifen-treated patients relapse within 15 years, emphasizing the clinical need for stratification/alternative strategies. (johmura2018fbxo22mediatedkdm4bdegradation pages 1-2)

4.2 Immuno-oncology and DNA damage therapy sensitization (NSCLC)

FBXO22-driven PD-L1 degradation suggests a therapeutic logic where increasing FBXO22 activity (or indirectly increasing FBXO22 via CDK5 inhibition) could lower PD-L1 and sensitize to DNA-damaging therapy, potentially complementing immune checkpoint blockade. (de2021theubiquitine3 pages 1-2)

4.3 Inflammation/CRC axis: pS2448-mTOR degradation

In a 2024 PNAS study, FBXO22 is positioned as protective in intestinal injury/CRC contexts by degrading pS2448-mTOR, a key node in mTOR signaling. Mechanistically anchored phospho-specific recognition (peptide competition; S2448A mutant weakening binding) provides a tractable substrate-state mechanism that could inform pathway-level interventions or biomarker development around phospho-mTOR states. (li2024fbxo22inhibitscolitis pages 5-6, li2024fbxo22inhibitscolitis media c1302dda)

4.4 Targeted protein degradation R&D

FBXO22 is now a demonstrated TPD-recruitable E3 via covalent chemistry (aldehyde/Cys326) and via genetic screens that nominate it as a functional ligase for induced degradation—an application area with immediate translational interest in oncology and beyond. (kagiou2024alkylaminetetheredmoleculesrecruit pages 1-2, basu2023acrispractivation pages 3-5)

5) Expert opinions and authoritative synthesis

Two reviews consolidate FBXO22 as a multi-context regulator in cancer-related biology:
- A focused review characterizes FBXO22 as coordinating senescence, hormone signaling, and metastasis through defined substrates (methylated p53; KDM4B; Bach1) and frames FBXO22 as an “epigenetic multiplayer” in cancer biology. (Johmura et al., July 2020; https://doi.org/10.1111/cas.14534) (johmura2020fbxo22anepigenetic pages 1-2)
- A broader review summarizes reported FBXO22 substrates spanning cell cycle regulators and tumor suppressors and emphasizes upstream regulation (e.g., p53, miR-155 and other ncRNAs), highlighting context-dependent oncogenic vs metastasis-suppressive roles. (Cheng et al., July 2020; https://doi.org/10.1038/s41420-020-00303-0) (cheng2020emergingroleof pages 2-3, cheng2020emergingroleof pages 1-2)

6) Statistics and quantitative data highlights (from recent and key studies)

KDM4A turnover: half-life ~2 h, extended to ~5 h with MG132; K48 ubiquitin requirement demonstrated by ubiquitin replacement experiments. (Tan et al., 2011; https://doi.org/10.1128/mcb.05746-11) (tan2011scffbxo22regulateshistone pages 4-5)
Tamoxifen clinical context: ~70% of breast cancers are ER-positive; up to 25% of early-stage tamoxifen-treated patients relapse within 15 years. (Johmura et al., 2018; https://doi.org/10.1172/JCI121679) (johmura2018fbxo22mediatedkdm4bdegradation pages 1-2)
CRISPRa TPD screen scale: 3,520 sgRNAs targeting 680 E3 ligases; FKBP12 degradation nearly complete within ~2 h and dependent on proteasome and CRL activity (MG132; MLN4924 rescue). (Basu et al., 2023 preprint; https://doi.org/10.1101/2023.09.15.557708) (basu2023acrispractivation pages 3-5)
pS2448-mTOR degradation assays: repeated quantifications with explicit significance thresholds (P < 0.05, P < 0.01, **P < 0.001). (Li et al., 2024; https://doi.org/10.1073/pnas.2402035121) (li2024fbxo22inhibitscolitis pages 5-6)

7) Consolidated evidence map (substrates, mechanisms, contexts)

The table below compiles the most directly evidenced substrates/partners, their ubiquitin outcomes, recognition logic, cellular context, and application relevance.

