FBXO41 (F-box only protein 41; KIAA1940) is a brain/neuron-enriched member of the FBXO family of F-box proteins. F-box proteins serve as the substrate-recognition (receptor/adaptor) subunits of SCF (SKP1-CUL1-RBX1-F-box) Cullin-RING E3 ubiquitin ligase complexes: the F-box motif docks the protein onto the SKP1-CUL1 scaffold, while a separate substrate-binding region recruits target proteins for poly-ubiquitination, committing them to proteasomal degradation. FBXO41 carries a C-terminal F-box domain together with an N-terminal C2H2 zinc-finger-like region, a long predicted coiled-coil, and extensive intrinsically disordered/low-complexity regions, and by sequence similarity is predicted to assemble into an SCF complex through direct interaction with SKP1 and CUL1. FBXO41 is a neuron-specific/CNS-enriched protein (expressed from early embryogenesis, abundant postnatally in cerebellum and hippocampus; not detected in astrocytes or oligodendrocytes). It is cytoplasmic and excluded from the nucleus, with a prominent centrosomal/pericentriolar pool: in neurons FBXO41 localizes adjacent to centriole markers and co-fractionates with centrosomes, and this targeting requires both its coiled-coil and F-box domains. Functionally, increased centrosomal/centriolar accumulation of FBXO41 promotes disassembly/shortening of neuronal primary cilia and thereby modulates the cilium-dependent Sonic hedgehog (Shh) pathway; this cilia disassembly activity depends on actin-cytoskeleton remodeling and, in mitotic contexts, on Aurora A kinase. F-box deletion or an F-box point mutation (W577A) abolishes SKP1/CUL1 binding, and a centrosome-localized F-box mutant fails to drive cilia shortening, indicating that FBXO41's biological activity is coupled to SCF/CRL assembly. In vivo, loss of Fbxo41 in mice causes cerebellar granule neuron migration defects, an ataxia-like phenotype and cerebellar neurodegeneration. Its direct, broadly validated ubiquitination substrate repertoire remains unestablished; a less-replicated (thesis-level) model proposes an FBXO41-CUL7 complex mediating non-proteolytic K63-linked ubiquitination of neurofilament medium (NFM) to promote axon growth, alongside proposed interactions with DISC1 and NDEL1. A rare homozygous human variant (p.Arg317Gln) has been reported segregating with a neurologic phenotype, and FBXO41 shows altered DNA methylation in 22q11.2 deletion syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005737
cytoplasm
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Electronic ortholog-transfer (from mouse Q6NS60) of a generic cytoplasmic localization. Plausible for an SCF substrate adaptor that acts in the cytoplasm/cytosol, but it is generic and derives from Ensembl Compara transfer rather than direct evidence on the human protein.
Reason: Generic compartment consistent with a cytoplasmic/cytosolic SCF adaptor, but derived from ortholog transfer (GO_REF:0000107) rather than experimental evidence for human FBXO41; subsumed by the more specific cytosol annotation.
Supporting Evidence:
file:human/FBXO41/FBXO41-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
|
|
GO:0005813
centrosome
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Electronic ortholog-transfer (from mouse Q6NS60) of centrosome localization, now corroborated by primary full text of the two mouse/rat studies. King et al. 2019 (PMID:31160656) show by immunostaining and super-resolution dSTORM that Fbxo41 co-localizes with Pericentrin and resides adjacent to the centriole protein Cep135 in primary hippocampal neurons, and Mukherjee et al. 2015 (PMID:26063905) report FBXO41 localizes to the centrosome and cytoplasm of neurons. The centriolar pool is mechanistically central (its accumulation there drives cilia disassembly), though the human UniProt record itself does not mention a centrosomal location.
Reason: The annotation rests on Ensembl Compara ortholog transfer (GO_REF:0000107), and the underlying mouse/rat evidence has now been verified from primary full text (King et al. 2019, PMID:31160656; Mukherjee et al. 2015, PMID:26063905), which directly demonstrate centriolar/centrosomal localization of the ortholog. This is a core functional location rather than merely generic compartment context because centriolar FBXO41 accumulation is the experimentally tested site of its cilium-disassembly activity.
Supporting Evidence:
PMID:31160656
Super-resolution stochastic optical reconstruction microscopy (STORM) revealed that Fbxo41-EGFP resides adjacent to centrosomal protein 135 (Cep135), a centriole proximal-end protein
PMID:26063905
we identify FBXO41 as a novel CNS-specific F-box protein that localizes to the centrosome and the cytoplasm of neurons
|
|
GO:0019005
SCF ubiquitin ligase complex
|
NAS
PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... |
ACCEPT |
Summary: FBXO41 is the substrate-recognition F-box subunit of an SCF (SKP1-CUL1-F-box) E3 ligase complex. ComplexPortal curates a dedicated SCF FBXO41-variant complex (CPX-7982), and UniProt states FBXO41 directly interacts with SKP1 and CUL1. This complex membership is the best-supported aspect of FBXO41's annotation.
Reason: Consistent with the F-box/SCF architecture (F-box domain at 496-540) and with UniProt's statement of direct SKP1/CUL1 interaction; ComplexPortal curates the SCF FBXO41-variant complex (CPX-7982). Core cellular-component context for an F-box protein.
Supporting Evidence:
file:human/FBXO41/FBXO41-uniprot.txt
Directly interacts with SKP1 and CUL1.
|
|
GO:1990756
ubiquitin-like ligase-substrate adaptor activity
|
ISO
PMID:31160656 Fbxo41 Promotes Disassembly of Neuronal Primary Cilia. |
NEW |
Summary: FBXO41 is an F-box substrate-receptor subunit of an SCF ubiquitin ligase. The ortholog study demonstrates F-box-dependent association with SKP1 and CUL1, while the reviewed human UniProt record identifies FBXO41 as the substrate-recognition component of the complex. This supports the adaptor activity rather than catalytic ubiquitin-protein ligase activity, which resides in the SCF catalytic core.
Reason: GO:1990756 is the appropriate molecular function for an F-box protein that confers substrate recognition on an SCF ligase. Proposed for human FBXO41 by orthology-supported inference because the primary experiments used rodent Fbxo41 and no human FBXO41 substrate has yet been established. The absence of an identified physiological substrate limits substrate-specific process claims but does not negate the conserved substrate-adaptor role supported by the intact F-box-dependent SCF assembly and reviewed UniProt family inference.
Supporting Evidence:
PMID:31160656
Generally, F-box proteins are modular substrate binding adaptors of a Skp1/Cullin1/F-box (SCF) E3-ligase complex
PMID:31160656
Indeed, Fbxo41 associated with Skp1 and Cullin1, albeit less efficiently than Fbxo21 which was included as a positive control. Deleting (Fbxo41ฮF-box) or mutating (Fbxo41W577A) the F-box domain abolished these interactions
file:human/FBXO41/FBXO41-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
file:human/FBXO41/FBXO41-deep-research-falcon.md
Removing the F-box (Fbxo41ฮF-box) or introducing an F-box point mutation (W577A) abolishes SKP1/CUL1 interactions, indicating the F-box is required for SCF recruitment.
|
|
GO:0031146
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
|
NAS
PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... |
KEEP AS NON CORE |
Summary: As an F-box substrate receptor of an SCF complex, FBXO41 is expected to participate in SCF-dependent proteasomal degradation of its (currently unidentified) substrates. This is a family-level inference; the cited reference (PMID:34445249) is a general SCF review and does not present FBXO41-specific substrate or degradation data, and no direct experimental evidence for a human FBXO41 substrate is available.
Reason: Reasonable family-level expectation for an SCF F-box protein, but rests on NAS/general-review and similarity inference rather than direct experimental evidence for FBXO41; retained as non-core pending identification of bona fide substrates.
Supporting Evidence:
file:human/FBXO41/FBXO41-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
|
|
GO:0061523
cilium disassembly
|
ISO
PMID:31160656 Fbxo41 Promotes Disassembly of Neuronal Primary Cilia. |
NEW |
Summary: King et al. 2019 (PMID:31160656; full text read) demonstrate in primary rat hippocampal neurons and hTERT-RPE1 cells that increased centriolar accumulation of Fbxo41 promotes disassembly/shortening of primary cilia. Centrosomal Fbxo41 levels inversely correlate with cilia length, the effect requires a functional F-box domain (SCF-assembly competence) and centriolar targeting, requires actin-cytoskeleton rearrangement, and disturbs Sonic hedgehog signaling. Annotated for human FBXO41 by orthology inference (ISO) from this mouse/rat ortholog evidence.
Reason: Not currently in GOA; proposed for the human protein by orthology inference (ISO) from the mouse/rat ortholog. The primary study (King et al., Sci Rep 2019, PMID:31160656) has now been read in full and verified to assay Fbxo41 cilia-disassembly activity directly, so it is cited as the supporting reference. Remains a proposal pending human-specific confirmation.
Supporting Evidence:
PMID:31160656
We identify Fbxo41 as a novel Skp1/Cullin1/F-box (SCF) E3-ligase complex subunit that targets to neuronal centrioles where its accumulation promotes disassembly of primary cilia, and affects sonic hedgehog signaling, a canonical ciliary pathway.
|
|
GO:0001764
neuron migration
|
ISO
PMID:26063905 Loss of the neuron-specific F-box protein FBXO41 models an a... |
NEW |
Summary: Mukherjee et al. 2015 (PMID:26063905; full text read) show by in vivo electroporation that cytoplasmic FBXO41 promotes neuronal migration, and that Fbxo41-knockout mice display a severely ataxic gait with delayed migration of cerebellar granule neurons in the developing cerebellum plus degeneration of the mature cerebellum. Annotated for human FBXO41 by orthology inference (ISO) from this in vivo mouse loss-of-function evidence.
