| Topic | Key findings | Evidence type | Year | Citation |
|---|---|---|---|---|
| identity/domains | Human FBXO40 corresponds to UniProt Q9UH90 and is consistently described in the literature as a muscle-enriched F-box protein; this matches its expected role as an SCF substrate-recognition component rather than a catalytic enzyme. | Database + review + primary | 2011–2020 | UniProt Q9UH90 / FBXO40; Shi et al., *SCF-Fbxo40 complex induces IRS1 ubiquitination* — https://doi.org/10.1016/j.devcel.2011.09.011; Blondelle et al., *Role of Cullin-RING Ligases in Striated Muscle* — https://doi.org/10.3390/ijms21217936 (pqac-00000001, pqac-00000004) |
| molecular function | FBXO40 functions as a substrate-recognition subunit of a Cullin-RING E3 ubiquitin ligase that promotes ubiquitin-proteasome-dependent degradation of IRS1, thereby limiting IGF1/insulin signaling in skeletal muscle. | Primary | 2011 | Shi et al., *SCF-Fbxo40 complex induces IRS1 ubiquitination* — https://doi.org/10.1016/j.devcel.2011.09.011 (pqac-00000001, pqac-00000005, pqac-00000007) |
| E3 complex | FBXO40 co-immunoprecipitates with IRS1 and canonical SCF components Skp1, Cullin1, and Rbx1; immunoprecipitated SCF-FBXO40 ubiquitinates recombinant IRS1 in vitro. | Primary | 2011 | Shi et al., *SCF-Fbxo40 complex induces IRS1 ubiquitination* — https://doi.org/10.1016/j.devcel.2011.09.011 (pqac-00000002, pqac-00000005, pqac-00000011) |
| confirmed substrate | IRS1 is the best-supported direct substrate. Its ubiquitination is enhanced by tyrosine phosphorylation and IGF1R activation; FBXO40 knockdown prolongs IRS1 half-life to >6 h and increases muscle IRS1 protein without changing Irs1 mRNA. | Primary | 2011 | Shi et al., *SCF-Fbxo40 complex induces IRS1 ubiquitination* — https://doi.org/10.1016/j.devcel.2011.09.011 (pqac-00000005, pqac-00000008) |
| regulation | IGF1 signaling promotes FBXO40-dependent IRS1 turnover in differentiated myotubes. In inflammatory/catabolic settings, STAT3 binds the Fbxo40 promoter; IL-6/STAT3 raises Fbxo40 expression and lowers IRS1 and p-Akt, while Fbxo40 knockdown preserves IRS1/p-Akt. | Primary | 2011, 2020 | Shi et al., *SCF-Fbxo40 complex induces IRS1 ubiquitination* — https://doi.org/10.1016/j.devcel.2011.09.011; Zhang et al., *Stat3 activation induces insulin resistance via Fbxo40* — https://doi.org/10.1152/ajpendo.00480.2019 (pqac-00000005, pqac-00000006) |
| tissue/cell type | FBXO40 is expressed almost exclusively in skeletal muscle and heart, increases during myogenic differentiation, and is implicated mainly in differentiated myotubes/myofibers rather than broadly across tissues. | Primary + review | 2011, 2020 | Shi et al., *SCF-Fbxo40 complex induces IRS1 ubiquitination* — https://doi.org/10.1016/j.devcel.2011.09.011; Blondelle et al., *Role of Cullin-RING Ligases in Striated Muscle* — https://doi.org/10.3390/ijms21217936 (pqac-00000005, pqac-00000004) |
| subcellular localization | Review evidence describes exogenous/forced FBXO40 as showing diffuse cytoplasmic localization in muscle cells; direct high-resolution localization evidence remains limited in the gathered sources. | Review | 2020 | Blondelle et al., *Role of Cullin-RING Ligases in Striated Muscle* — https://doi.org/10.3390/ijms21217936 (pqac-00000004, pqac-00000009) |
| phenotypes | Fbxo40 knockdown causes myotube hypertrophy and this depends on IRS1. Fbxo40 knockout mice show increased IRS1 protein and larger body/muscle size during growth; one summary reports IRS1/eIF4E densitometry ~1.0 in WT vs ~2.97 in KO muscle. Review evidence also notes CRISPR Fbxo40 knockout pigs with ~4% higher muscle mass. | Primary + review | 2011, 2020 | Shi et al., *SCF-Fbxo40 complex induces IRS1 ubiquitination* — https://doi.org/10.1016/j.devcel.2011.09.011; Blondelle et al., *Role of Cullin-RING Ligases in Striated Muscle* — https://doi.org/10.3390/ijms21217936 (pqac-00000001, pqac-00000003, pqac-00000009, pqac-00000010) |
| 2023-2024 developments/applications | Recent literature uses FBXO40 mainly as a mechanistic/therapeutic node in muscle wasting and insulin-resistance contexts rather than as a validated clinical target. Open Targets shows only weak, sparse disease associations outside muscle-focused literature, underscoring limited direct human disease validation so far. | Database | 2023–2024 platform context | Open Targets FBXO40 disease-association summary — https://platform.opentargets.org/target/ENSG00000163833 (pqac-00000000) |


*Table: This table compacts the strongest gathered evidence for human FBXO40/Q9UH90, emphasizing its role as a muscle-enriched SCF E3-ligase substrate receptor for IRS1. It also distinguishes primary mechanistic evidence from review and database-level associations to support functional annotation.*