Substrate/Binding partner	Modification/outcome	Upstream signal/recognition motif	Cellular compartment/context	Key phenotypic consequence/application	Key source with year + URL
KDM4A	SCF^FBXO22^-dependent ubiquitin-proteasome turnover; requires K48-linked ubiquitin; KDM4A half-life ~2 h, extended to ~5 h with MG132	FBXO22 C-terminal FIST-C binds KDM4A catalytic JmjN/JmjC region	KDM4A nuclear; FBXO22 mainly cytoplasmic with some nuclear presence; chromatin/histone methylation context	Regulates histone H3K9/H3K36 methylation states through demethylase abundance control (tan2011scffbxo22regulateshistone pages 4-5)	Tan 2011 — https://doi.org/10.1128/mcb.05746-11 (tan2011scffbxo22regulateshistone pages 4-5)
Methylated p53 (with KDM4A complex)	Ubiquitylation and degradation by SCF^FBXO22^-KDM4A	p53-dependent induction of FBXO22 during late senescence; substrate is methylated p53	Senescent cells; late senescence program	Required for p16 induction and SASP; Fbxo22 loss causes p53 accumulation and reduced body size in mice (johmura2020fbxo22anepigenetic pages 1-2, johmura2016scffbxo22kdm4atargetsmethylated pages 1-2)	Johmura 2016 — https://doi.org/10.1038/ncomms10574 (johmura2016scffbxo22kdm4atargetsmethylated pages 1-2)
KDM4B (complexed with tamoxifen-bound ER)	SCF^FBXO22^-mediated ubiquitylation and degradation; releases SRC from ER	Tamoxifen/4-OHT-bound ER; proteasome sensitive (MG132 blocks cofactor dynamics)	ER-positive/HER2-negative breast cancer; ER enhancers/promoters	Determines SERM antagonism; tamoxifen failed to suppress growth when FBXO22 was depleted; ~70% of breast cancers are ER+, and up to 25% of early-stage tamoxifen-treated patients relapse within 15 years (johmura2018fbxo22mediatedkdm4bdegradation pages 1-2)	Johmura 2018 — https://doi.org/10.1172/JCI121679 (johmura2018fbxo22mediatedkdm4bdegradation pages 1-2)
PD-L1	Ubiquitination and proteasomal degradation	FBXO22 activation by phosphorylation; CDK5 inhibition increases FBXO22 and lowers PD-L1	NSCLC	Sensitizes cancer cells to ionizing radiation and cisplatin; supports rationale for combining CDK5 inhibition with checkpoint/DNA-damage therapy (de2021theubiquitine3 pages 1-2)	De 2021 — https://doi.org/10.1073/pnas.2112674118 (de2021theubiquitine3 pages 1-2)
Nuclear PTEN	Ubiquitylation of nuclear PTEN at Lys221 and proteasomal degradation; selective for nuclear, not cytoplasmic PTEN	Nuclear PTEN instability; accumulation with MG132/Bortezomib	Nucleus; colorectal cancer and other cancers	Nuclear PTEN downregulation promotes tumorigenesis; suggests strategy to reactivate nuclear PTEN by blocking FBXO22 axis (ge2020fbxo22degradesnuclear pages 1-2)	Ge 2020 — https://doi.org/10.1038/s41467-020-15578-1 (ge2020fbxo22degradesnuclear pages 1-2)
BAG3	Ubiquitination and degradation by SCF^FBXO22^	ERK-dependent phosphorylation at S377; FBXO22-recognized phosphodegron motif XXPpSPXPXX	Tumorigenesis context; apoptosis/cell-cycle regulation	FBXO22 depletion or stable BAG3 S377A mutant promotes tumor growth in vitro and in vivo; defines ERK-FBXO22-BAG3 axis (liu2022globalidentificationof pages 1-2)	Liu 2022 — https://doi.org/10.1038/s41418-021-00827-7 (liu2022globalidentificationof pages 1-2)
pS2448-mTOR	Ubiquitination and proteasomal degradation of the S2448-phosphorylated form of mTOR	Phospho-specific recognition of pS2448; BT-PS2448 peptide binds FBXO22 better than non-phospho peptide; S2448A weakens interaction; AKT activity supports pS2448 state	Colon epithelium; HCT116/MC38 cells; colitis/colorectal carcinogenesis	FBXO22 restrains colitis and CRC-associated signaling by lowering pS2448-mTOR; effects supported by co-IP, colocalization, and peptide competition assays (li2024fbxo22inhibitscolitis pages 5-6, li2024fbxo22inhibitscolitis media c1302dda)	Li 2024 — https://doi.org/10.1073/pnas.2402035121 (li2024fbxo22inhibitscolitis pages 5-6, li2024fbxo22inhibitscolitis media c1302dda)
Cys326 in FBXO22 C-terminal domain (ligase recruitment site)	Covalent adduction by aldehyde metabolite enables ternary complex formation, ubiquitylation, and degradation of recruited targets	Alkylamine-tethered degraders metabolized to active aldehyde; Cys326 is critical	Targeted protein degradation (TPD) chemical biology	Establishes FBXO22 as a druggable E3 for TPD; demonstrated with FKBP12 and noted as a generalizable strategy for alkylamine-based degraders (kagiou2024alkylaminetetheredmoleculesrecruit pages 1-2)	Kagiou 2024 — https://doi.org/10.1038/s41467-024-49739-3 (kagiou2024alkylaminetetheredmoleculesrecruit pages 1-2)
FKBP12 (neo-substrate in degrader system) via FBXO22	PROTAC/molecular glue-like FBXO22-dependent degradation; proteasome-, CRL-, and target-binding dependent	CRISPRa screen with 3,520 sgRNAs targeting 680 E3 ligases identified FBXO22; 22-SLF hit; rescued by MG132, MLN4924, and SLF; nearly complete degradation within ~2 h	Engineered TPD reporter systems	Demonstrates FBXO22 can support induced degradation of multiple neo-substrates and expands E3 ligase toolbox for TPD (basu2023acrispractivation pages 3-5)	Basu 2023/2024 — https://doi.org/10.1101/2023.09.15.557708 ; https://doi.org/10.1038/s41589-024-01655-9 (basu2023acrispractivation pages 3-5, basu2024acrispractivation pages 1-6)
FBXO22 loss-of-function / KDM4B accumulation	Loss of FBXO22 protein in patient fibroblasts leads to increased known substrate KDM4B	Homozygous frameshift LOF variants p.(Arg53Serfs13), p.(Pro3Leufs3), p.(Val240Alafs*6)	Human developmental disorder; peripheral blood epigenetic signature; patient fibroblasts	Defines FBXO22 deficiency syndrome with prenatal-onset growth restriction, neurodevelopmental delay, and multisystem anomalies across 14 cases from 12 families (ramakrishna2024fbxo22deficiencydefines pages 1-4, OpenTargets Search: -FBXO22)	Ramakrishna 2024 — https://doi.org/10.1101/2024.09.28.24314530 (ramakrishna2024fbxo22deficiencydefines pages 1-4, OpenTargets Search: -FBXO22)

Table: This table summarizes experimentally supported human FBXO22 functions, substrates, recognition mechanisms, and disease or translational implications. It is useful as a compact evidence map linking molecular biochemistry to cellular context and emerging therapeutic applications.

8) Curated disease-target associations (database support; interpret cautiously)

OpenTargets reports disease associations for FBXO22 including neurodevelopmental disorder and Tayoun-Maawali syndrome (and others in their list). These associations help prioritize phenotypic domains but should be traced to primary evidence for mechanism. (OpenTargets Search: -FBXO22)

9) Conclusions and functional annotation summary

FBXO22 (Q8NEZ5) is best annotated as a substrate receptor of SCF (CRL1) ubiquitin ligases that:
1) recognizes specific substrates—often via post-translational marks (methylation; phosphorylation-defined degrons; phospho-state-specific sites such as pS2448-mTOR),
2) mediates ubiquitination leading frequently to proteasomal degradation, and
3) thereby regulates key pathways spanning chromatin/epigenetic control (KDM4A/KDM4B), senescence feedback (methylated p53), immune checkpoint abundance (PD-L1), compartment-specific tumor suppression (nuclear PTEN), stress/tumorigenesis (ERK–BAG3), and intestinal injury/CRC signaling (pS2448-mTOR). (tan2011scffbxo22regulateshistone pages 4-5, johmura2016scffbxo22kdm4atargetsmethylated pages 1-2, johmura2018fbxo22mediatedkdm4bdegradation pages 1-2, de2021theubiquitine3 pages 1-2, ge2020fbxo22degradesnuclear pages 1-2, liu2022globalidentificationof pages 1-2, li2024fbxo22inhibitscolitis pages 5-6)