Reason: Not currently in GOA; proposed for the human protein by orthology inference (ISO) from in vivo mouse loss-of-function evidence. The primary study (Mukherjee et al., J Neurosci 2015, PMID:26063905) has now been read in full and verified to assay Fbxo41's role in granule-neuron migration directly, so it is cited as the supporting reference. A developmental process distinct from the core SCF-adaptor molecular function; remains a proposal pending human-specific confirmation.
Supporting Evidence:
PMID:26063905
we identify FBXO41 as a novel CNS-specific F-box protein that localizes to the centrosome and the cytoplasm of neurons and demonstrate that cytoplasmic FBXO41 promotes neuronal migration. Interestingly, deletion of the FBXO41 gene results in a severely ataxic gait in mice, which show delayed neuronal migration of granule neurons in the developing cerebellum
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8952618 |
KEEP AS NON CORE |
Summary: Reactome pathway-level cytosol localization assigned within generic Cullin-RING ligase (CRL1/neddylation) reactions. Plausible compartment for an SCF adaptor, but reflects pathway curation of the CRL machinery rather than FBXO41-specific experimental localization.
Reason: Cytosol is a plausible site for an SCF adaptor, but this annotation derives from Reactome CRL1 pathway reactions, not from direct FBXO41 evidence; retained as supporting localization context.
Supporting Evidence:
file:human/FBXO41/FBXO41-uniprot.txt
Directly interacts with SKP1 and CUL1.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8952620 |
KEEP AS NON CORE |
Summary: Reactome pathway-level cytosol localization assigned within generic CRL1/neddylation reactions. Duplicate of the cytosol annotation from a related Reactome reaction.
Reason: Plausible compartment for an SCF adaptor but derived from generic Reactome CRL pathway curation rather than FBXO41-specific evidence; redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXO41/FBXO41-uniprot.txt
Directly interacts with SKP1 and CUL1.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8955241 |
KEEP AS NON CORE |
Summary: Reactome pathway-level cytosol localization from the CAND1-binds-CRL reaction. Reflects generic CRL machinery curation, not FBXO41-specific localization.
Reason: Plausible but pathway-derived (generic CRL reaction); redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXO41/FBXO41-uniprot.txt
Directly interacts with SKP1 and CUL1.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8955289 |
KEEP AS NON CORE |
Summary: Reactome pathway-level cytosol localization from the COMMD-displaces-CAND1 reaction. Reflects generic CRL machinery curation, not FBXO41-specific localization.
Reason: Plausible but pathway-derived (generic CRL reaction); redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXO41/FBXO41-uniprot.txt
Directly interacts with SKP1 and CUL1.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8956040 |
KEEP AS NON CORE |
Summary: Reactome pathway-level cytosol localization from the COP9-signalosome-deneddylates-CRL reaction. Reflects generic CRL machinery curation, not FBXO41-specific localization.
Reason: Plausible but pathway-derived (generic CRL reaction); redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXO41/FBXO41-uniprot.txt
Directly interacts with SKP1 and CUL1.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-8956200 |
KEEP AS NON CORE |
Summary: Reactome pathway-level cytosol localization from the DCUN1D3-binds-CRL1 reaction. Reflects generic CRL machinery curation, not FBXO41-specific localization.
Reason: Plausible but pathway-derived (generic CRL reaction); redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXO41/FBXO41-uniprot.txt
Directly interacts with SKP1 and CUL1.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-983140 |
KEEP AS NON CORE |
Summary: Reactome pathway-level cytosol localization from a generic ubiquitination reaction (transfer of Ub from E2 to substrate). Reflects generic ubiquitin-pathway curation, not FBXO41-specific localization.
Reason: Plausible but pathway-derived (generic ubiquitination reaction); redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXO41/FBXO41-uniprot.txt
Directly interacts with SKP1 and CUL1.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-983147 |
KEEP AS NON CORE |
Summary: Reactome pathway-level cytosol localization from a generic ubiquitination reaction (release of E3 from polyubiquitinated substrate). Reflects generic ubiquitin-pathway curation, not FBXO41-specific localization.
Reason: Plausible but pathway-derived (generic ubiquitination reaction); redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXO41/FBXO41-uniprot.txt
Directly interacts with SKP1 and CUL1.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-983156 |
KEEP AS NON CORE |
Summary: Reactome pathway-level cytosol localization from a generic ubiquitination reaction (polyubiquitination of substrate). Reflects generic ubiquitin-pathway curation, not FBXO41-specific localization.
Reason: Plausible but pathway-derived (generic ubiquitination reaction); redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXO41/FBXO41-uniprot.txt
Directly interacts with SKP1 and CUL1.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-983157 |
KEEP AS NON CORE |
Summary: Reactome pathway-level cytosol localization from a generic ubiquitination reaction (interaction of E3 with substrate and E2-Ub complex). Reflects generic ubiquitin-pathway curation, not FBXO41-specific localization.
Reason: Plausible but pathway-derived (generic ubiquitination reaction); redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXO41/FBXO41-uniprot.txt
Directly interacts with SKP1 and CUL1.
|
Q: What are the physiological substrate(s) of the SCF-FBXO41 complex, and are they neuron- or brain-specific given FBXO41's strong brain/hippocampal enrichment?
Q: Does FBXO41 function as a canonical degradative SCF substrate receptor, or does it (like some FBXO proteins) have non-degradative or SCF-independent roles in neurons?
Q: What is the role of FBXO41's N-terminal C2H2 zinc-finger-like region and long coiled-coil in substrate recognition or complex assembly, distinct from the C-terminal F-box domain?
Q: Is FBXO41-driven primary cilia disassembly mediated by SCF-dependent ubiquitination of a centriolar/ciliary substrate, and which substrate links FBXO41 to actin remodeling and Aurora A in modulating Sonic hedgehog signaling?
Q: Does FBXO41 use an alternative CUL7-based ligase context in neurons to catalyze non-proteolytic K63-linked ubiquitination of neurofilament medium (NFM), and are DISC1 and NDEL1 bona fide partners/substrates relevant to axon growth and cerebellar neuron migration?
Experiment: Affinity-purify FBXO41 (e.g. tagged or endogenous) from neuronal cells or brain tissue followed by mass spectrometry to define its SCF-complex partners (confirming SKP1/CUL1/RBX1) and to identify candidate ubiquitination substrates.
Experiment: Perform comparative ubiquitinome/proteome profiling in FBXO41-knockout versus wild-type neurons (with and without proteasome inhibition) to identify proteins that accumulate upon loss of FBXO41 and are therefore candidate substrates.
Experiment: Reconstitute the SCF-FBXO41 complex in vitro with purified SKP1, CUL1, RBX1, an E1, an E2 and candidate substrates to test for direct, F-box-dependent substrate ubiquitination and to determine ubiquitin-chain linkage type.
Experiment: In primary neurons and ciliated epithelial models, quantify primary cilium length, percent ciliation and Sonic hedgehog pathway output upon FBXO41 overexpression, knockout and F-box/centrosome-targeting mutants, with actin (e.g. cytochalasin D) and Aurora A perturbations, to define how centrosomal FBXO41 couples SCF assembly to cilia disassembly.
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.
