id: Q8NI29 gene_symbol: FBXO27 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXO27 (FBG5, FBX27) is a member of the FBA/FBG (F-box-associated, "sugar recognition") subfamily of F-box proteins that act as the substrate-recognition receptor of SCF (SKP1-CUL1-F-box)-type E3 ubiquitin ligase complexes. Like its paralogs FBXO2, FBXO6, FBXO17 and FBXO44, FBXO27 contains an N-terminal F-box domain that docks the protein onto SKP1 (and thereby onto the CUL1-RBX1 catalytic core) and a C-terminal FBA/G domain that functions as a lectin, recognizing N-linked oligosaccharides on glycoproteins through a conserved hydrophobic pocket (the aromatic Phe-Trp pair at positions 262-263 is required for high-affinity glycan binding). As an F-box protein, FBXO27 has no intrinsic catalytic activity; it confers substrate specificity to the assembled SCF complex, in which the RING subunit RBX1 recruits the ubiquitin-charged E2 enzyme and catalyzes ubiquitin transfer onto the bound glycoprotein. By binding glycans normally hidden inside the secretory pathway, FBXO27 contributes to recognition of N-glycosylated proteins that become aberrantly exposed to the cytosol. Its best-characterized cellular role is in the endo-lysosomal damage response: unlike its mostly cytosolic paralogs, FBXO27 is N-terminally myristoylated and membrane-associated, and after lysosomal membrane rupture it is recruited to damaged lysosomes where luminal glycans become exposed to the cytosol. There SCF(FBXO27) ubiquitinates the exposed luminal glycans of lysosomal membrane glycoproteins, most prominently LAMP2 (and LAMP1) along with other candidate damaged-lysosome glycoproteins, triggering recruitment of the autophagy adaptors p62/SQSTM1 and LC3 and promoting selective autophagy of the damaged lysosome (lysophagy). This couples a physical damage cue (cytosolic glycan exposure) to ubiquitin signaling and autophagic clearance; the same LAMP2-directed activity has been implicated in cardiomyocyte and neuronal autophagy/lysosomal quality control. FBXO27 may also act on misfolded glycoproteins retrotranslocated from the ER, but it contributes only partially to lysosomal ubiquitylation and shows cell-type-specific (brain, heart, kidney) expression, consistent with redundancy among lysophagy E3 ligases. existing_annotations: - term: id: GO:0036503 label: ERAD pathway evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic (PAN-GO) assignment of involvement in ERAD, propagated across the FBA/FBG lectin F-box family from members such as FBXO2/FBXO6 that recognize high-mannose glycans on retrotranslocated ER glycoproteins. action: KEEP_AS_NON_CORE reason: FBXO27 is a glycoprotein-recognition SCF substrate receptor, and ERAD/GERAD is a plausible context for the family; however the original characterization of FBXO27 itself found only modest high-mannose glycoprotein binding and did not demonstrate a direct ERAD role. The best-characterized FBXO27 function is instead recognition of luminal glycans exposed on damaged lysosomes and ubiquitylation of lysosomal glycoproteins (LAMP2/LAMP1) to drive lysophagy, not ER-associated degradation. ERAD is therefore retained as a non-core, family-level process annotation rather than the core function; the broader glycoprotein catabolic process better captures FBXO27's role. supported_by: - reference_id: PMID:18203720 supporting_text: Our results lead us to conclude that only some members of the FBA family (FBXO2 and FBXO6) could function in GERAD by recognizing the signature high mannose glycan moiety present on retrotranslocated ER proteins. - reference_id: file:human/FBXO27/FBXO27-deep-research-falcon.md supporting_text: after lysosomal membrane rupture, SCF^FBXO27 ubiquitylates **luminally glycosylated regions** of lysosomal membrane proteins, prominently **LAMP2** (and also LAMP1). In LLOMe-induced lysosomal damage models, FBXO27-dependent ubiquitylation of LAMP2 facilitates recruitment of autophagy machinery (e.g., p62 and LC3), thereby promoting lysophagy. - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic assignment of cytoplasmic localization, consistent with FBA-family F-box proteins acting on the cytosolic face of the ubiquitin-proteasome system where glycoproteins are exposed to cytosolic SCF complexes. action: KEEP_AS_NON_CORE reason: Correct but generic compartment; FBXO27 acts as a cytosolic SCF substrate receptor. The cytosol (GO:0005829) and SCF complex (GO:0019005) annotations are more specific. Retained as a supporting localization. supported_by: - reference_id: PMID:18203720 supporting_text: It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. - term: id: GO:0006516 label: glycoprotein catabolic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic assignment of involvement in glycoprotein catabolism, the defining biological role of the FBA/FBG lectin F-box family that recognizes glycans on glycoproteins and targets them for ubiquitin-mediated degradation. action: ACCEPT reason: Core biological process; FBXO27 is a glycan-recognition SCF substrate receptor that routes bound glycoproteins to ubiquitin-dependent degradation. Directly supported by the lectin activity and SCF-complex