| 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 (pqac-00000006, pqac-00000017) | Tan 2011 — https://doi.org/10.1128/mcb.05746-11 (pqac-00000006, pqac-00000017) |
| 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 (pqac-00000005, pqac-00000014) | Johmura 2016 — https://doi.org/10.1038/ncomms10574 (pqac-00000014) |
| 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 (pqac-00000018, pqac-00000019) | Johmura 2018 — https://doi.org/10.1172/JCI121679 (pqac-00000018, pqac-00000019) |
| 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 (pqac-00000007, pqac-00000009) | De 2021 — https://doi.org/10.1073/pnas.2112674118 (pqac-00000007, pqac-00000009) |
| 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 (pqac-00000002, pqac-00000013) | Ge 2020 — https://doi.org/10.1038/s41467-020-15578-1 (pqac-00000002, pqac-00000013) |
| 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 (pqac-00000010) | Liu 2022 — https://doi.org/10.1038/s41418-021-00827-7 (pqac-00000010) |
| 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 (pqac-00000004, pqac-00000016, pqac-00000022) | Li 2024 — https://doi.org/10.1073/pnas.2402035121 (pqac-00000004, pqac-00000016, pqac-00000022) |
| 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 (pqac-00000015) | Kagiou 2024 — https://doi.org/10.1038/s41467-024-49739-3 (pqac-00000015) |
| 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 (pqac-00000020) | Basu 2023/2024 — https://doi.org/10.1101/2023.09.15.557708 ; https://doi.org/10.1038/s41589-024-01655-9 (pqac-00000020, pqac-00000011) |
| FBXO22 loss-of-function / KDM4B accumulation | Loss of FBXO22 protein in patient fibroblasts leads to increased known substrate KDM4B | Homozygous frameshift LOF variants p.(Arg53Serfs*13), p.(Pro3Leufs*3), 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 (pqac-00000012, pqac-00000000) | Ramakrishna 2024 — https://doi.org/10.1101/2024.09.28.24314530 (pqac-00000012, pqac-00000000) |


*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.*