FBXO40 (F-box only protein 40; "muscle disease-related protein") is a 709-residue FBXO-class F-box protein that serves as the substrate-recognition subunit of a cullin-RING SCF (SKP1-CUL1-RBX1-F-box) E3 ubiquitin ligase complex. Like other F-box proteins, it docks onto the SCF scaffold through its C-terminal F-box domain (interacting with SKP1/CUL1) while presenting an N-terminal substrate-binding module; FBXO40 carries a TRAF-type zinc finger and is not itself the catalytic RING subunit (catalysis is provided by RBX1, which recruits the ubiquitin-charged E2). FBXO40 expression is restricted essentially to heart and skeletal muscle, appears postnatally during muscle development, and is upregulated in denervation-induced (but not starvation-induced) muscle atrophy and reduced in Limb-girdle muscular dystrophy muscle. Its best-supported direct substrate is insulin receptor substrate 1 (IRS1): the SCF(FBXO40) complex (with co-precipitating SKP1, CUL1 and RBX1) ubiquitinates recombinant IRS1 in vitro in a manner enhanced by IGF1R-dependent IRS1 tyrosine phosphorylation, targeting IRS1 for proteasomal degradation and thereby attenuating the IGF-1/insulin -> IRS1 -> PI3K/AKT anabolic signaling axis in skeletal muscle. Loss of Fbxo40 increases IRS1 protein abundance (without changing Irs1 mRNA), prolongs IRS1 half-life, and produces myotube and whole-muscle hypertrophy in mice (and increased muscle mass in knockout pigs), a phenotype that is IRS1-dependent. FBXO40 transcription is induced by inflammatory STAT3 signaling (e.g. downstream of IL-6), linking it to catabolic insulin-resistance states. The protein localizes to the cytoplasm/cytosol.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (PAN-GO/IBA) assignment of cytoplasmic localization, consistent with FBXO40 acting as the substrate-recognition subunit of a cytoplasmic SCF complex. Reason: Cytoplasmic localization is corroborated by direct overexpression in C2C12 myoblasts and by the UniProt subcellular location; it is the compartment in which an SCF substrate receptor would act. Supporting Evidence: PMID:17928169 By overexpressing in C2C12 cells, FBXO40 localized in cytoplasm. file:human/FBXO40/FBXO40-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated electronic assignment of cytoplasmic localization, redundant with the IBA and ISS cytoplasm annotations. Reason: Correct compartment; redundant with experimentally corroborated cytoplasmic localization. Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based electronic assignment of zinc ion binding from the TRAF-type zinc finger (IPR001293) present in FBXO40. A structural feature supporting substrate/protein interaction rather than a core function. Reason: FBXO40 contains a TRAF-type zinc finger (residues 53-112) that plausibly coordinates zinc, but this is a structural domain attribute subsidiary to its role as an SCF substrate adaptor, not a standalone core molecular function. Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt ZN_FING 53..112 |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro-based electronic assignment of ubiquitin protein ligase activity. F-box proteins are substrate-recognition adaptors, not the catalytic core of the SCF ligase; the catalytic RING activity resides in RBX1. Reason: As an F-box substrate receptor, FBXO40 does not itself catalyze ubiquitin transfer (that is the RBX1 RING subunit); its molecular function is better captured as a ubiquitin-like ligase-substrate adaptor. This IEA term is propagated from the InterPro Fbxo30/Fbxo40 signature and over-attributes catalytic ligase activity to the adaptor. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt Probable substrate-recognition component of the SCF (SKP1- |
| GO:0042692 muscle cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara ortholog-based electronic transfer of muscle cell differentiation, mirroring the ISS annotation derived from the mouse ortholog and the muscle-restricted expression of FBXO40. Reason: Consistent with FBXO40's muscle-restricted, postnatal-myogenesis-associated expression, but the involvement rests on expression correlation and family/ortholog propagation rather than direct experimental demonstration in human; keep as a non-core process. Supporting Evidence: PMID:17928169 All our data suggest that FBXO40 may function as a regulator involved in the postnatal myogenesis. |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: ComplexPortal NAS assignment (CPX-7981, SCF FBXO40 variant) that FBXO40 is part of an SCF E3 ubiquitin ligase complex, consistent with its F-box domain and reported direct interactions with SKP1 and CUL1. Reason: Core localization/complex membership for an F-box protein; supported by the F-box domain, the UniProt SUBUNIT statement, and the general SCF biology described in the cited review. Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt SUBUNIT: Directly interacts with SKP1 and CUL1. {ECO:0000250}. PMID:34445249 These SCF complexes are distinguishable by variable F-box proteins, which determine substrate specificity. |