Recent 2024 research substantially expands FBXO22’s translational relevance by (i) identifying pS2448-mTOR as a phospho-state selective substrate in colitis/CRC biology and (ii) establishing covalent hijacking of FBXO22 (Cys326) as a generalizable targeted protein degradation strategy. (li2024fbxo22inhibitscolitis pages 5-6, kagiou2024alkylaminetetheredmoleculesrecruit pages 1-2)

References

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Artifacts

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Citations

liu2022globalidentificationof pages 1-2
kagiou2024alkylaminetetheredmoleculesrecruit pages 1-2
basu2023acrispractivation pages 3-5
cheng2020emergingroleof pages 1-2
cheng2020emergingroleof pages 2-3
basu2024acrispractivation pages 1-6
https://doi.org/10.1111/cas.14534
https://doi.org/10.1038/s41420-020-00303-0
https://doi.org/10.1128/mcb.05746-11
https://doi.org/10.1172/JCI121679
https://doi.org/10.1101/2023.09.15.557708
https://doi.org/10.1073/pnas.2402035121
https://doi.org/10.1038/ncomms10574
https://doi.org/10.1073/pnas.2112674118
https://doi.org/10.1038/s41467-020-15578-1
https://doi.org/10.1038/s41418-021-00827-7
https://doi.org/10.1038/s41467-024-49739-3
https://doi.org/10.1038/s41589-024-01655-9
https://doi.org/10.1101/2024.09.28.24314530
https://doi.org/10.1111/cas.14534,
https://doi.org/10.1128/mcb.05746-11,
https://doi.org/10.1038/s41420-020-00303-0,
https://doi.org/10.1073/pnas.2402035121,
https://doi.org/10.1172/jci121679,
https://doi.org/10.1038/ncomms10574,
https://doi.org/10.1038/s41467-020-15578-1,
https://doi.org/10.1073/pnas.2112674118,
https://doi.org/10.1038/s41418-021-00827-7,
https://doi.org/10.1038/s41467-024-49739-3,
https://doi.org/10.1101/2023.09.15.557708,
https://doi.org/10.1101/2024.09.28.24314530,
https://doi.org/10.1038/s41589-024-01655-9,

📚 Additional Documentation

Pn Notes

(FBXO22-pn-notes.md)

FBXO22 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q8NEZ5
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FBXO22/FBXO22-ai-review.yaml
AIGR review HTML: missing - genes/human/FBXO22/FBXO22-ai-review.html
Gene notes: missing - genes/human/FBXO22/FBXO22-notes.md
GOA TSV: present - genes/human/FBXO22/FBXO22-goa.tsv
UniProt record: present - genes/human/FBXO22/FBXO22-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FBXO22.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FBXO22.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/FBXO22/FBXO22-deep-research-falcon.md

AIGR Review Snapshot

Description: FBXO22 (F-box only protein 22, FBX22p44) is a 403-residue F-box protein that serves as the substrate-recognition receptor of a SCF (SKP1-CUL1-F-box)-type CUL1-RING E3 ubiquitin ligase complex. It binds the SCF core through an N-terminal F-box motif (residues ~21-67) that docks onto SKP1, while a C-terminal FIST-C/substrate-binding region engages target proteins; in the assembled SCF, the catalytic RING subunit RBX1 recruits the ubiquitin-charged E2, so FBXO22 itself contributes substrate selection rather than catalysis. Through this adaptor role FBXO22 directs polyubiquitination and proteasomal degradation of a defined set of substrates and thereby influences chromatin/transcriptional regulation, the DNA-damage and senescence response, oxidative-stress signaling, nutrient sensing, immune-checkpoint control, and antiviral defense. Documented substrates include the histone demethylases KDM4A/JMJD2A (controlling H3K9 and H3K36 methylation) and KDM4B (when KDM4B is complexed with tamoxifen-bound estrogen receptor, governing selective-estrogen-receptor- modulator pharmacology in breast cancer), methylated TP53 (in complex with KDM4A, at late senescence), the transcription factor BACH1 (upon oxidative-stress-induced exposure of its degron), nuclear (but not cytoplasmic) PTEN (ubiquitinated at Lys221), the immune-checkpoint ligand PD-L1 (CD274; degradation sensitizes cells to DNA-damaging therapy), the co-chaperone BAG3 (via an ERK-dependent phosphodegron, S377), the kinase MTOR (both K27-linked ubiquitination at Lys2066 upon amino-acid depletion to inhibit mTORC1, and degradation of the Ser2448-phosphorylated form), the transcription factor KLF4, and sarcomeric proteins; it also degrades the SARS-CoV-2 3C-like proteinase NSP5 via K48-linked chains to restrict viral replication. Many of these recognition events are post-translational-mark dependent (methylation marks, or phosphodegrons such as ERK-phosphorylated S377 of BAG3), consistent with a C-terminal substrate-binding region that reads modified degrons. A surface cysteine (Cys326) in the C-terminal domain can be covalently engaged by small molecules, making FBXO22 a recruitable E3 for targeted protein degradation. FBXO22 is broadly expressed with enrichment in liver and cardiac muscle and localizes to both the cytoplasm and nucleus, with its subcellular distribution modulated by EIF2AK4/GCN2-dependent phosphorylation at Thr-127. Biallelic loss-of-function causes Tayoun-Maawali syndrome (TYMAS), an autosomal-recessive multisystem developmental disorder.
Existing/core annotation action counts: ACCEPT: 10; KEEP_AS_NON_CORE: 18; MARK_AS_OVER_ANNOTATED: 2; MODIFY: 1

