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 (Fbxo41ΔF-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 (Fbxo41ΔF-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 (Fbxo41ΔF-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 Fbxo41ΔCΔF 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 179–354) 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 (Fbxo41ΔF-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 (Fbxo41ΔF-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 (Fbxo41ΔF-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.