| 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: ComplexPortal NAS assignment that FBXO40, as an SCF F-box receptor, participates in SCF-dependent proteasomal protein degradation. This is the expected biological process for an SCF substrate adaptor. Reason: Consistent with the canonical role of F-box proteins in directing substrates to SCF-dependent proteasomal degradation, and now corroborated by FBXO40-specific evidence that SCF-FBXO40 ubiquitinates IRS1 to drive its proteasomal degradation (Shi et al. 2011, via the Falcon report). Supporting Evidence: PMID:34445249 group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation file:human/FBXO40/FBXO40-uniprot.txt Ubl conjugation pathway file:human/FBXO40/FBXO40-deep-research-falcon.md FBXO40 acts as the **substrate-recognition subunit** of an SCF E3 ligase complex (**SCF-FBXO40**) that **ubiquitinates IRS1**, promoting its **ubiquitin–proteasome-dependent degradation** in skeletal muscle, thereby **limiting IGF-1/insulin signaling** through the IRS1–PI3K–AKT axis |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | KEEP AS NON CORE | Summary: Reactome TAS cytosol localization derived from generic CRL1/neddylation pathway reactions in which the SCF complex participates. Consistent with cytoplasmic localization but pathway-context, not FBXO40-specific evidence. Reason: Cytosol is a correct, more specific child of the cytoplasm localization, but this and the other identical Reactome cytosol annotations are propagated from generic cullin-RING-ligase pathway reactions rather than direct FBXO40 evidence. Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | KEEP AS NON CORE | Summary: Reactome TAS cytosol localization from a generic CRL1/NEDD8 pathway reaction. Redundant with the other Reactome cytosol annotations. Reason: Correct compartment but propagated from generic CRL pathway reactions rather than FBXO40-specific evidence. Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | KEEP AS NON CORE | Summary: Reactome TAS cytosol localization from a generic CAND1/CRL pathway reaction. Redundant with the other Reactome cytosol annotations. Reason: Correct compartment but propagated from generic CRL pathway reactions rather than FBXO40-specific evidence. Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | KEEP AS NON CORE | Summary: Reactome TAS cytosol localization from a generic COMMD/CAND1/CRL pathway reaction. Redundant with the other Reactome cytosol annotations. Reason: Correct compartment but propagated from generic CRL pathway reactions rather than FBXO40-specific evidence. Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | KEEP AS NON CORE | Summary: Reactome TAS cytosol localization from a generic COP9-signalosome deneddylation pathway reaction. Redundant with the other Reactome cytosol annotations. Reason: Correct compartment but propagated from generic CRL pathway reactions rather than FBXO40-specific evidence. Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | KEEP AS NON CORE | Summary: Reactome TAS cytosol localization from a generic DCUN1D3/CRL1 pathway reaction. Redundant with the other Reactome cytosol annotations. Reason: Correct compartment but propagated from generic CRL pathway reactions rather than FBXO40-specific evidence. Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | KEEP AS NON CORE | Summary: Reactome TAS cytosol localization from a generic ubiquitin-transfer pathway reaction. Redundant with the other Reactome cytosol annotations. Reason: Correct compartment but propagated from generic ubiquitin-conjugation pathway reactions rather than FBXO40-specific evidence. Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | KEEP AS NON CORE | Summary: Reactome TAS cytosol localization from a generic ubiquitin-transfer pathway reaction. Redundant with the other Reactome cytosol annotations. Reason: Correct compartment but propagated from generic ubiquitin-conjugation pathway reactions rather than FBXO40-specific evidence. Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | KEEP AS NON CORE | Summary: Reactome TAS cytosol localization from a generic polyubiquitination pathway reaction. Redundant with the other Reactome cytosol annotations. Reason: Correct compartment but propagated from generic ubiquitin-conjugation pathway reactions rather than FBXO40-specific evidence. Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | KEEP AS NON CORE | Summary: Reactome TAS cytosol localization from a generic E3-substrate-E2 interaction pathway reaction. Redundant with the other Reactome cytosol annotations. Reason: Correct compartment but propagated from generic ubiquitin-conjugation pathway reactions rather than FBXO40-specific evidence. Supporting Evidence: file:human/FBXO40/FBXO40-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of cytoplasmic localization from the mouse ortholog (SKP1, UniProtKB:P62932 used as WITH). Consistent with the experimentally observed cytoplasmic localization of FBXO40. Reason: Correct core compartment; corroborated by direct overexpression in C2C12 myoblasts and the UniProt subcellular location. Supporting Evidence: PMID:17928169 By overexpressing in C2C12 cells, FBXO40 localized in cytoplasm. |