PN Consistency Summary

Consistency: Strong. Deep research (Falcon), UniProt, GOA, and review YAML all agree FBXO22 is the SCF/CRL1 substrate receptor (substrates KDM4A/B, methylated TP53, BACH1, nuclear PTEN K221, PD-L1, BAG3, MTOR, NSP5). Review MODIFY of GO:0004842 (TAS transferase) → GO:1990756 exactly matches the PN group target. No contradictions.
PN story / NEW pressure: PN asserts only the generic adaptor role, already captured by the review (core_function MF = GO:1990756, verified real, def. "Usually mediated by F-box…proteins"). The rich substrate biology vastly exceeds GOA but the review correctly declines substrate-specific NEW terms (proposed_new_terms empty). Conclusion: PN adaptor claim ALREADY CAPTURED; substrate detail belongs in core_functions, not new GO.
Evidence alignment: PN cites only "15340381 / rev" (PMID:15340381, an F-box family review; not in this review's reference list). Review is anchored on substrate-specific primary papers (PMID:37979583 MTOR, PMID:39223933 NSP5) plus founding F-box papers (PMID:10531035/10531037) and PMID:34445249. Divergence: PN's single review reference is thinner than and disjoint from the review's evidence base, but both support the same adaptor framing.
Verdict: CONSISTENT — no changes needed. Exemplary application of the F-box adaptor pattern.

Full Consistency Review

UniProt: Q8NEZ5 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE (well-developed; ~30 annotations reviewed)
PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|other ; PN-node mapping: group=mapped, scope=ok_for_propagation_to_go, GO:1990756 (ubiquitin-like ligase-substrate adaptor activity); subtype/type/branch=no_mapping; class=context_only (GO:0061630, too_broad).
Consistency: Strong. Deep research (Falcon), UniProt, GOA, and review YAML all agree FBXO22 is the SCF/CRL1 substrate receptor (substrates KDM4A/B, methylated TP53, BACH1, nuclear PTEN K221, PD-L1, BAG3, MTOR, NSP5). Review MODIFY of GO:0004842 (TAS transferase) → GO:1990756 exactly matches the PN group target. No contradictions.
PN story / NEW pressure: PN asserts only the generic adaptor role, already captured by the review (core_function MF = GO:1990756, verified real, def. "Usually mediated by F-box…proteins"). The rich substrate biology vastly exceeds GOA but the review correctly declines substrate-specific NEW terms (proposed_new_terms empty). Conclusion: PN adaptor claim ALREADY CAPTURED; substrate detail belongs in core_functions, not new GO.
Mapping strategy: Correct. This gene does not change the node; it is the canonical exemplar of the MODIFY-catalytic-MF→GO:1990756 pattern. GO:1990756 is neither broader nor narrower than the review's chosen core MF — they are identical. Class-level GO:0061630 correctly held as context_only/too_broad.
Evidence alignment: PN cites only "15340381 / rev" (PMID:15340381, an F-box family review; not in this review's reference list). Review is anchored on substrate-specific primary papers (PMID:37979583 MTOR, PMID:39223933 NSP5) plus founding F-box papers (PMID:10531035/10531037) and PMID:34445249. Divergence: PN's single review reference is thinner than and disjoint from the review's evidence base, but both support the same adaptor framing.
Verdict: CONSISTENT — no changes needed. Exemplary application of the F-box adaptor pattern.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/FBXO22/FBXO22-ai-review.yaml
PN workbook rows: 1