FBXO41 (F-box only protein 41; synonyms FBX41, KIAA1940) is a human F-box protein reported as an ~875 aa protein with a canonical F-box domain, consistent with the UniProt target Q8TF61 and its interpretation as a substrate-recognition/adaptor component of CullinโRING ubiquitin ligases (CRLs), especially SCF/CRL1-type complexes. The sources used here explicitly refer to FBXO41/F-box protein 41 and are not attributable to a different gene with a similar symbol. (gregianin2014identificationandcharacterisationa pages 80-83, gregianin2014identificationandcharacterisation pages 80-83)
F-box proteins are typically substrate receptors in SCF ubiquitin ligases (Skp1โCullin1โF-box), where the F-box domain mediates interaction with SKP1 and thereby recruits the substrate receptor into a CUL1-based CRL. This architecture is consistent with how FBXO41 is experimentally characterized in cell systems (association with SKP1/CUL1, dependence on an intact F-box). (king2019fbxo41promotesdisassembly pages 2-3)
The best-supported mechanistic model is that FBXO41 functions as an E3 ligase adaptor/substrate receptor that can assemble into an SCF (SKP1โCUL1) complex and, when enriched at neuronal centrosomes/centrioles, regulates primary cilium structure and associated signaling. Deleting or mutating the F-box domain abolishes SKP1/CUL1 binding, supporting the interpretation that FBXO41โs biological effects are coupled to CRL assembly. (king2019fbxo41promotesdisassembly pages 2-3)
A second, less widely replicated model (presented in thesis-level work) proposes that FBXO41 can also participate in a FBXO41โCUL7 E3 ligase complex in the nervous system, with proposed non-proteolytic ubiquitination of a neuronal cytoskeletal substrate (neurofilament medium). This suggests FBXO41 may have multiple Cullin contexts depending on cell state/compartment, but the SCF/CRL1 connection is the most directly demonstrated in the peer-reviewed cilia work. (mukherjee2015functionalanalysisof pages 142-144, mukherjee2015functionalanalysisof pages 153-156)
A human genetics/characterization study reports FBXO41 as an 875-aa F-box protein, with InterProScan predicting a canonical F-box in the C-terminal half; the N-terminus was discussed as having an โapolipophorin III-likeโ region in earlier reports, though structural modeling was limited by lack of templates. These domain-level features support an adaptor role in ubiquitin ligase systems but do not identify a catalytic reaction (FBXO41 is not an enzyme catalytic subunit). (gregianin2014identificationandcharacterisationa pages 80-83, gregianin2014identificationandcharacterisation pages 80-83)
In neuronal/cell models, FBXO41 associates with SKP1 and CUL1 (SCF complex components). Removing the F-box (Fbxo41ฮF-box) or introducing an F-box point mutation (W577A) abolishes SKP1/CUL1 interactions, indicating the F-box is required for SCF recruitment. (king2019fbxo41promotesdisassembly pages 2-3)
Importantly, a definitive, broadly validated human substrate repertoire for FBXO41 is not established in the retrieved literature; the most robust mechanistic readouts relate to centrosomal targeting and cilia phenotypes rather than identified ubiquitination substrates. (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3)
Mouse studies report FBXO41 is cytoplasmic and excluded from nucleus, and localizes prominently near the nucleus at the centrosome (pericentrin-positive). FBXO41 can be recovered with centrosome-enriched fractions, supporting authentic centrosomal association. (mukherjee2015lossofthe pages 4-4)
In the cilia-disassembly study, endogenous and overexpressed FBXO41 localizes to the pericentriolar/centriolar region in neurons; super-resolution imaging places it adjacent to centriole markers, supporting centriolar positioning as a functional compartment for regulating cilia structure. (king2019fbxo41promotesdisassembly pages 2-3)
Centrosomal targeting requires both coiled-coil and F-box domains; importantly, a centrosome-localized mutant lacking the F-box does not recapitulate cilia shortening, suggesting that localization alone is insufficient and that SCF assembly (or other F-box-dependent interactions) is required. (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 3-5)
A peer-reviewed 2019 study identifies Fbxo41 as an SCF complex subunit that targets neuronal centrioles; increased centriolar accumulation of Fbxo41 promotes primary cilia disassembly/shortening and affects Sonic hedgehog (Shh) signaling, a canonical ciliary pathway. Levels of centrosomal Fbxo41 inversely correlate with cilia length, and disrupting SCF assembly or centrosome targeting disrupts function. (King et al., Scientific Reports, publication year 2019; URL https://doi.org/10.1038/s41598-019-44589-2) (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3)
Mechanistically, Fbxo41-dependent cilia disassembly requires actin cytoskeleton rearrangements in both mitotic and post-mitotic cells, and requires Aurora A kinase activation only in mitotic contextsโhighlighting that the same adaptor can couple into distinct cilia disassembly circuitry depending on cell-cycle state. (king2019fbxo41promotesdisassembly pages 1-2)
Key experimental timing/statistics: neuronal infections at DIV1โDIV15 (to assess developing ciliogenesis) and DIV13โDIV21 (to assess disassembly after ciliogenesis) both supported a disassembly role. Knockdown was effective but did not change basal cilia parameters under the tested conditions, emphasizing that overexpression/centrosomal enrichment is a major driver in their system. (king2019fbxo41promotesdisassembly pages 3-5, king2019fbxo41promotesdisassembly pages 2-3)
Mouse knockout and developmental studies support a role for FBXO41 in cerebellar development. Loss of Fbxo41 produces an ataxia-like phenotype with neuronal migration defects and cerebellar degeneration. FBXO41 is detected early in embryogenesis (E10) and is abundant postnatally in cerebellum; it is not detected in astrocytes or oligodendrocytes in those studies, supporting neuron-enriched expression. (Mukherjee et al., Journal of Neuroscience, 2015; URL https://doi.org/10.1523/jneurosci.2133-14.2015) (mukherjee2015lossofthe pages 4-4)
Thesis-level work further argues that cytoplasmic FBXO41 is necessary and sufficient to stimulate cerebellar granule neuron migration, linking compartment-specific pools (cytoplasmic vs centrosomal) to distinct developmental outputs. (mukherjee2015functionalanalysisof pages 142-144)
The 2015 dissertation proposes that FBXO41โCUL7 mediates K63-linked polyubiquitination of NFM in a non-proteolytic manner to stabilize NFM and promote axon growth, and also suggests interactions with DISC1 and possibly NDEL1. These claims provide a plausible mechanistic bridge between ubiquitin signaling and neuronal morphogenesis but should be treated as less established than the SCF/CUL1 cilia findings because they are not presented here as a peer-reviewed primary article. (mukherjee2015functionalanalysisof pages 153-156, mukherjee2015functionalanalysisof pages 142-144)
A 2014 human study reports a novel homozygous FBXO41 variant c.950G>A (p.Arg317Gln) segregating with affected family members and absent from 400 control chromosomes. Multiple prediction metrics were reported as consistent with deleteriousness (e.g., PolyPhen2 ~0.99; MutationTaster ~0.99; GERP++ 5.17), though SIFT was reported as tolerated (0.15). This provides suggestive but not definitive evidence that FBXO41 disruption can contribute to a neurodevelopmental/neurologic phenotype in humans. (gregianin2014identificationandcharacterisationa pages 80-83, gregianin2014identificationandcharacterisation pages 80-83)
Open Targets lists FBXO41 associations to movement/ataxia-related disease concepts (e.g., generalized dystonia; infantile-onset autosomal recessive nonprogressive cerebellar ataxia; dysequilibrium syndrome), with modest overall association scores (example shown ~0.19 for generalized dystonia) and evidence largely traceable to the cerebellar/ataxia literature. (OpenTargets Search: -FBXO41)
A June 2024 medRxiv preprint studying DNA methylation in 22q11.2 deletion syndrome (22q11.2DS) reported FBXO41 as one of 15 genes consistent with a previously described episignature. In their comparison of 14 22q11.2DS patients vs 14 matched controls, FBXO41 showed 14 significant differentially methylated positions (DMPs) and a detected differentially methylated region (DMR) located on exon 2 that was hypermethylated in 22q11.2DS. This positions FBXO41 as an epigenetically altered locus in a high-risk neuropsychiatric syndrome background, although methylation changes do not directly establish FBXO41 as a causal gene for schizophrenia or other 22q11.2DS phenotypes. (Jiao et al., medRxiv; posted June 24, 2024; URL https://doi.org/10.1101/2024.06.23.24309352) (jiao2024epigeneticfactorsin pages 10-13, jiao2024epigeneticfactorsin pages 7-10)
The most concrete โreal-worldโ implementation is as a research target for dissecting neuronal centrosome/cilium biology and cilia-dependent signaling (e.g., Shh pathway modulation) in primary neuron culture and epithelial cilia models. The 2019 study also uses pharmacologic perturbations (e.g., actin modulation; Aurora A pathway modulation) to probe mechanism and rescue phenotypes, demonstrating tractable experimental levers for FBXO41-dependent cilia dynamics. (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3)
FBXO41 appears in recent multi-gene cancer/omics analyses (e.g., renal cancer panels) in which higher expression can correlate with poorer overall survival in univariate tests, but without evidence of FBXO41 as an independent predictor or mechanistic driver in the provided excerpts. Thus, at present FBXO41โs โapplicationโ in oncology is primarily as a candidate feature in bioinformatic signatures rather than an established biomarker or drug target. (yang2025fboxproteinfbxo21 pages 4-5)
Because FBXO41 is a substrate receptor rather than a catalytic enzyme, translational strategiesโif pursuedโwould likely involve (i) modulating its recruitment to centrioles/centrosomes, (ii) disrupting its interaction with SCF components, or (iii) targeting downstream substrates/pathways (e.g., actin/Aurora A-dependent cilia disassembly machinery). However, no FBXO41-directed drugs or clinical trials were identified in the retrieved evidence set. (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3)
Most reliable, mechanistically supported claims (peer-reviewed):
* FBXO41 assembles into SCF/CRL1 complexes via SKP1/CUL1 in a F-box-dependent manner and targets neuronal centrosomes/centrioles. (king2019fbxo41promotesdisassembly pages 2-3)
* Increased centrosomal FBXO41 promotes neuronal primary cilia disassembly/shortening and perturbs Shh signaling, with dependence on actin remodeling and context-dependent Aurora A involvement. (king2019fbxo41promotesdisassembly pages 1-2)
Strong phenotypic evidence (in vivo mouse):
* Fbxo41 loss leads to cerebellar migration defects, ataxia-like phenotypes, and neurodegeneration; FBXO41 is neuron-enriched and developmentally regulated in brain. (mukherjee2015lossofthe pages 4-4)
Promising but less mature areas:
* Specific ubiquitination substrates (e.g., NFM K63-ubiquitination) and alternative Cullin usage (CUL7) require more independent replication in peer-reviewed primary literature. (mukherjee2015functionalanalysisof pages 153-156)
* Human disease causality remains suggestive (segregating variant; curated disease mappings; methylation signatures) but not definitively established for specific clinical syndromes based on the evidence retrieved here. (gregianin2014identificationandcharacterisationa pages 80-83, OpenTargets Search: -FBXO41, jiao2024epigeneticfactorsin pages 10-13)
The following table consolidates identity, mechanisms, localization, processes, interaction/substrate evidence, and disease/omics findings.