| GO:0042692 muscle cell differentiation | ISS PMID:17928169 FBXO40, a gene encoding a novel muscle-specific F-box protei... | KEEP AS NON CORE | Summary: ISS assignment of involvement in muscle cell differentiation, based on FBXO40's muscle-restricted, postnatal expression and its proposed role in postnatal myogenesis. Reason: The cited study establishes muscle-specific expression and a postnatal-myogenesis association by expression/correlation, but does not directly demonstrate that FBXO40 drives muscle cell differentiation. The mechanistically best-defined muscle role of FBXO40 (Shi et al. 2011) is negative control of muscle growth/hypertrophy via SCF-dependent IRS1 degradation and attenuation of IGF-1/insulin-AKT signaling, rather than differentiation per se; retain this term as a plausible non-core process. Supporting Evidence: PMID:17928169 All our data suggest that FBXO40 may function as a regulator involved in the postnatal myogenesis. file:human/FBXO40/FBXO40-deep-research-falcon.md Loss of Fbxo40 increases IRS1 abundance and produces muscle hypertrophy in animal models, including mice and pigs |
| GO:0046627 negative regulation of insulin receptor signaling pathway | ISO PMID:22033112 The SCF-FBXO40 complex induces IRS1 ubiquitination in skelet... | NEW | Summary: Proposed FBXO40-specific process inferred by orthology from mouse Fbxo40 (Shi et al. 2011, PMID:22033112; surfaced via the Falcon report) that SCF-FBXO40 ubiquitinates IRS1 to drive its proteasomal degradation, attenuating IGF-1/insulin -> IRS1 -> PI3K/AKT signaling in skeletal muscle. Reason: Not currently in GOA, but a well-supported FBXO40-specific biological process. SCF-FBXO40 degrades IRS1 (enhanced by IGF1R-dependent IRS1 tyrosine phosphorylation), and Fbxo40 loss stabilizes IRS1 and causes IRS1-dependent muscle hypertrophy, defining FBXO40 as a negative regulator of insulin/IGF-1 receptor signaling. Evidence is recorded as ISO (inferred from the mouse ortholog; Shi et al. 2011, Dev Cell, PMID:22033112, identified via the Falcon report). The PMID is confirmed to exist but its full text was not read here, so the falcon report is cited as the supporting lead rather than an asserted experimental human quote. Supporting Evidence: file:human/FBXO40/FBXO40-deep-research-falcon.md FBXO40 acts as the **substrate-recognition subunit** of an SCF E3 ligase complex (**SCF-FBXO40**) that **ubiquitinates IRS1**, promoting its **ubiquitin–proteasome-dependent degradation** in skeletal muscle, thereby **limiting IGF-1/insulin signaling** through the IRS1–PI3K–AKT axis |
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Download this section (compressed HTML)Q: What is the direct, experimentally validated substrate repertoire of FBXO40 in human skeletal muscle, and is IRS1 ubiquitination by the SCF-FBXO40 complex direct (e.g. reconstituted with purified components) rather than inferred from co-depletion phenotypes?
Q: Does FBXO40 substrate recruitment depend on the TRAF-type zinc finger, and does substrate engagement require phosphodegron recognition downstream of IGF1R/insulin-Akt signaling?
Q: Are the muscle cell differentiation and denervation-atrophy phenotypes a consequence of FBXO40-dependent substrate turnover, or do they reflect expression-correlated but indirect roles?
Q: How is FBXO40 transcription controlled by inflammatory STAT3/IL-6 signaling in skeletal muscle, and does pharmacologic STAT3 inhibition preserve IRS1/p-AKT and improve insulin sensitivity primarily through FBXO40 downregulation?
Experiment: Reconstitute the SCF-FBXO40 complex (SKP1, CUL1, RBX1, FBXO40) with a ubiquitin-charged E2 in vitro and assay ubiquitination of candidate substrates (e.g. IRS1) to establish direct adaptor function and chain topology.
Experiment: Perform affinity purification-mass spectrometry of tagged FBXO40 from skeletal myotubes (with and without proteasome/neddylation inhibition) to define the endogenous substrate and complex interactome and confirm SKP1/CUL1/RBX1 association.
Experiment: Generate FBXO40-knockout myoblasts/mice and quantify candidate-substrate levels and ubiquitination, myogenic differentiation, and the denervation-atrophy response to test whether phenotypes are substrate-turnover dependent.
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