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

UniProt: Q8NEZ5
In branches: UPS
Signature domains: IPR001810
Auxiliary domains: (none)
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|other
  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: Q8NEZ5
gene_symbol: FBXO22
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXO22 (F-box only protein 22, FBX22p44) is a 403-residue F-box protein that
  serves as the substrate-recognition receptor of a SCF (SKP1-CUL1-F-box)-type
  CUL1-RING E3 ubiquitin ligase complex. It binds the SCF core through an
  N-terminal F-box motif (residues ~21-67) that docks onto SKP1, while a
  C-terminal FIST-C/substrate-binding region engages target proteins; in the
  assembled SCF, the catalytic RING subunit RBX1 recruits the
  ubiquitin-charged E2, so FBXO22 itself contributes substrate selection
  rather than catalysis. Through this adaptor role FBXO22 directs
  polyubiquitination and proteasomal degradation of a defined set of
  substrates and thereby influences chromatin/transcriptional regulation, the
  DNA-damage and senescence response, oxidative-stress signaling, nutrient
  sensing, immune-checkpoint control, and antiviral defense. Documented
  substrates include the histone demethylases KDM4A/JMJD2A (controlling H3K9
  and H3K36 methylation) and KDM4B (when KDM4B is complexed with
  tamoxifen-bound estrogen receptor, governing selective-estrogen-receptor-
  modulator pharmacology in breast cancer), methylated TP53 (in complex with
  KDM4A, at late senescence), the transcription factor BACH1 (upon
  oxidative-stress-induced exposure of its degron), nuclear (but not
  cytoplasmic) PTEN (ubiquitinated at Lys221), the immune-checkpoint ligand
  PD-L1 (CD274; degradation sensitizes cells to DNA-damaging therapy), the
  co-chaperone BAG3 (via an ERK-dependent phosphodegron, S377), the kinase MTOR
  (both K27-linked ubiquitination at Lys2066 upon amino-acid depletion to
  inhibit mTORC1, and degradation of the Ser2448-phosphorylated form), the
  transcription factor KLF4, and sarcomeric proteins; it also degrades the
  SARS-CoV-2 3C-like proteinase NSP5 via K48-linked chains to restrict viral
  replication. Many of these recognition events are post-translational-mark
  dependent (methylation marks, or phosphodegrons such as ERK-phosphorylated
  S377 of BAG3), consistent with a C-terminal substrate-binding region that
  reads modified degrons. A surface cysteine (Cys326) in the C-terminal domain
  can be covalently engaged by small molecules, making FBXO22 a recruitable E3
  for targeted protein degradation. FBXO22 is broadly expressed with enrichment
  in liver and cardiac muscle and localizes to both the cytoplasm and nucleus,
  with its subcellular distribution modulated by EIF2AK4/GCN2-dependent
  phosphorylation at Thr-127. Biallelic loss-of-function causes Tayoun-Maawali
  syndrome (TYMAS), an autosomal-recessive multisystem developmental disorder.
existing_annotations:
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of involvement in protein polyubiquitination, consistent with FBXO22's role as the substrate-recognition subunit of an SCF E3 ligase that directs polyubiquitination of substrates.
    action: ACCEPT
    reason: Core biological role; FBXO22 mediates polyubiquitination of substrates such as KDM4A, KDM4B, methylated TP53, BACH1, nuclear PTEN, PD-L1, BAG3, MTOR and NSP5 through the SCF complex.
    supported_by:
    - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
    - reference_id: file:human/FBXO22/FBXO22-deep-research-falcon.md
      supporting_text: FBXO22 contains an N-terminal **F-box domain** mediating SCF assembly via SKP1, and a C-terminal **FIST/FIST-C** substrate-binding region (e.g., KDM4A binding mapped to the FBXO22 FIST-C domain).
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic
      process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of a positive regulatory role in proteasomal ubiquitin-dependent catabolism, consistent with FBXO22 promoting proteasomal degradation of its substrates.
    action: ACCEPT
    reason: Supported by multiple experimental studies in which FBXO22 promotes proteasome-dependent degradation of substrates (e.g. KDM4A, NSP5).
    supported_by:
    - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
      supporting_text: Promotes the proteasome-dependent degradation of key sarcomeric proteins
- term:
    id: GO:0048742
    label: regulation of skeletal muscle fiber development
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of a role in skeletal muscle fiber development. FBXO22 is enriched in cardiac muscle and is reported to regulate sarcomeric protein turnover, but a specific role in skeletal muscle fiber development is thinly supported and likely propagated from family/ortholog context.
    action: MARK_AS_OVER_ANNOTATED
    reason: FBXO22's documented muscle link is regulation of sarcomeric protein turnover (cardiac-enriched); a specific "skeletal muscle fiber development" process is not directly demonstrated for FBXO22 and appears to be an over-propagated IBA inference. Not a core function.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic (ortholog-based) assignment of nuclear localization. Concordant with the experimentally supported nuclear localization of FBXO22, where it acts on nuclear substrates such as KDM4A, methylated TP53 and BACH1.
    action: ACCEPT
    reason: Correct compartment; redundant with the EXP nucleus annotations. FBXO22 acts on chromatin-associated/nuclear substrates.
    supported_by:
    - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
      supporting_text: 'Nucleus {ECO:0000269|PubMed:37979583, ECO:0000269|PubMed:39223933}'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic (ortholog-based) assignment of cytoplasmic localization, concordant with the experimentally supported cytoplasmic pool of FBXO22.
    action: ACCEPT
    reason: Correct compartment; redundant with the EXP cytoplasm annotations. FBXO22 accumulates in the cytoplasm upon amino-acid depletion to ubiquitinate MTOR.
    supported_by:
    - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000269|PubMed:37979583, ECO:0000269|PubMed:39223933}'
- term:
    id: GO:0030018
    label: Z disc
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic localization (UniProt subcellular-location mapping) to the Z disc/sarcomere, derived from a by-similarity (ECO:0000250) sarcomere annotation. This is an inferred, non-core localization tied to the proposed sarcomeric-protein-turnover role.
    action: KEEP_AS_NON_CORE
    reason: The sarcomere/Z-line localization in UniProt is by-similarity (ECO:0000250), not experimentally demonstrated for human FBXO22; it reflects a peripheral, tissue-specific role rather than the core nuclear/cytoplasmic SCF function.
    supported_by:
    - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
      supporting_text: Cytoplasm, myofibril, sarcomere, Z line
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21145461
  qualifier: enables
  review:
    summary: High-throughput quantitative proteomics of the cullin-RING ligase network; the recorded partner is CUL1 (Q13616), the SCF scaffold FBXO22 assembles with. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real and expected SCF-scaffold interaction (CUL1), but bare protein binding is uninformative per curation guidelines; the SCF-complex membership is captured by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
      supporting_text: Directly interacts with SKP1 and CUL1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: High-throughput quantitative interactome (stoichiometries and abundances); the recorded partner is SKP1 (P63208), the F-box-binding SCF adaptor. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the expected F-box-SKP1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: High-throughput affinity-purification map of the human Polycomb complexome; the recorded partner is SKP1 (P63208). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction (SKP1); bare protein binding is uninformative and not a core function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary protein interactome reference map; the recorded partner is SKP1 (P63208). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput binary interactome (SKP1); bare protein binding is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Proteome-scale BioPlex interactome; the recorded partner is SKP1 (P63208). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome (SKP1); bare protein binding is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map interactome study; the recorded partner is SKP1 (P63208). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome (SKP1); bare protein binding is uninformative.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:37979583
  qualifier: located_in
  review:
    summary: Experimental evidence for nuclear localization of FBXO22, consistent with its action on nuclear substrates and its regulated nuclear/cytoplasmic partitioning.
    action: ACCEPT
    reason: Experimentally supported localization; FBXO22 partitions between nucleus and cytoplasm, with cytoplasmic accumulation triggered by amino-acid depletion.
    supported_by:
    - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