| Aspect | FBXO41-specific finding | Evidence type | Organism/system | Key quantitative/statistical notes | Citations |
|---|---|---|---|---|---|
| Identity verification | Target matches human FBXO41 / F-box only protein 41, UniProt Q8TF61; reported as an 875-aa F-box protein with higher expression in nervous system, helping distinguish it from unrelated FBX genes | Human genetic / bioinformatic annotation | Human | Gregianin reports FBXO41 as 1 of 46 F-box family members; transcript/protein identifiers linked to human FBXO41 | (gregianin2014identificationandcharacterisationa pages 80-83, gregianin2014identificationandcharacterisation pages 80-83) |
| Domain architecture | Canonical F-box domain in the C-terminal half supports SCF-type adaptor role; literature also reports an N-terminal apolipophorin III-like region, while newer domain resources/UniProt list F-box-like and LRR-related signatures | Bioinformatic / domain inference | Human | Domain inference used to support ubiquitin-ligase adaptor hypothesis; N-terminal structure remained poorly templated in 2014 analysis | (gregianin2014identificationandcharacterisationa pages 80-83, gregianin2014identificationandcharacterisation pages 80-83) |
| Proposed molecular function | FBXO41 behaves as an SCF/CRL substrate adaptor: associates with SKP1 and CUL1; deletion or mutation of the F-box abolishes these interactions | Cell biology / biochemical interaction | Mouse protein in neuronal cells and hTERT-RPE1 model | FBXO41 assembles with SCF โless efficiently than Fbxo21โ; ฮF-box or W577A disrupts SKP1/CUL1 binding | (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3) |
| Alternative ligase complex model | Separate mouse work proposes a FBXO41โCUL7 E3 ligase complex in CNS neurons, implying FBXO41 may not be limited to canonical CRL1/SCF usage | Mouse functional study / thesis-level evidence | Mouse cerebellar granule neurons | Evidence is mechanistic but less independently validated than SCF/CUL1 data | (mukherjee2015functionalanalysisof pages 142-144, mukherjee2015functionalanalysisof pages 153-156) |
| Subcellular localization | FBXO41 is cytoplasmic, excluded from nucleus, with a strong centrosomal/pericentriolar/centriole pool in neurons | Mouse knockout / cell biology | Mouse neurons | Colocalizes with pericentrin; endogenous FBXO41 recovered in centrosome-enriched fraction | (king2019fbxo41promotesdisassembly pages 2-3, mukherjee2015lossofthe pages 4-4) |
| Cell-type/tissue expression | FBXO41 is neuron-enriched/CNS-selective rather than broadly glial; expression rises during brain development and is abundant postnatally in cerebellum | Expression profiling | Mouse; human inference from genetics | Detectable from E10 in mouse; not expressed in astrocytes or oligodendrocytes in cited mouse studies | (king2019fbxo41promotesdisassembly pages 2-3, mukherjee2015lossofthe pages 4-4) |
| Biological process: neuronal migration | FBXO41 is required for proper cerebellar granule neuron migration; loss causes delayed migration and persistence of cells in inappropriate layers | Mouse knockout | Mouse | FBXO41-null mice show residual external granule layer at P16 and increased cells in molecular layer; severe ataxia-like phenotype | (mukherjee2015functionalanalysisof pages 142-144, king2019fbxo41promotesdisassembly pages 3-5) |
| Biological process: axon growth | Cytoplasmic FBXO41 promotes axon growth in cerebellar granule neurons; thesis work links this to non-proteolytic ubiquitination | Mouse neuronal culture / in vivo inference | Mouse | Proposed K63-linked ubiquitination of NFM stabilizes substrate and promotes axon extension | (mukherjee2015functionalanalysisof pages 142-144, mukherjee2015functionalanalysisof pages 153-156) |
| Biological process: primary cilia disassembly | Centrosomal FBXO41 promotes neuronal primary cilia disassembly/shortening; higher centrosomal FBXO41 correlates with shorter cilia | Cell culture overexpression | Mouse primary hippocampal neurons; hTERT-RPE1 cells | Overexpression reduced both cilia length and % ciliated neurons; infected at DIV1โDIV15 or DIV13โDIV21 with similar effect | (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 3-5, king2019fbxo41promotesdisassembly pages 2-3) |
| Pathway impact: Sonic Hedgehog | By altering cilia structure, FBXO41 perturbs Sonic hedgehog (Shh) signaling, a canonical cilium-dependent pathway | Cell culture functional assay | Mouse neurons / hTERT-RPE1 cells | Cilia-disassembly phenotype depends on centrosomal targeting and SCF assembly competence | (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3) |
| Mechanistic modifiers of cilia phenotype | FBXO41-dependent cilia disassembly requires actin-cytoskeleton rearrangement; Aurora A kinase requirement is seen in mitotic but not post-mitotic cells | Cell biology / pharmacology | Mouse neurons; hTERT-RPE1 cells | Cytochalasin D and Aurora A pathway manipulation rescue/prevent shortening in the relevant contexts; PDBU recruits overexpressed FBXO41 to centrioles | (king2019fbxo41promotesdisassembly pages 1-2, king2019fbxo41promotesdisassembly pages 2-3) |
| Known/putative partners and substrates | Reported partners/substrates include SKP1, CUL1, proposed CUL7, DISC1, possible NDEL1, and proposed substrate NFM | Biochemical interaction / mouse functional study | Mouse | Direct ubiquitination substrate identification remains limited; strongest replicated partners are SCF components SKP1/CUL1 | (mukherjee2015functionalanalysisof pages 142-144, king2019fbxo41promotesdisassembly pages 2-3, mukherjee2015functionalanalysisof pages 153-156) |
| Human rare-disease genetics | A homozygous c.950G>A (p.Arg317Gln) FBXO41 variant segregated in an affected family and was absent in controls, supporting possible disease relevance but not definitive causality | Human genetic | Human | Variant absent from 400 control chromosomes; predicted damaging by PolyPhen2 ~0.99, MutationTaster ~0.99, GERP++ 5.17; SIFT 0.15 reported tolerated | (gregianin2014identificationandcharacterisationa pages 80-83, gregianin2014identificationandcharacterisation pages 80-83) |
| Phenotype association from animal model | FBXO41 loss causes early mortality, severe ataxia-like gait, cerebellar migration defects, and neurodegeneration | Mouse knockout | Mouse | Phenotypes reported around P12โP30, with strong motor abnormalities at P16/P30 | (mukherjee2015functionalanalysisof pages 142-144, mukherjee2015functionalanalysisof pages 153-156) |
| Curated disease associations | Disease databases link FBXO41 to cerebellar ataxia/dysequilibrium/dystonia-related terms, largely traceable to literature around cerebellar phenotypes rather than established therapeutic targeting | Database curation / literature aggregation | Human | Open Targets evidence scores are modest; example diseases include generalized dystonia and infantile-onset autosomal recessive nonprogressive cerebellar ataxia | (OpenTargets Search: -FBXO41) |
| 2024 epigenetic development | In 22q11.2 deletion syndrome, FBXO41 showed 14 significant DMPs and an exon 2 DMR hypermethylated in patients vs controls, placing FBXO41 among replicated episignature genes | Human epigenetics | Human blood in 22q11.2DS cohort | Comparison used 14 patients vs 14 controls; 15 genes overlapped prior episignature, including FBXO41; enrichment p-value for replicated genes 1.12e-6 | (jiao2024epigeneticfactorsin pages 7-10, jiao2024epigeneticfactorsin pages 10-13) |
| 2024 cancer/biomarker signal | FBXO41 appears in some recent pan-gene or cancer bioinformatic analyses, but evidence is indirect and not functionally validated for FBXO41 itself | Bioinformatic association | Human cancer datasets | In KIRC-related panel analyses, high FBXO41 expression associated with worse OS in univariate analysis, but not an independent predictor; no FBXO41-specific HR given in excerpt | (yang2025fboxproteinfbxo21 pages 4-5) |
| Evidence gaps / current understanding | No definitive catalytic activity, no validated small-molecule targeting, and no firmly established human substrate repertoire are currently available; best-supported role is as a neuronal ubiquitin-ligase adaptor regulating centrosome/cilia and cerebellar development | Synthesis of available evidence | Human with strong support from mouse/cell models | Strongest mechanistic evidence predates 2023; 2023โ2024 updates are mainly epigenetic or bioinformatic rather than new core biochemistry | (king2019fbxo41promotesdisassembly pages 1-2, mukherjee2015functionalanalysisof pages 142-144, king2019fbxo41promotesdisassembly pages 2-3, jiao2024epigeneticfactorsin pages 10-13) |
Table: This table summarizes verified identity, domain architecture, molecular function, localization, biological roles, partners, and disease/epigenetic associations for human FBXO41 (UniProt Q8TF61). It highlights where evidence is strongest, especially mouse and cell-based studies, and where recent human findings remain associative rather than mechanistically definitive.
References
(gregianin2014identificationandcharacterisationa pages 80-83): E Gregianin. Identification and characterisation of novel genes in motor neuron disorders. Unknown journal, 2014.
(gregianin2014identificationandcharacterisation pages 80-83): E Gregianin. Identification and characterisation of novel genes in motor neuron disorders. Unknown journal, 2014.
(king2019fbxo41promotesdisassembly pages 2-3): Cillian R. King, Ana R. A. A. Quadros, Anaรซl Chazeau, Ingrid Saarloos, Anne Jolien van der Graaf, Matthijs Verhage, and Ruud F. Toonen. Fbxo41 promotes disassembly of neuronal primary cilia. Scientific Reports, Jun 2019. URL: https://doi.org/10.1038/s41598-019-44589-2, doi:10.1038/s41598-019-44589-2. This article has 18 citations and is from a peer-reviewed journal.
(mukherjee2015functionalanalysisof pages 142-144): Chaitali Mukherjee. Functional analysis of the cns-specific f-box protein fbxo41 in cerebellar development. Unknown journal, 2015. URL: https://doi.org/10.53846/goediss-5309, doi:10.53846/goediss-5309.
