| Functional role/pathway | Key substrates/interactors | Ubiquitin linkage/site | Experimental system | 2023-2024 highlights and quantitative stats | Representative citation IDs |
|---|---|---|---|---|---|
| SCF E3 ligase adaptor / core architecture | SKP1, CUL1, RBX1; PI31/PSMF1 via FP domain; PRR and Ubl domains contribute substrate/receptor interactions | F-box mediates SKP1 binding; linkage varies by substrate | Domain mapping/review synthesis; cultured mammalian cells | Human FBXO7 isoform 1 contains Ubl, FP, F-box, and PRR domains; dynamic nucleo-cytoplasmic localization and SCF assembly are central to function | (pqac-00000001, pqac-00000002, pqac-00000004, pqac-00000035, pqac-00000036) |
| Proteasome assembly / proteostasis | PSMA2, PI31/PSMF1, proteasome holoenzyme | PSMA2 mainly K63-linked ubiquitination; PI31 binds but is not established as a degradative substrate | Mouse systemic and neuron-specific Fbxo7 knockout; patient fibroblasts; biochemical assays | FBXO7 loss reduces proteasome activity and causes parkinsonism-like phenotypes in mice; FBXO7 associates with proteasome and promotes assembly; brain proteasome activity reduced in knockout models | (pqac-00000009, pqac-00000011, pqac-00000029) |
| Mitophagy / mitochondrial quality control | Parkin, PINK1, TOMM20, GSK3β | TOMM20 ubiquitinated with stabilizing non-degradative effect; GSK3β modified with K63-linked chains | HEK293/cell-based ubiquitination assays; neuronal and fly/mouse disease models | FBXO7 promotes Parkin recruitment to damaged mitochondria; PD-linked T22M disrupts Parkin binding; R378G impairs Skp1 binding/localization; GSK3β and TOMM20 validated as SCF^FBXO7 substrates linked to PD-relevant pathways | (pqac-00000002, pqac-00000003, pqac-00000005, pqac-00000015, pqac-00000032) |
| ER stress / apoptosis regulation upstream of FBXO7 | USP7, FBXO7 | USP7 removes K48-linked ubiquitin from FBXO7, stabilizing it | HEK293 co-IP/GST pull-down; USP7+/+ and USP7-/- HeLa; SH-SY5Y cells; tunicamycin stress | USP7-/- cells showed ~7.8-fold higher cleaved PARP1 under ER stress; restoring FBXO7 in USP7-/- cells reduced tunicamycin-induced cytotoxicity by ~10% and lowered cleaved PARP1 by ~1.5-fold; USP7 overexpression reduced cytotoxicity by ~8%, while FBXO7 knockdown blunted this protection by ~5% | (pqac-00000010, pqac-00000012, pqac-00000014) |
| Oxidative stress / apoptosis downstream of FBXO7 | SIRT7 | K48-linked polyubiquitination of SIRT7 at K292, K395, K397, K398 | HEK293 transfection; SH-SY5Y cells treated with 500 μM H2O2 for 6 h; mouse brain lysates | FBXO7 promotes proteasomal degradation of SIRT7 and enhances H2O2-induced cell death; SIRT7-4KR mutant resists FBXO7-mediated ubiquitination/degradation and shows stronger deacetylase/repressor activity; PD-linked R498X fails to destabilize SIRT7 unlike WT/T22M/R378G FBXO7 | (pqac-00000019, pqac-00000024) |
| Endometrial carcinoma / mitochondrial dynamics tumor suppression | INF2, DRP1/DNM1L axis | Predominantly K48-linked polyubiquitination of INF2; FBXO7 UBL domain (aa 1-74) required for INF2 binding | AN3 CA and HEC-1-A endometrial carcinoma cells; TCGA/CPTAC datasets; AP-MS/co-IP; MG132 20 μM for 8 h | FBXO7 downregulated in ECa; mutation frequency 31/528 (5.87%) in TCGA; TCGA mRNA cohorts: tumor n=546 vs normal n=35, paired n=23; CPTAC protein cohorts: tumor n=100 vs normal n=31, paired n=30; FBXO7 was top INF2-associated FBX protein (3 peptides/3 unique peptides), docking Z-score 20.46; low FBXO7 correlated with high INF2 and mitochondrial hyper-division | (pqac-00000017, pqac-00000018, pqac-00000037) |
| Hepatocellular carcinoma / serine synthesis metabolism | PRMT1, PHGDH | PRMT1 ubiquitination at K37; proteasome-dependent degradation; ΔF-box mutant loses activity | Huh7 and PLC/PRF/5 HCC cells; HEK293T co-IP; GST pull-down; MG132 25 μM for 6 h; CHX 50 μg/mL | FBXO7 is significantly downregulated in HCC and inversely associated with PRMT1 protein and PHGDH methylation; FBXO7 loss increases PRMT1 stability, PHGDH R236 methylation, serine synthesis, and tumor growth, whereas FBXO7 suppresses these processes; K37R PRMT1 resists FBXO7-mediated ubiquitination and has longer half-life | (pqac-00000020, pqac-00000021, pqac-00000022, pqac-00000025, pqac-00000026, pqac-00000039) |
| Clinical / translational relevance | FBXO7 in PARK15/parkinsonian-pyramidal syndrome; PI31 pathway; SKP1/SCF machinery | Not a single linkage; disease relevance arises from disrupted SCF, proteasome, and mitophagy functions | Human genetics, mouse models, OpenTargets, chemical biology | OpenTargets links FBXO7 to Parkinson disease and parkinsonian-pyramidal syndrome; patients often respond to L-Dopa but can develop early dyskinesia/psychosis; translational strategies include restoring FBXO7 function, modulating USP7-FBXO7 stability, targeting PI31/proteasome pathway, and exploiting SKP1-SCF for degrader design | (pqac-00000000, pqac-00000027, pqac-00000031, pqac-00000033) |


*Table: This table summarizes experimentally supported roles, interactors, ubiquitination features, model systems, and quantitative highlights for human FBXO7/Q9Y3I1. It is designed to support a concise evidence-based overview of FBXO7 biology and translational relevance.*