      supporting_text: 'Nucleus {ECO:0000269|PubMed:37979583, ECO:0000269|PubMed:39223933}'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:39223933
  qualifier: located_in
  review:
    summary: Experimental evidence for nuclear localization of FBXO22 from the NSP5-degradation study.
    action: ACCEPT
    reason: Experimentally supported localization corroborating the nucleus annotation.
    supported_by:
    - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
      supporting_text: 'Nucleus {ECO:0000269|PubMed:37979583, ECO:0000269|PubMed:39223933}'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:37979583
  qualifier: located_in
  review:
    summary: Experimental evidence for cytoplasmic localization; FBXO22 accumulates in the cytoplasm upon amino-acid depletion (GCN2/EIF2AK4-dependent Thr-127 phosphorylation) to ubiquitinate MTOR.
    action: ACCEPT
    reason: Experimentally supported localization directly tied to the mTORC1-regulatory function.
    supported_by:
    - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
      supporting_text: Amino acid depletion lead to a time-dependent increase of FBXO22 in the cytoplasm
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:39223933
  qualifier: located_in
  review:
    summary: Experimental evidence for cytoplasmic localization from the NSP5-degradation study.
    action: ACCEPT
    reason: Experimentally supported localization corroborating the cytoplasm annotation.
    supported_by:
    - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
      supporting_text: 'Cytoplasm {ECO:0000269|PubMed:37979583, ECO:0000269|PubMed:39223933}'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: Membership in the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, the defining macromolecular assembly for FBXO22 as an F-box substrate receptor. ComplexPortal records an SCF FBXO22 variant complex.
    action: ACCEPT
    reason: Core component; FBXO22 is the F-box substrate receptor of an SCF complex, directly interacting with SKP1 and CUL1.
    supported_by:
    - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
      supporting_text: Directly interacts with SKP1 and CUL1
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: involved_in
  review:
    summary: Involvement in SCF-dependent proteasomal degradation, the core biological process executed by FBXO22 as an SCF substrate receptor.
    action: ACCEPT
    reason: Core biological process; FBXO22-containing SCF targets substrates (e.g. KDM4A, methylated TP53, BACH1) for proteasomal degradation.
    supported_by:
    - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization within a generic CRL1 neddylation reaction (AcM-UBE2M transfers NEDD8 to CRL1). Generic compartment annotation propagated to all CRL1 members.
    action: KEEP_AS_NON_CORE
    reason: Cytosol is consistent with the cytoplasmic pool of FBXO22, but this is a generic CRL-machinery Reactome annotation; the more informative compartment annotations are the EXP nucleus/cytoplasm terms.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome cytosol localization within a generic CRL1 neddylation reaction (NEDD8:AcM-UBE2M binds CRL1). Generic compartment annotation.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL-machinery Reactome localization; redundant with and less informative than the EXP compartment annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome cytosol localization within a generic CRL reaction (CAND1 binds cytosolic CRL E3 ligases). Generic compartment annotation.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome cytosol localization within a generic CRL reaction (COMMDs displace CAND1 from cytosolic CRL complexes). Generic compartment annotation.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome cytosol localization within a generic CRL reaction (COP9 signalosome deneddylates cytosolic CRL complexes). Generic compartment annotation.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome cytosol localization within a generic CRL1 reaction (MyrG-DCUN1D3 binds CRL1). Generic compartment annotation.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome cytosol localization within a generic ubiquitination reaction (transfer of Ub from E2 to substrate). Generic compartment annotation.
    action: KEEP_AS_NON_CORE
    reason: Generic ubiquitination-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome cytosol localization within a generic ubiquitination reaction (release of E3 from polyubiquitinated substrate). Generic compartment annotation.
    action: KEEP_AS_NON_CORE
    reason: Generic ubiquitination-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome cytosol localization within a generic ubiquitination reaction (polyubiquitination of substrate). Generic compartment annotation.
    action: KEEP_AS_NON_CORE
    reason: Generic ubiquitination-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome cytosol localization within a generic ubiquitination reaction (interaction of E3 with substrate and E2-Ub complex). Generic compartment annotation.
    action: KEEP_AS_NON_CORE
    reason: Generic ubiquitination-machinery Reactome localization; not a core, FBXO22-specific compartment annotation.
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: TAS
  original_reference_id: PMID:10531037
  qualifier: enables
  review:
    summary: Legacy F-box-family TAS annotation of ubiquitin-protein transferase activity. As an F-box substrate receptor, FBXO22 is the substrate-specific adaptor of the SCF; the catalytic transferase activity resides in the RBX1-RING/E2 module, not in the F-box protein itself.
    action: MODIFY
    reason: FBXO22 is the substrate-recognition subunit of the SCF, not the catalytic transferase. The essence (participation in ubiquitin transfer) is sound, but the more accurate molecular function is the ubiquitin-like ligase-substrate adaptor activity; replace the catalytic transferase term with GO:1990756.
    proposed_replacement_terms:
    - id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    supported_by:
    - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Legacy TAS annotation (F-box family identification paper) of involvement in ubiquitin-dependent protein catabolism. Correct but generic relative to the SCF-dependent catabolism term.
    action: KEEP_AS_NON_CORE
    reason: Correct but a generic parent of GO:0031146 (SCF-dependent proteasomal catabolism), which more specifically captures FBXO22's role.
    supported_by:
    - reference_id: PMID:10531035
      supporting_text: F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs
- term:
    id: GO:0036211
    label: protein modification process
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Legacy TAS annotation of involvement in protein modification, a very high-level parent term. Uninformative relative to the specific (poly)ubiquitination/SCF-catabolism annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Extremely generic parent term; the specific protein polyubiquitination and SCF-dependent catabolism annotations fully and more informatively capture FBXO22's role.
    supported_by:
    - reference_id: PMID:10531035
      supporting_text: F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10531035
  title: Identification of a family of human F-box proteins.
  findings:
  - statement: FBXO22 (FBX22) was identified among a family of 26 human F-box proteins; F-box proteins are the substrate-recognition subunits of SCF ubiquitin protein ligases (together with Skp1, a cullin, and Roc1/Rbx1).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Original identification paper establishing FBXO22 as an F-box protein/SCF substrate receptor; source of the legacy TAS catabolism and protein-modification annotations.
- id: PMID:10531037
  title: A family of mammalian F-box proteins.
  findings:
  - statement: F-box proteins contain a C-terminal substrate-binding domain and an F-box motif that binds Skp1, linking the F-box protein to a core ubiquitin ligase composed of Cul1, Rbx1 and an E2; the catalytic core is the cullin-RING module, not the F-box protein.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes the F-box/SCF architecture; supports MODIFY of the catalytic transferase annotation to the substrate-adaptor function.
- id: PMID:21145461
  title: Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative
    proteomics.
  findings:
  - statement: Quantitative proteomics of the cullin-RING ligase (CRL) network; a large fraction of cullins are assembled with substrate-adaptor modules. Recorded FBXO22 interaction partner is CUL1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput CRL-network proteomics; source of a bare protein binding (CUL1) annotation.
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput quantitative interactome; FBXO22 partner recorded is SKP1; source of a bare protein binding annotation.
- id: PMID:27705803
  title: A High-Density Map for Navigating the Human Polycomb Complexome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput AP-MS Polycomb complexome map; FBXO22 partner recorded is SKP1; source of a bare protein binding annotation. Abstract-only in cache.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome reference map; FBXO22 partner recorded is SKP1; source of a bare protein binding annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex proteome-scale interactome; FBXO22 partner recorded is SKP1; source of a bare protein binding annotation.