(mukherjee2015functionalanalysisof pages 153-156): Chaitali Mukherjee. Functional analysis of the cns-specific f-box protein fbxo41 in cerebellar development. Unknown journal, 2015. URL: https://doi.org/10.53846/goediss-5309, doi:10.53846/goediss-5309.
(king2019fbxo41promotesdisassembly pages 1-2): Cillian R. King, Ana R. A. A. Quadros, Anaรซl Chazeau, Ingrid Saarloos, Anne Jolien van der Graaf, Matthijs Verhage, and Ruud F. Toonen. Fbxo41 promotes disassembly of neuronal primary cilia. Scientific Reports, Jun 2019. URL: https://doi.org/10.1038/s41598-019-44589-2, doi:10.1038/s41598-019-44589-2. This article has 18 citations and is from a peer-reviewed journal.
(mukherjee2015lossofthe pages 4-4): Chaitali Mukherjee, Anna Hoลubowska, Nicola Schwedhelm-Domeyer, M. Mitkovski, Shih-Ju Lee, Madhuvanthi Kannan, Annika Matz, Mayur Vadhvani, and Judith Stegmรผller. Loss of the neuron-specific f-box protein fbxo41 models an ataxia-like phenotype in mice with neuronal migration defects and degeneration in the cerebellum. The Journal of Neuroscience, 35:8701-8717, Jun 2015. URL: https://doi.org/10.1523/jneurosci.2133-14.2015, doi:10.1523/jneurosci.2133-14.2015. This article has 20 citations.
(king2019fbxo41promotesdisassembly pages 3-5): Cillian R. King, Ana R. A. A. Quadros, Anaรซl Chazeau, Ingrid Saarloos, Anne Jolien van der Graaf, Matthijs Verhage, and Ruud F. Toonen. Fbxo41 promotes disassembly of neuronal primary cilia. Scientific Reports, Jun 2019. URL: https://doi.org/10.1038/s41598-019-44589-2, doi:10.1038/s41598-019-44589-2. This article has 18 citations and is from a peer-reviewed journal.
(OpenTargets Search: -FBXO41): Open Targets Query (-FBXO41, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(jiao2024epigeneticfactorsin pages 10-13): Chuan Jiao, Fanny Demars, Anton Iftimovici, Qin He, Oussama Kebir, Anushree Tripathi, Hugo Turbรฉ, Caroline Demily, Marie-Odile Krebs, Thรฉrรจse M Jay, and Boris Chaumette. Epigenetic factors in the 22q11.2 deletion syndrome in relation to stress and schizophrenia. MedRxiv, Jun 2024. URL: https://doi.org/10.1101/2024.06.23.24309352, doi:10.1101/2024.06.23.24309352. This article has 0 citations.
(jiao2024epigeneticfactorsin pages 7-10): Chuan Jiao, Fanny Demars, Anton Iftimovici, Qin He, Oussama Kebir, Anushree Tripathi, Hugo Turbรฉ, Caroline Demily, Marie-Odile Krebs, Thรฉrรจse M Jay, and Boris Chaumette. Epigenetic factors in the 22q11.2 deletion syndrome in relation to stress and schizophrenia. MedRxiv, Jun 2024. URL: https://doi.org/10.1101/2024.06.23.24309352, doi:10.1101/2024.06.23.24309352. This article has 0 citations.
(yang2025fboxproteinfbxo21 pages 4-5): Wuping Yang, Taile Jing, Cunjin Wu, Minghao Lu, Xiaolin Yao, Dan Xia, and Ding Peng. F-box protein fbxo21 overexpression inhibits the proliferation and metastasis of clear cell renal cell carcinoma and is closely related to the creb pathway and tumor immune cell infiltration. Journal of Translational Medicine, Mar 2025. URL: https://doi.org/10.1186/s12967-025-06356-y, doi:10.1186/s12967-025-06356-y. This article has 2 citations and is from a peer-reviewed journal.
modules/cerebellum_development.yaml.neuron migration annotation:ubiquitin-like ligase-substrate adaptor activitySCF ubiquitin ligase complex in in_complex for the synthesizedUPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|LRR ; PN-node mapping: F-box subtype/type = no_mapping; group = mapped, ok_for_propagation_to_go, GO:1990756; class = context_only/too_broad (GO:0061630).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.
id: Q8TF61
gene_symbol: FBXO41
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
FBXO41 (F-box only protein 41; KIAA1940) is a brain/neuron-enriched member of
the FBXO family of F-box proteins. F-box proteins serve as the
substrate-recognition (receptor/adaptor) subunits of SCF (SKP1-CUL1-RBX1-F-box)
Cullin-RING E3 ubiquitin ligase complexes: the F-box motif docks the protein
onto the SKP1-CUL1 scaffold, while a separate substrate-binding region recruits
target proteins for poly-ubiquitination, committing them to proteasomal
degradation. FBXO41 carries a C-terminal F-box domain together with an
N-terminal C2H2 zinc-finger-like region, a long predicted coiled-coil, and
extensive intrinsically disordered/low-complexity regions, and by sequence
similarity is predicted to assemble into an SCF complex through direct
interaction with SKP1 and CUL1. FBXO41 is a neuron-specific/CNS-enriched protein
(expressed from early embryogenesis, abundant postnatally in cerebellum and
hippocampus; not detected in astrocytes or oligodendrocytes). It is cytoplasmic and
excluded from the nucleus, with a prominent centrosomal/pericentriolar pool: in
neurons FBXO41 localizes adjacent to centriole markers and co-fractionates with
centrosomes, and this targeting requires both its coiled-coil and F-box domains.
Functionally, increased centrosomal/centriolar accumulation of FBXO41 promotes
disassembly/shortening of neuronal primary cilia and thereby modulates the
cilium-dependent Sonic hedgehog (Shh) pathway; this cilia disassembly activity
depends on actin-cytoskeleton remodeling and, in mitotic contexts, on Aurora A
kinase. F-box deletion or an F-box point mutation (W577A) abolishes SKP1/CUL1
binding, and a centrosome-localized F-box mutant fails to drive cilia shortening,
indicating that FBXO41's biological activity is coupled to SCF/CRL assembly. In vivo,
loss of Fbxo41 in mice causes cerebellar granule neuron migration defects, an
ataxia-like phenotype and cerebellar neurodegeneration. Its direct, broadly validated
ubiquitination substrate repertoire remains unestablished; a less-replicated
(thesis-level) model proposes an FBXO41-CUL7 complex mediating non-proteolytic
K63-linked ubiquitination of neurofilament medium (NFM) to promote axon growth,
alongside proposed interactions with DISC1 and NDEL1. A rare homozygous human variant
(p.Arg317Gln) has been reported segregating with a neurologic phenotype, and FBXO41
shows altered DNA methylation in 22q11.2 deletion syndrome.
existing_annotations:
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: is_active_in
review:
summary: Electronic ortholog-transfer (from mouse Q6NS60) of a generic cytoplasmic
localization. Plausible for an SCF substrate adaptor that acts in the cytoplasm/cytosol,
but it is generic and derives from Ensembl Compara transfer rather than direct
evidence on the human protein.
action: KEEP_AS_NON_CORE
reason: Generic compartment consistent with a cytoplasmic/cytosolic SCF adaptor,
but derived from ortholog transfer (GO_REF:0000107) rather than experimental
evidence for human FBXO41; subsumed by the more specific cytosol annotation.
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Substrate-recognition component of the SCF (SKP1-CUL1-F-box
protein)-type E3 ubiquitin ligase complex.'
- term:
id: GO:0005813
label: centrosome
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: is_active_in
review:
summary: Electronic ortholog-transfer (from mouse Q6NS60) of centrosome localization,
now corroborated by primary full text of the two mouse/rat studies. King et al. 2019
(PMID:31160656) show by immunostaining and super-resolution dSTORM that Fbxo41
co-localizes with Pericentrin and resides adjacent to the centriole protein Cep135
in primary hippocampal neurons, and Mukherjee et al. 2015 (PMID:26063905) report
FBXO41 localizes to the centrosome and cytoplasm of neurons. The centriolar pool is
mechanistically central (its accumulation there drives cilia disassembly), though
the human UniProt record itself does not mention a centrosomal location.
action: ACCEPT
reason: The annotation rests on Ensembl Compara ortholog transfer (GO_REF:0000107),
and the underlying mouse/rat evidence has now been verified from primary full text
(King et al. 2019, PMID:31160656; Mukherjee et al. 2015, PMID:26063905), which
directly demonstrate centriolar/centrosomal localization of the ortholog. This is
a core functional location rather than merely generic compartment context because
centriolar FBXO41 accumulation is the experimentally tested site of its
cilium-disassembly activity.
additional_reference_ids:
- PMID:31160656
- PMID:26063905
supported_by:
- reference_id: PMID:31160656
supporting_text: Super-resolution stochastic optical reconstruction microscopy (STORM)
revealed that Fbxo41-EGFP resides adjacent to centrosomal protein 135 (Cep135), a
centriole proximal-end protein
- reference_id: PMID:26063905
supporting_text: we identify FBXO41 as a novel CNS-specific F-box protein that
localizes to the centrosome and the cytoplasm of neurons
- term:
id: GO:0019005
label: SCF ubiquitin ligase complex
evidence_type: NAS
original_reference_id: PMID:34445249
qualifier: part_of
review:
summary: FBXO41 is the substrate-recognition F-box subunit of an SCF (SKP1-CUL1-F-box)
E3 ligase complex. ComplexPortal curates a dedicated SCF FBXO41-variant complex
(CPX-7982), and UniProt states FBXO41 directly interacts with SKP1 and CUL1.