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings:
  - statement: The SCF (SKP1-CUL1-F-box) complex comprises ~69 E3 ubiquitin ligases distinguished by variable F-box proteins that determine substrate specificity and modify substrates with poly-ubiquitin chains for proteasomal degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Review/NAS source for SCF complex membership and SCF-dependent catabolism annotations; abstract supports the F-box-as-substrate-receptor framing.
- id: PMID:37979583
  title: The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid
    insufficiency.
  findings:
  - statement: Upon amino-acid depletion, uncharged tRNAs stimulate GCN2 to phosphorylate FBXO22, which accumulates in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner, inhibiting mTORC1 by preventing substrate recruitment.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes FBXO22 as an MTOR-ubiquitinating SCF receptor and its regulated cytoplasmic localization; source of the EXP nucleus/cytoplasm annotations. Abstract-only in cache (full_text_available false).
- id: PMID:39223933
  title: E3 ubiquitin ligase FBXO22 inhibits SARS-CoV-2 replication via promoting
    proteasome-dependent degradation of NSP5.
  findings:
  - statement: FBXO22 ubiquitinates SARS-CoV-2 NSP5 with K48-linked polyubiquitin chains at Lys5 and Lys90, promoting its proteasome-dependent degradation and restricting viral replication.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes an antiviral substrate (NSP5) and the K48-linked degradative activity; source of the EXP nucleus/cytoplasm annotations. Abstract-only in cache (full_text_available false).
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput multimodal cell-map interactome; FBXO22 partner recorded is SKP1; source of a bare protein binding annotation.
- id: file:human/FBXO22/FBXO22-deep-research-falcon.md
  title: Falcon deep research report for human FBXO22
  findings:
  - statement: FBXO22 is the substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1/CRL1) E3 ligase; its N-terminal F-box binds SKP1 and its C-terminal FIST-C region binds substrates such as KDM4A.
    supporting_text: FBXO22 contains an N-terminal **F-box domain** mediating SCF assembly via SKP1, and a C-terminal **FIST/FIST-C** substrate-binding region (e.g., KDM4A binding mapped to the FBXO22 FIST-C domain).
  - statement: In ER-positive breast cancer, SCF(FBXO22) ubiquitylates and degrades KDM4B when KDM4B is complexed with tamoxifen-bound estrogen receptor, releasing steroid receptor coactivator and shaping SERM pharmacology.
    supporting_text: In ER-positive breast cancer models, **SCF^FBXO22^ ubiquitylates and degrades KDM4B** when KDM4B is **complexed with tamoxifen-bound ER**, which in turn **releases steroid receptor coactivator (SRC)** from ER and shapes SERM pharmacology.
  - statement: FBXO22 ubiquitinates nuclear, but not cytoplasmic, PTEN at Lys221 for proteasomal degradation.
    supporting_text: FBXO22 **ubiquitylates nuclear (but not cytoplasmic) PTEN** at **lysine 221**, leading to proteasome-mediated degradation and nuclear PTEN depletion.
  - statement: FBXO22 recognizes a phosphodegron motif XXPpSPXPXX and degrades BAG3 in an ERK-S377-phosphorylation-dependent manner, defining an ERK-FBXO22-BAG3 axis.
    supporting_text: A 2022 systems/biochemical study defined a **FBXO22-recognized phosphodegron motif** **XXPpSPXPXX** and validated **BAG3** as a bona fide FBXO22 substrate. BAG3 degradation requires **ERK-dependent phosphorylation at S377**, establishing an ERK→FBXO22→BAG3 axis linked to tumorigenesis phenotypes.
  - statement: FBXO22 is a recruitable E3 ligase for targeted protein degradation; an aldehyde metabolite of alkylamine-tethered degraders covalently adducts Cys326 in its C-terminal domain to drive ternary-complex formation and degradation.
    supporting_text: Alkylamine-tethered degraders can be metabolized to an **active aldehyde** that **covalently adduces Cys326** in the FBXO22 C-terminal domain.
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: Falcon (Edison Scientific) deep-research synthesis. Cross-checked against the UniProt FUNCTION block (KDM4A, methylated TP53, BACH1, MTOR, NSP5) and used as leads for substrates not yet in UniProt (KDM4B/SERM, nuclear PTEN K221, PD-L1, BAG3 phosphodegron, pS2448-mTOR, Cys326 TPD handle); cites author-year/DOIs rather than PMIDs, so individual primary claims remain UNVERIFIED here.
- id: Reactome:R-HSA-8952618
  title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8952620
  title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8955241
  title: CAND1 binds cytosolic CRL E3 ubiquitin ligases
  findings: []
- id: Reactome:R-HSA-8955289
  title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956040
  title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956200
  title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-983140
  title: Transfer of Ub from E2 to substrate and release of E2
  findings: []
- id: Reactome:R-HSA-983147
  title: Release of E3 from polyubiquitinated substrate
  findings: []
- id: Reactome:R-HSA-983156
  title: Polyubiquitination of substrate
  findings: []
- id: Reactome:R-HSA-983157
  title: Interaction of E3 with substrate and E2-Ub complex
  findings: []
core_functions:
- description: Substrate-recognition receptor of a SCF (SKP1-CUL1-F-box) CUL1-RING E3 ubiquitin ligase complex; binds SKP1 via its F-box motif and selects substrates via its C-terminal domain, directing their SCF-dependent polyubiquitination and proteasomal degradation.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
    supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: As the SCF(FBXO22) substrate receptor, targets the histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation, thereby regulating H3K9 and H3K36 methylation levels and, in complex with KDM4A, the abundance of methylated TP53 at late senescence.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
    supporting_text: Acts as a key regulator of histone methylation marks namely H3K9 and H3K36 methylation through the regulation of histone demethylase KDM4A protein levels
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: Upon amino-acid depletion, FBXO22 (after GCN2/EIF2AK4-dependent phosphorylation) accumulates in the cytoplasm and ubiquitinates MTOR at Lys2066 in a K27-linked manner, inhibiting mTORC1 substrate recruitment and linking nutrient stress to mTORC1 activity.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/FBXO22/FBXO22-uniprot.txt
    supporting_text: mediates 'Lys-27'-linked ubiquitination of MTOR and thereby inhibits substrate recruitment to mTORC1
- description: As the SCF(FBXO22) substrate receptor, recognizes phospho- and modification-defined degrons on additional substrates (the oxidative-stress transcription factor BACH1, nuclear PTEN at Lys221, the immune-checkpoint ligand PD-L1/CD274, and the ERK-phosphorylated co-chaperone BAG3 at Ser377), directing their proteasomal degradation and thereby coupling SCF activity to oxidative-stress signaling, tumor-suppressor control, immune-checkpoint abundance, and proteostasis.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/FBXO22/FBXO22-deep-research-falcon.md
    supporting_text: A 2022 systems/biochemical study defined a **FBXO22-recognized phosphodegron motif** **XXPpSPXPXX** and validated **BAG3** as a bona fide FBXO22 substrate. BAG3 degradation requires **ERK-dependent phosphorylation at S377**, establishing an ERK→FBXO22→BAG3 axis linked to tumorigenesis phenotypes.
  - reference_id: file:human/FBXO22/FBXO22-deep-research-falcon.md
    supporting_text: FBXO22 **ubiquitylates nuclear (but not cytoplasmic) PTEN** at **lysine 221**, leading to proteasome-mediated degradation and nuclear PTEN depletion.
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms: []
suggested_questions:
- question: What structural determinants in the FBXO22 C-terminal FIST-C domain dictate its broad substrate repertoire (KDM4A, methylated TP53, BACH1, MTOR, KLF4, NSP5), and how are degrons such as the oxidation-exposed BACH1 bZIP region recognized?
- question: How is FBXO22's choice of ubiquitin-chain linkage controlled (K48-linked degradative chains on NSP5/most substrates vs K27-linked chains on MTOR), given that chain topology is normally set by the E2/RBX1 module rather than the F-box adaptor?
- question: To what extent do the diverse FBXO22 substrate-degradation activities each contribute to the Tayoun-Maawali syndrome phenotype caused by biallelic FBXO22 loss of function?
suggested_experiments:
- description: Reconstitute SCF(FBXO22) ubiquitination in vitro with purified SKP1-CUL1-RBX1, an E2, and candidate substrates to confirm direct, adaptor-dependent substrate selection and to map lysine sites and chain linkages for each substrate.
- description: Perform quantitative ubiquitinome and proteome profiling in FBXO22-knockout versus wild-type cells under basal, amino-acid-starved, and oxidative-stress conditions to define the endogenous, context-dependent FBXO22 substrate repertoire.
- description: Dissect the regulated nuclear/cytoplasmic partitioning of FBXO22 by mutating the EIF2AK4/GCN2 phosphosite (Thr-127) and quantifying the effect on substrate-specific degradation (e.g. nuclear KDM4A vs cytoplasmic MTOR).

FBXO22

Gene Description

Existing Annotations Review

Core Functions

Substrate-recognition receptor of a SCF (SKP1-CUL1-F-box) CUL1-RING E3 ubiquitin ligase complex; binds SKP1 via its F-box motif and selects substrates via its C-terminal domain, directing their SCF-dependent polyubiquitination and proteasomal degradation.

As the SCF(FBXO22) substrate receptor, targets the histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation, thereby regulating H3K9 and H3K36 methylation levels and, in complex with KDM4A, the abundance of methylated TP53 at late senescence.

Upon amino-acid depletion, FBXO22 (after GCN2/EIF2AK4-dependent phosphorylation) accumulates in the cytoplasm and ubiquitinates MTOR at Lys2066 in a K27-linked manner, inhibiting mTORC1 substrate recruitment and linking nutrient stress to mTORC1 activity.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human FBXO22 (UniProt Q8NEZ5) — functional annotation, mechanisms, and applications

0) Target identity verification (mandatory)

1) Key concepts and definitions (current understanding)

1.1 SCF E3 ubiquitin ligases and F-box proteins

1.2 What FBXO22 “does” at the molecular level

2) Core functional annotation of FBXO22: mechanisms, substrates, pathways, and localization

2.1 SCF complex assembly and subcellular distribution

2.2 Established substrate mechanisms (selected high-confidence examples)

(A) Epigenetic regulators: KDM4A and KDM4B

(B) p53 network and senescence control

(C) Nuclear tumor suppressor PTEN

(D) Immune checkpoint regulation: PD-L1

(E) Phosphodegron logic and the ERK–FBXO22–BAG3 axis

(F) 2024 advance: phospho-specific degradation of pS2448-mTOR in colitis/CRC

3) Recent developments and latest research (prioritizing 2023–2024)

3.1 FBXO22 as a recruitable E3 ligase for targeted protein degradation (TPD)

3.2 Human genetics: FBXO22 deficiency syndrome (2024 preprint)

4) Current applications and real-world implementations

4.1 Biomarkers and therapy response: ER+ breast cancer endocrine treatment

4.2 Immuno-oncology and DNA damage therapy sensitization (NSCLC)

4.3 Inflammation/CRC axis: pS2448-mTOR degradation

4.4 Targeted protein degradation R&D

5) Expert opinions and authoritative synthesis

6) Statistics and quantitative data highlights (from recent and key studies)

7) Consolidated evidence map (substrates, mechanisms, contexts)

8) Curated disease-target associations (database support; interpret cautiously)

9) Conclusions and functional annotation summary

Artifacts

Citations

📚 Additional Documentation

Pn Notes

FBXO22 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 | other

Projected GO annotations (1)

Note

📄 View Raw YAML