This complex membership is the best-supported aspect of FBXO41's annotation.
action: ACCEPT
reason: Consistent with the F-box/SCF architecture (F-box domain at 496-540) and
with UniProt's statement of direct SKP1/CUL1 interaction; ComplexPortal curates
the SCF FBXO41-variant complex (CPX-7982). Core cellular-component context for
an F-box protein.
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Directly interacts with SKP1 and CUL1.'
- term:
id: GO:1990756
label: ubiquitin-like ligase-substrate adaptor activity
evidence_type: ISO
original_reference_id: PMID:31160656
qualifier: enables
review:
summary: FBXO41 is an F-box substrate-receptor subunit of an SCF ubiquitin
ligase. The ortholog study demonstrates F-box-dependent association with SKP1
and CUL1, while the reviewed human UniProt record identifies FBXO41 as the
substrate-recognition component of the complex. This supports the adaptor
activity rather than catalytic ubiquitin-protein ligase activity, which resides
in the SCF catalytic core.
action: NEW
reason: GO:1990756 is the appropriate molecular function for an F-box protein
that confers substrate recognition on an SCF ligase. Proposed for human FBXO41
by orthology-supported inference because the primary experiments used rodent
Fbxo41 and no human FBXO41 substrate has yet been established. The absence of
an identified physiological substrate limits substrate-specific process claims
but does not negate the conserved substrate-adaptor role supported by the intact
F-box-dependent SCF assembly and reviewed UniProt family inference.
additional_reference_ids:
- file:human/FBXO41/FBXO41-uniprot.txt
- file:human/FBXO41/FBXO41-deep-research-falcon.md
supported_by:
- reference_id: PMID:31160656
supporting_text: Generally, F-box proteins are modular substrate binding adaptors
of a Skp1/Cullin1/F-box (SCF) E3-ligase complex
- reference_id: PMID:31160656
supporting_text: Indeed, Fbxo41 associated with Skp1 and Cullin1, albeit less
efficiently than Fbxo21 which was included as a positive control. Deleting
(Fbxo41ฮF-box) or mutating (Fbxo41W577A) the F-box domain abolished these
interactions
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Substrate-recognition component of the SCF (SKP1-CUL1-F-box
protein)-type E3 ubiquitin ligase complex.'
- reference_id: file:human/FBXO41/FBXO41-deep-research-falcon.md
supporting_text: Removing the F-box (Fbxo41ฮF-box) or introducing an F-box
point mutation (W577A) abolishes SKP1/CUL1 interactions, indicating the F-box
is required for SCF recruitment.
- 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: As an F-box substrate receptor of an SCF complex, FBXO41 is expected to
participate in SCF-dependent proteasomal degradation of its (currently unidentified)
substrates. This is a family-level inference; the cited reference (PMID:34445249)
is a general SCF review and does not present FBXO41-specific substrate or degradation
data, and no direct experimental evidence for a human FBXO41 substrate is available.
action: KEEP_AS_NON_CORE
reason: Reasonable family-level expectation for an SCF F-box protein, but rests on
NAS/general-review and similarity inference rather than direct experimental
evidence for FBXO41; retained as non-core pending identification of bona fide
substrates.
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Substrate-recognition component of the SCF (SKP1-CUL1-F-box
protein)-type E3 ubiquitin ligase complex.'
- term:
id: GO:0061523
label: cilium disassembly
evidence_type: ISO
original_reference_id: PMID:31160656
qualifier: involved_in
review:
summary: King et al. 2019 (PMID:31160656; full text read) demonstrate in primary rat
hippocampal neurons and hTERT-RPE1 cells that increased centriolar accumulation of
Fbxo41 promotes disassembly/shortening of primary cilia. Centrosomal Fbxo41 levels
inversely correlate with cilia length, the effect requires a functional F-box domain
(SCF-assembly competence) and centriolar targeting, requires actin-cytoskeleton
rearrangement, and disturbs Sonic hedgehog signaling. Annotated for human FBXO41 by
orthology inference (ISO) from this mouse/rat ortholog evidence.
action: NEW
reason: Not currently in GOA; proposed for the human protein by orthology inference
(ISO) from the mouse/rat ortholog. The primary study (King et al., Sci Rep 2019,
PMID:31160656) has now been read in full and verified to assay Fbxo41
cilia-disassembly activity directly, so it is cited as the supporting reference.
Remains a proposal pending human-specific confirmation.
supported_by:
- reference_id: PMID:31160656
supporting_text: We identify Fbxo41 as a novel Skp1/Cullin1/F-box (SCF) E3-ligase
complex subunit that targets to neuronal centrioles where its accumulation promotes
disassembly of primary cilia, and affects sonic hedgehog signaling, a canonical
ciliary pathway.
- term:
id: GO:0001764
label: neuron migration
evidence_type: ISO
original_reference_id: PMID:26063905
qualifier: involved_in
review:
summary: Mukherjee et al. 2015 (PMID:26063905; full text read) show by in vivo
electroporation that cytoplasmic FBXO41 promotes neuronal migration, and that
Fbxo41-knockout mice display a severely ataxic gait with delayed migration of
cerebellar granule neurons in the developing cerebellum plus degeneration of the
mature cerebellum. Annotated for human FBXO41 by orthology inference (ISO) from this
in vivo mouse loss-of-function evidence.
action: NEW
reason: Not currently in GOA; proposed for the human protein by orthology inference
(ISO) from in vivo mouse loss-of-function evidence. The primary study (Mukherjee et
al., J Neurosci 2015, PMID:26063905) has now been read in full and verified to assay
Fbxo41's role in granule-neuron migration directly, so it is cited as the supporting
reference. A developmental process distinct from the core SCF-adaptor molecular
function; remains a proposal pending human-specific confirmation.
supported_by:
- reference_id: PMID:26063905
supporting_text: we identify FBXO41 as a novel CNS-specific F-box protein that
localizes to the centrosome and the cytoplasm of neurons and demonstrate that
cytoplasmic FBXO41 promotes neuronal migration. Interestingly, deletion of the
FBXO41 gene results in a severely ataxic gait in mice, which show delayed neuronal
migration of granule neurons in the developing cerebellum
- 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 assigned within generic Cullin-RING
ligase (CRL1/neddylation) reactions. Plausible compartment for an SCF adaptor,
but reflects pathway curation of the CRL machinery rather than FBXO41-specific
experimental localization.
action: KEEP_AS_NON_CORE
reason: Cytosol is a plausible site for an SCF adaptor, but this annotation derives
from Reactome CRL1 pathway reactions, not from direct FBXO41 evidence; retained
as supporting localization context.
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Directly interacts with SKP1 and CUL1.'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8952620
qualifier: located_in
review:
summary: Reactome pathway-level cytosol localization assigned within generic CRL1/neddylation
reactions. Duplicate of the cytosol annotation from a related Reactome reaction.
action: KEEP_AS_NON_CORE
reason: Plausible compartment for an SCF adaptor but derived from generic Reactome
CRL pathway curation rather than FBXO41-specific evidence; redundant with the
other cytosol annotations.
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Directly interacts with SKP1 and CUL1.'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8955241
qualifier: located_in
review:
summary: Reactome pathway-level cytosol localization from the CAND1-binds-CRL reaction.
Reflects generic CRL machinery curation, not FBXO41-specific localization.
action: KEEP_AS_NON_CORE
reason: Plausible but pathway-derived (generic CRL reaction); redundant with the
other cytosol annotations.
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Directly interacts with SKP1 and CUL1.'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8955289
qualifier: located_in
review:
summary: Reactome pathway-level cytosol localization from the COMMD-displaces-CAND1
reaction. Reflects generic CRL machinery curation, not FBXO41-specific localization.
action: KEEP_AS_NON_CORE
reason: Plausible but pathway-derived (generic CRL reaction); redundant with the
other cytosol annotations.
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Directly interacts with SKP1 and CUL1.'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8956040
qualifier: located_in
review:
summary: Reactome pathway-level cytosol localization from the COP9-signalosome-deneddylates-CRL
reaction. Reflects generic CRL machinery curation, not FBXO41-specific localization.
action: KEEP_AS_NON_CORE
reason: Plausible but pathway-derived (generic CRL reaction); redundant with the
other cytosol annotations.
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Directly interacts with SKP1 and CUL1.'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8956200
qualifier: located_in
review:
summary: Reactome pathway-level cytosol localization from the DCUN1D3-binds-CRL1
reaction. Reflects generic CRL machinery curation, not FBXO41-specific localization.
action: KEEP_AS_NON_CORE
reason: Plausible but pathway-derived (generic CRL reaction); redundant with the
other cytosol annotations.
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Directly interacts with SKP1 and CUL1.'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-983140
qualifier: located_in
review:
summary: Reactome pathway-level cytosol localization from a generic ubiquitination
reaction (transfer of Ub from E2 to substrate). Reflects generic ubiquitin-pathway
curation, not FBXO41-specific localization.
action: KEEP_AS_NON_CORE
reason: Plausible but pathway-derived (generic ubiquitination reaction); redundant
with the other cytosol annotations.
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Directly interacts with SKP1 and CUL1.'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-983147
qualifier: located_in
review:
summary: Reactome pathway-level cytosol localization from a generic ubiquitination
reaction (release of E3 from polyubiquitinated substrate). Reflects generic
ubiquitin-pathway curation, not FBXO41-specific localization.
action: KEEP_AS_NON_CORE
reason: Plausible but pathway-derived (generic ubiquitination reaction); redundant
with the other cytosol annotations.
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Directly interacts with SKP1 and CUL1.'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-983156
qualifier: located_in
review:
summary: Reactome pathway-level cytosol localization from a generic ubiquitination
reaction (polyubiquitination of substrate). Reflects generic ubiquitin-pathway
curation, not FBXO41-specific localization.
action: KEEP_AS_NON_CORE
reason: Plausible but pathway-derived (generic ubiquitination reaction); redundant
with the other cytosol annotations.
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Directly interacts with SKP1 and CUL1.'
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-983157
qualifier: located_in
review:
summary: Reactome pathway-level cytosol localization from a generic ubiquitination
reaction (interaction of E3 with substrate and E2-Ub complex). Reflects generic
ubiquitin-pathway curation, not FBXO41-specific localization.
action: KEEP_AS_NON_CORE
reason: Plausible but pathway-derived (generic ubiquitination reaction); redundant
with the other cytosol annotations.
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Directly interacts with SKP1 and CUL1.'
references:
- id: PMID:31160656
title: Fbxo41 Promotes Disassembly of Neuronal Primary Cilia.
findings:
- statement: Fbxo41 assembles into an SCF (Skp1/Cullin1/F-box) E3-ligase complex, and
this requires an intact F-box domain; deletion or W577A point mutation of the F-box
abolishes Skp1/Cullin1 binding.
supporting_text: Fbxo41 associated with Skp1 and Cullin1, albeit less efficiently than
Fbxo21 which was included as a positive control. Deleting (Fbxo41ฮF-box) or mutating
(Fbxo41W577A) the F-box domain abolished these interactions
reference_section_type: RESULTS
- statement: Fbxo41 is a neuron-specific protein (expressed in cultured neurons but not
astrocytes) that targets to neuronal centrioles, residing adjacent to the centriole
proximal-end protein Cep135 by super-resolution dSTORM.
supporting_text: Super-resolution stochastic optical reconstruction microscopy (STORM)
revealed that Fbxo41-EGFP resides adjacent to centrosomal protein 135 (Cep135), a
centriole proximal-end protein
reference_section_type: RESULTS
- statement: Centrosomal targeting of Fbxo41 requires both its coiled-coil and F-box
domains.
supporting_text: this suggests that both the Coiled-coil and the F-box domains are
required for centrosome targeting
reference_section_type: RESULTS
- statement: Increased Fbxo41 expression promotes disassembly of primary cilia (rather
than inhibiting ciliogenesis), demonstrated in primary neurons and hTERT-RPE1 cells
with multiple cilia markers; Fbxo41 silencing has no effect, so Fbxo41 is not
required for ciliogenesis.
supporting_text: using two independent model systems and three different cilia markers,
we demonstrate that increased Fbxo41 expression robustly disassembles primary cilia
reference_section_type: RESULTS
- statement: Centrosomal Fbxo41 levels inversely correlate with neuronal cilia length,
and a functional F-box domain is required for centriole targeting and cilia
disassembly (the centriole-targeted but SCF-incompetent Fbxo41ฮCฮF does not shorten
cilia).
supporting_text: these results demonstrate that Fbxo41 requires a functional F-box
domain for centriole targeting and cilia disassembly
reference_section_type: RESULTS
- statement: Fbxo41-mediated cilia disassembly requires actin-cytoskeleton rearrangement
and proceeds by different mechanisms in mitotic cells versus neurons (Aurora A kinase
inhibition rescues disassembly only in mitotic cells, not neurons).
supporting_text: rearrangements of the actin-cytoskeleton are required for Fbxo41
mediated cilia disassembly, and that ciliary disassembly occurs via different
mechanisms in mitotic cells and neurons
reference_section_type: RESULTS
- statement: Fbxo41-induced cilia shortening impairs the ciliary Sonic hedgehog pathway,
blunting Shh-induced Gli1/Ptch1 transcriptional responses.
supporting_text: these data indicate that Fbxo41-indcued cilia disassembly affects
their signaling capacity in mitotic cells and, albeit to a lesser extent, in neurons
reference_section_type: RESULTS
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Full text read from PMC (PMC6546786). Primary Fbxo41 study in rat/mouse primary hippocampal neurons and hTERT-RPE1 cells. Verified to directly demonstrate that Fbxo41 assembles into an SCF complex, targets neuronal centrioles (Pericentrin co-localization; dSTORM adjacency to Cep135), and that its centriolar accumulation promotes primary-cilia disassembly (inverse correlation of centrosomal Fbxo41 with cilia length, F-box-domain-dependent) while perturbing Sonic hedgehog signaling. Citation is correct and supports the centrosome localization and cilium-disassembly (ISO) annotations.
- id: PMID:26063905
title: Loss of the neuron-specific F-box protein FBXO41 models an ataxia-like phenotype in mice with neuronal migration defects and degeneration in the cerebellum.
findings:
- statement: FBXO41 is a novel CNS/neuron-specific F-box protein that localizes to the
centrosome and cytoplasm of neurons, and cytoplasmic FBXO41 promotes neuronal
migration.
supporting_text: we identify FBXO41 as a novel CNS-specific F-box protein that localizes
to the centrosome and the cytoplasm of neurons and demonstrate that cytoplasmic
FBXO41 promotes neuronal migration
reference_section_type: ABSTRACT
- statement: FBXO41 protein is restricted to CNS tissues (cortex, hippocampus, cerebellum,
spinal cord), absent from peripheral nerve and non-neural tissues, detectable from
embryonic day 10, and expressed in cultured granule neurons but not astrocytes or
oligodendrocytes.
supporting_text: We found FBXO41 to be expressed in CNS tissues including cortex,
hippocampus, cerebellum, and spinal cord, but absent from the peripheral nervous
system tissue such as sciatic nerve and from non-neural tissues
reference_section_type: RESULTS
- statement: Endogenous FBXO41 is cytoplasmic and excluded from the nucleus, with a
centrosomal pool confirmed by GFP-FBXO41 colocalization with pericentrin 2 and
cosegregation of endogenous FBXO41 with gamma-tubulin in centrosome purifications.
supporting_text: we discovered a conspicuous dot-like accumulation of FBXO41 near the
nucleus, which we later confirmed to be the centrosome because GFP-FBXO41 colocalized
with the centrosomal marker pericentrin 2
reference_section_type: RESULTS
- statement: A centrosomal targeting region (CTR, aa 179-354) directs FBXO41 to the
centrosome; FBXO41 lacking the CTR fails to localize to the centrosome and disperses
in the cytoplasm, establishing dual centrosomal/cytoplasmic localization.
supporting_text: we refer to it as centrosomal targeting region (CTR, aa 179โ354)
hereafter
reference_section_type: RESULTS
- statement: In vivo electroporation knockdown of FBXO41 in P4 rat cerebellum stalls
granule neurons in the EGL/molecular layer with fewer reaching the inner IGL,
indicating slower migration; FBXO41 promotes neuronal migration.
supporting_text: we found that significantly more FBXO41 knock-down neurons were stalled
in the EGL/ML
reference_section_type: RESULTS
- statement: Rescue with the cytoplasm-only FBXO41 (lacking the CTR), but not
centrosome-targeted forms, restores migration, and FBXO41 gain-of-function
accelerates migration into the inner IGL, showing the cytoplasmic pool is the crucial
one for migration.
supporting_text: Collectively, these data indicate that the FBXO41 RNAi-induced
phenotype is specific to FBXO41 and suggest that cytoplasmic FBXO41 is crucial to
stimulate the migration of cerebellar granule neurons
reference_section_type: RESULTS
- statement: FBXO41-knockout mice have high perinatal lethality and at P16 display a
severely ataxic gait with hind-limb dragging, impaired balance, tremors, and hindlimb
clasping.
supporting_text: mice displayed an abnormal gait characterized by dragging of the hind
limbs, impaired balance, and tremors
reference_section_type: RESULTS
- statement: The FBXO41-knockout cerebellum shows delayed granule-neuron migration
(residual EGL and excess molecular-layer cells across P12-P30); migrating cells
eventually reach the IGL, so FBXO41 sets migration speed rather than being strictly
essential.
supporting_text: although the migrating cells eventually catch up and reach the IGL,
FBXO41 is required to maintain a normal migration speed in the cerebellum
reference_section_type: RESULTS
- statement: Neurodegeneration in the knockout is age-dependent, absent at P16 but by P30
showing a significant increase in apoptotic (TUNEL+) cells in hippocampus and
cerebellum, alongside a distorted, smaller cerebellum.
supporting_text: found little or no increase of apoptotic cells in the cortex but a
significant increase in the hippocampus and the cerebellum
reference_section_type: RESULTS
- statement: FBXO41 has a cell-autonomous prosurvival role in neurons; functional RNAi
knockdown increases cleaved-caspase-3+ granule neurons, rescued by RNAi-resistant
FBXO41.
supporting_text: These results support a prosurvival role for FBXO41 in neurons.
reference_section_type: RESULTS
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: 'Full text read from PMC (PMC6605212), including the Results section
retrieved from the PMC HTML and appended to the cached publication (the eutils HTML
fallback had captured only Abstract/Introduction/Discussion). Primary in vivo study
of the neuron-specific F-box protein FBXO41 in mouse/rat cerebellum. Verified to
directly demonstrate CNS-restricted neuron-specific expression; cytoplasmic plus
centrosomal localization (pericentrin 2 / gamma-tubulin) via a CTR (aa 179-354); that
cytoplasmic FBXO41 promotes granule-neuron migration (RNAi knockdown, CTR rescue, and
gain-of-function in vivo electroporation); a severely ataxic FBXO41-knockout
phenotype with delayed cerebellar migration; and age-dependent (P30) cerebellar/
hippocampal neurodegeneration plus a cell-autonomous prosurvival role. Citation is
correct and supports the neuron-migration (ISO) and centrosome annotations.'
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to
orthologs using Ensembl Compara
findings: []
- id: PMID:34445249
title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
findings:
- statement: The SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complexes modify substrates
with poly-ubiquitin chains to target them for proteasomal degradation, with
variable F-box proteins determining substrate specificity.
reference_section_type: ABSTRACT
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: 'PubMed-verified (Int J Mol Sci 2021, PMC8395177); a general review
of SCF complex biology. Abstract-only in cache (full_text_available: false).
It establishes the general F-box/SCF substrate-receptor framework but does NOT
present FBXO41-specific substrate or process data, so it supports the SCF-context
annotations only at the family level.'
- id: file:human/FBXO41/FBXO41-deep-research-falcon.md
title: Falcon deep research report for human FBXO41
findings:
- statement: FBXO41 assembles into SCF/CRL1 complexes via SKP1/CUL1 in an F-box-dependent manner (deletion or W577A mutation of the F-box abolishes SKP1/CUL1 binding) and targets neuronal centrosomes/centrioles.
supporting_text: 'In neuronal/cell models, FBXO41 associates with **SKP1** and **CUL1** (SCF complex components). Removing the F-box (Fbxo41ฮF-box) or introducing an F-box point mutation (W577A) abolishes SKP1/CUL1 interactions, indicating the F-box is required for SCF recruitment.'
- statement: FBXO41 is cytoplasmic, excluded from the nucleus, and has a prominent centrosomal/pericentriolar pool (pericentrin-positive, recoverable in centrosome-enriched fractions).
supporting_text: Mouse studies report FBXO41 is cytoplasmic and excluded from nucleus, and localizes prominently near the nucleus at the **centrosome** (pericentrin-positive). FBXO41 can be recovered with centrosome-enriched fractions, supporting authentic centrosomal association.
- statement: Increased centrosomal FBXO41 promotes disassembly/shortening of neuronal primary cilia and perturbs Sonic hedgehog signaling, dependent on actin remodeling and (in mitotic cells) Aurora A kinase.
supporting_text: increased centriolar accumulation of Fbxo41 **promotes primary cilia disassembly/shortening** and affects **Sonic hedgehog (Shh)** signaling, a canonical ciliary pathway. Levels of centrosomal Fbxo41 inversely correlate with cilia length, and disrupting SCF assembly or centrosome targeting disrupts function.
- statement: Loss of Fbxo41 in mice produces cerebellar granule neuron migration defects, an ataxia-like phenotype and cerebellar neurodegeneration; FBXO41 is neuron-enriched and developmentally regulated.
supporting_text: Loss of Fbxo41 produces an ataxia-like phenotype with neuronal migration defects and cerebellar degeneration. FBXO41 is detected early in embryogenesis (E10) and is abundant postnatally in cerebellum; it is not detected in astrocytes or oligodendrocytes in those studies, supporting neuron-enriched expression.
- statement: A definitive, broadly validated human ubiquitination substrate repertoire for FBXO41 is not established; the strongest mechanistic readouts concern centrosomal targeting and cilia phenotypes rather than identified substrates.
supporting_text: a definitive, broadly validated human substrate repertoire for FBXO41 is not established in the retrieved literature; the most robust mechanistic readouts relate to centrosomal targeting and cilia phenotypes rather than identified ubiquitination substrates.
reference_review:
relevance: HIGH
correctness: UNVERIFIED
review_notes: 'Falcon (Edison Scientific) deep-research synthesis. It names peer-reviewed primary literature (King et al., Sci Rep 2019, PMID:31160656 / DOI 10.1038/s41598-019-44589-2: SCF/CUL1 assembly, centrosomal targeting, cilia disassembly, Shh; Mukherjee et al., J Neurosci 2015, PMID:26063905 / DOI 10.1523/jneurosci.2133-14.2015: centrosomal localization, cerebellar migration/ataxia). The FBXO41-CUL7/NFM K63-ubiquitination and DISC1/NDEL1 partner claims are thesis-level (Mukherjee 2015 dissertation) and treated as preliminary. The named PMIDs are confirmed to exist but their full texts were not read here, so this synthesis is marked UNVERIFIED and used only as leads (the orthology-based annotations are recorded as ISO citing the primaries).'
- 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 (F-box) subunit of an SCF (SKP1-CUL1-RBX1-F-box)
Cullin-RING E3 ubiquitin ligase complex; FBXO41 contributes a substrate-binding
receptor function and assembles onto the SKP1-CUL1 scaffold via its F-box domain
(F-box deletion or the W577A mutation abolishes SKP1/CUL1 binding). The catalytic
ubiquitin-transfer activity of the complex resides in RBX1, not in FBXO41. FBXO41's
specific physiological ubiquitination substrate(s) remain unidentified, so this is
an adaptor/complex-membership function rather than a defined substrate-degradation role.
molecular_function:
id: GO:1990756
label: ubiquitin-like ligase-substrate adaptor activity
supported_by:
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Substrate-recognition component of the SCF (SKP1-CUL1-F-box
protein)-type E3 ubiquitin ligase complex.'
- reference_id: file:human/FBXO41/FBXO41-uniprot.txt
supporting_text: 'Directly interacts with SKP1 and CUL1.'
- reference_id: PMID:31160656
supporting_text: Fbxo41 associated with Skp1 and Cullin1, albeit less efficiently than
Fbxo21 which was included as a positive control. Deleting (Fbxo41ฮF-box) or mutating
(Fbxo41W577A) the F-box domain abolished these interactions
- reference_id: file:human/FBXO41/FBXO41-deep-research-falcon.md
supporting_text: Removing the F-box (Fbxo41ฮF-box) or introducing an F-box
point mutation (W577A) abolishes SKP1/CUL1 interactions, indicating the F-box
is required for SCF recruitment.
in_complex:
id: GO:0019005
label: SCF ubiquitin ligase complex
- description: Neuron-specific regulator of primary cilium structure that, from its
centrosomal/centriolar pool, promotes disassembly/shortening of neuronal primary
cilia (centrosomal FBXO41 levels inversely correlate with cilium length) and thereby
modulates cilium-dependent Sonic hedgehog signaling; this activity requires actin
remodeling and, in mitotic contexts, Aurora A kinase, and is coupled to SCF/CRL
assembly (an F-box mutant that still localizes to the centrosome fails to shorten cilia).
molecular_function:
id: GO:1990756
label: ubiquitin-like ligase-substrate adaptor activity
locations:
- id: GO:0005813
label: centrosome
supported_by:
- reference_id: PMID:31160656
supporting_text: We identify Fbxo41 as a novel Skp1/Cullin1/F-box (SCF) E3-ligase
complex subunit that targets to neuronal centrioles where its accumulation promotes
disassembly of primary cilia, and affects sonic hedgehog signaling, a canonical
ciliary pathway.
- reference_id: PMID:31160656
supporting_text: these results demonstrate that Fbxo41 requires a functional F-box
domain for centriole targeting and cilia disassembly
directly_involved_in:
- id: GO:0061523
label: cilium disassembly
in_complex:
id: GO:0019005
label: SCF ubiquitin ligase complex
proposed_new_terms: []
suggested_questions:
- question: What are the physiological substrate(s) of the SCF-FBXO41 complex, and
are they neuron- or brain-specific given FBXO41's strong brain/hippocampal
enrichment?
- question: Does FBXO41 function as a canonical degradative SCF substrate receptor,
or does it (like some FBXO proteins) have non-degradative or SCF-independent
roles in neurons?
- question: What is the role of FBXO41's N-terminal C2H2 zinc-finger-like region and
long coiled-coil in substrate recognition or complex assembly, distinct from the
C-terminal F-box domain?
- question: Is FBXO41-driven primary cilia disassembly mediated by SCF-dependent
ubiquitination of a centriolar/ciliary substrate, and which substrate links FBXO41
to actin remodeling and Aurora A in modulating Sonic hedgehog signaling?
- question: Does FBXO41 use an alternative CUL7-based ligase context in neurons to
catalyze non-proteolytic K63-linked ubiquitination of neurofilament medium (NFM),
and are DISC1 and NDEL1 bona fide partners/substrates relevant to axon growth and
cerebellar neuron migration?
suggested_experiments:
- description: Affinity-purify FBXO41 (e.g. tagged or endogenous) from neuronal cells
or brain tissue followed by mass spectrometry to define its SCF-complex partners
(confirming SKP1/CUL1/RBX1) and to identify candidate ubiquitination substrates.
- description: Perform comparative ubiquitinome/proteome profiling in FBXO41-knockout
versus wild-type neurons (with and without proteasome inhibition) to identify
proteins that accumulate upon loss of FBXO41 and are therefore candidate substrates.
- description: Reconstitute the SCF-FBXO41 complex in vitro with purified SKP1, CUL1,
RBX1, an E1, an E2 and candidate substrates to test for direct, F-box-dependent
substrate ubiquitination and to determine ubiquitin-chain linkage type.
- description: In primary neurons and ciliated epithelial models, quantify primary
cilium length, percent ciliation and Sonic hedgehog pathway output upon FBXO41
overexpression, knockout and F-box/centrosome-targeting mutants, with actin
(e.g. cytochalasin D) and Aurora A perturbations, to define how centrosomal FBXO41
couples SCF assembly to cilia disassembly.