assembly demonstrated for FBXO27. supported_by: - reference_id: PMID:18203720 supporting_text: These differences in substrate recognition, SCF complex formation, and tissue distribution suggest that FBA proteins play diverse roles in glycoprotein quality control. - reference_id: file:human/FBXO27/FBXO27-uniprot.txt supporting_text: Able to recognize and bind denatured glycoproteins, which are modified with complex-type oligosaccharides. - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: Phylogenetic assignment of FBXO27 as part of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, the canonical complex in which all FBA-family F-box proteins act as substrate-recognition subunits. action: ACCEPT reason: Core cellular component; FBXO27 assembles into the SCF complex via its F-box domain. Independently supported by IDA (PMID:18203720, co-IP of SKP1/CUL1/RBX1) and a dedicated ComplexPortal entry (CPX-7966, SCF E3 ubiquitin ligase complex, FBXO27 variant). supported_by: - reference_id: PMID:18203720 supporting_text: All FBA family members co-immunoprecipitated components of the SCF complex - reference_id: file:human/FBXO27/FBXO27-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex. - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic assignment of involvement in SCF-dependent proteasomal degradation, reflecting FBXO27's role as the substrate-recognition subunit that delivers glycoprotein substrates to the SCF complex for ubiquitination and proteasomal turnover. action: ACCEPT reason: Core biological process; consistent with FBXO27 functioning as an SCF substrate receptor. The SCF complex assembles poly-ubiquitin chains that target substrates to the proteasome. supported_by: - reference_id: PMID:18203720 supporting_text: When an SCF complex binds a substrate protein, a ubiquitin-conjugating enzyme associates with the complex via Rbx1 and ubiquitinates the substrate protein. - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: contributes_to review: summary: Phylogenetic assignment of ubiquitin protein ligase activity with a contributes_to qualifier, reflecting that the F-box substrate receptor contributes to the ligase activity of the assembled SCF complex rather than possessing intrinsic catalytic activity. action: KEEP_AS_NON_CORE reason: FBXO27 itself has no catalytic ubiquitin ligase activity; the catalytic RING subunit of the SCF complex is RBX1. The contributes_to qualifier correctly frames this as a contribution to the holoenzyme's activity rather than a property of FBXO27 alone, but the informative core molecular function of FBXO27 is carbohydrate (glycan) binding, not ligase catalysis. Retained as non-core; using contributes_to it is defensible, so MODIFY/REMOVE are not warranted. supported_by: - reference_id: PMID:18203720 supporting_text: As the substrate recognition subunits of multiprotein ubiquitin ligase complexes, F-box proteins have no intrinsic catalytic activity of their own. - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: ARBA machine-learning electronic assignment of cytoplasmic localization, consistent with FBXO27 acting as a cytosolic SCF substrate receptor. action: KEEP_AS_NON_CORE reason: Correct but generic; redundant with the IBA cytoplasm and the more specific cytosol/SCF complex annotations. supported_by: - reference_id: PMID:18203720 supporting_text: It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: HuRI binary interactome capture of the FBXO27-SKP1 interaction (WITH UniProtKB:P63208), the F-box/SKP1 contact that anchors FBXO27 into the SCF complex. Bare protein binding is uninformative as a function. action: KEEP_AS_NON_CORE reason: Records the real, functionally meaningful FBXO27-SKP1 interaction, but per curation guidelines bare protein binding is uninformative; the SCF-complex membership (GO:0019005) captures the biology. supported_by: - reference_id: file:human/FBXO27/FBXO27-uniprot.txt supporting_text: 'Q8NI29; P63208: SKP1; NbExp=3; IntAct=EBI-6425694, EBI-307486;' - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:34445249 qualifier: part_of review: summary: ComplexPortal/author-statement assignment of FBXO27 as part of an SCF E3 ubiquitin ligase complex, in which variable F-box proteins determine substrate specificity. Core cellular component. action: ACCEPT reason: Core cellular component; consistent with the IDA SCF-complex annotation and the dedicated ComplexPortal entry CPX-7966 (SCF E3 ubiquitin ligase complex, FBXO27 variant). supported_by: - reference_id: PMID:34445249 supporting_text: These SCF complexes are distinguishable by variable F-box proteins, which determine substrate specificity. - 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: ComplexPortal/author-statement assignment of involvement in SCF-dependent proteasomal protein catabolism, the canonical process of the SCF E3 ligases that target substrates with poly-ubiquitin chains for proteasomal degradation. action: ACCEPT reason: Core biological process; consistent with FBXO27 acting as the substrate receptor of an SCF complex that drives proteasomal degradation. supported_by: - reference_id: PMID:34445249 supporting_text: a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952618 qualifier: located_in review: summary: Reactome curation of cytosolic localization within CRL/SCF neddylation reactions (AcM-UBE2M transfers NEDD8 to CRL1). FBXO27 acts as a cytosolic SCF substrate receptor. action: ACCEPT reason: Correct localization; FBXO27 functions in the cytosol as part of cytosolic CRL1/SCF complexes. Redundant with the IBA/IEA cytoplasm annotations. supported_by: - reference_id: PMID:18203720 supporting_text: It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome curation of cytosolic localization within a CRL1/SCF neddylation reaction (NEDD8:AcM-UBE2M binds CRL1). Consistent with FBXO27's cytosolic SCF context. action: ACCEPT reason: Correct localization; redundant with other cytosol/cytoplasm annotations. supported_by: - reference_id: PMID:18203720 supporting_text: It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome curation of cytosolic localization within a CRL regulation reaction (CAND1 binds cytosolic CRL E3 ligases). Consistent with FBXO27's cytosolic SCF context. action: ACCEPT reason: Correct localization; redundant with other cytosol/cytoplasm annotations. supported_by: - reference_id: PMID:18203720 supporting_text: It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome curation of cytosolic localization within a CRL regulation reaction (COMMDs displace CAND1 from cytosolic CRL complexes). Consistent with FBXO27's cytosolic SCF context. action: ACCEPT reason: Correct localization; redundant with other cytosol/cytoplasm annotations. supported_by: - reference_id: PMID:18203720 supporting_text: It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome curation of cytosolic localization within a CRL regulation reaction (COP9 signalosome deneddylates cytosolic CRL complexes). Consistent with FBXO27's cytosolic SCF context. action: ACCEPT reason: Correct localization; redundant with other cytosol/cytoplasm annotations. supported_by: - reference_id: PMID:18203720 supporting_text: It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome curation of cytosolic localization within a CRL1 neddylation reaction (MyrG-DCUN1D3 binds CRL1). Consistent with FBXO27's cytosolic SCF context. action: ACCEPT reason: Correct localization; redundant with other cytosol/cytoplasm annotations. supported_by: - reference_id: PMID:18203720 supporting_text: It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (transfer of Ub from E2 to substrate). Consistent with FBXO27's cytosolic SCF context. action: ACCEPT reason: Correct localization; redundant with other cytosol/cytoplasm annotations. supported_by: - reference_id: PMID:18203720 supporting_text: When an SCF complex binds a substrate protein, a ubiquitin-conjugating enzyme associates with the complex via Rbx1 and ubiquitinates the substrate protein. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (release of E3 from polyubiquitinated substrate). Consistent with FBXO27's cytosolic SCF context. action: ACCEPT reason: Correct localization; redundant with other cytosol/cytoplasm annotations. supported_by: - reference_id: PMID:18203720 supporting_text: When an SCF complex binds a substrate protein, a ubiquitin-conjugating enzyme associates with the complex via Rbx1 and ubiquitinates the substrate protein. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (polyubiquitination of substrate). Consistent with FBXO27's cytosolic SCF context. action: ACCEPT reason: Correct localization; redundant with other cytosol/cytoplasm annotations. supported_by: - reference_id: PMID:18203720 supporting_text: When an SCF complex binds a substrate protein, a ubiquitin-conjugating enzyme associates with the complex via Rbx1 and ubiquitinates the substrate protein. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (interaction of E3 with substrate and E2-Ub complex). Consistent with FBXO27's cytosolic SCF context. action: ACCEPT reason: Correct localization; redundant with other cytosol/cytoplasm annotations. supported_by: - reference_id: PMID:18203720 supporting_text: When an SCF complex binds a substrate protein, a ubiquitin-conjugating enzyme associates with the complex via Rbx1 and ubiquitinates the substrate protein. - term: id: GO:0005515 label: protein binding evidence_type: IDA original_reference_id: PMID:18203720 qualifier: enables review: summary: IDA capture of FBXO27 binding to glycoproteins/SCF components in the lectin-family study. Bare protein binding is uninformative; the informative function is carbohydrate (glycan) binding via the FBA/G domain. action: MODIFY reason: The underlying experiments demonstrate that FBXO27 binds glycoproteins through their N-linked oligosaccharides via the FBA/G-domain lectin pocket (Phe262-Trp263), which is FBXO27's core, informative molecular function. Bare protein binding (GO:0005515) under-describes this; replace with carbohydrate binding (and specifically high-mannose oligosaccharide binding). proposed_replacement_terms: - id: GO:0030246 label: carbohydrate binding - id: GO:0005537 label: D-mannose binding supported_by: - reference_id: file:human/FBXO27/FBXO27-uniprot.txt supporting_text: Able to recognize and bind denatured glycoproteins, which are modified with complex-type oligosaccharides. - reference_id: PMID:18203720 supporting_text: revealed that glycan binding requires the conserved hydrophobic pocket within the FBA domain - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18203720 qualifier: enables review: summary: IPI capture of FBXO27 interactions with SCF components (WITH UniProtKB:P63208 SKP1 and UniProtKB:Q13616 CUL1), the F-box/SKP1-CUL1 contacts that integrate FBXO27 into the SCF complex. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the real and functionally important FBXO27-SKP1 and FBXO27-CUL1 interactions, but bare protein binding is uninformative; the SCF-complex membership annotation (GO:0019005) captures this biology. supported_by: - reference_id: file:human/FBXO27/FBXO27-uniprot.txt supporting_text: Interacts with SKP1 and CUL1. - reference_id: PMID:18203720 supporting_text: All FBA family members co-immunoprecipitated components of the SCF complex - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:18203720 qualifier: part_of review: summary: Direct experimental demonstration (co-immunoprecipitation of SKP1, Cullin1 and RBX1) that FBXO27 assembles into a canonical SCF E3 ubiquitin ligase complex. Core cellular component. action: ACCEPT reason: Core cellular component with direct experimental support; FBXO27 co-precipitates the SKP1, Cullin1 and RBX1 components of the SCF complex. supported_by: - reference_id: PMID:18203720 supporting_text: All FBA family members co-immunoprecipitated components of the SCF complex - reference_id: PMID:18203720 supporting_text: All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1) references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:18203720 title: Diversity in tissue expression, substrate binding, and SCF complex formation for a lectin family of ubiquitin ligases. findings: - statement: FBXO27 is a member of the FBA/FBG lectin family of F-box proteins; it binds glycoproteins via a conserved hydrophobic pocket in the FBA/G domain (the aromatic residues at 262-263 in FBXO27), assembles with SKP1, Cullin1 and RBX1 into the canonical SCF E3 ubiquitin ligase complex, and as an F-box protein has no intrinsic catalytic activity. reference_section_type: RESULTS reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Full text available (PMC2442310). Foundational characterization of FBXO27 as an FBA-family lectin SCF substrate receptor; source of the sugar-binding/FUNCTION, SKP1/CUL1 interaction, SCF-complex (IDA) and G-domain mutagenesis (262-263) annotations. Note FBXO27 showed only modest high-mannose glycoprotein binding by co-IP and little binding on the glycan array, so its precise glycan substrate set is less well-defined than that of FBXO2/FBXO6. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: - statement: HuRI binary interactome map; captures the FBXO27-SKP1 (P63208) interaction. reference_section_type: ABSTRACT reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput binary interactome (HuRI); source of a bare protein binding annotation supporting the FBXO27-SKP1 interaction. - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: - statement: Review of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complexes; variable F-box proteins determine substrate specificity and the complexes poly-ubiquitinate substrates for proteasomal degradation. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Abstract-only review (full_text_available false); ComplexPortal-cited NAS source for FBXO27 SCF-complex membership and SCF-dependent proteasomal catabolism annotations. - 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: [] - id: file:human/FBXO27/FBXO27-deep-research-falcon.md title: Falcon deep research report for human FBXO27 findings: - statement: FBXO27 (Fbs3/FBG5) is the substrate-recognition subunit of an SCF-type E3 ubiquitin ligase (SCF^FBXO27), directing ubiquitylation of substrates that present accessible N-glycans. supporting_text: FBXO27 functions as the **substrate-recognition subunit** of an SCF-type E3 ubiquitin ligase (**SCF^FBXO27**), directing ubiquitylation of substrates that present accessible **N-glycans**. - statement: After lysosomal membrane rupture, SCF^FBXO27 ubiquitylates luminally glycosylated regions of lysosomal membrane proteins, prominently LAMP2 (and LAMP1), recruiting p62 and LC3 to promote lysophagy. supporting_text: after lysosomal membrane rupture, SCF^FBXO27 ubiquitylates **luminally glycosylated regions** of lysosomal membrane proteins, prominently **LAMP2** (and also LAMP1). In LLOMe-induced lysosomal damage models, FBXO27-dependent ubiquitylation of LAMP2 facilitates recruitment of autophagy machinery (e.g., p62 and LC3), thereby promoting lysophagy. - statement: FBXO27 is N-terminally myristoylated and membrane-associated, which is required for efficient recruitment to damaged lysosomes; myristoylation-defective mutants become cytosolic and fail to be recruited. supporting_text: FBXO27 is distinguished among glycoprotein-binding F-box proteins by **N-terminal myristoylation**, conferring **membrane association** that is required for efficient recruitment to damaged lysosomes. In the PNAS lysophagy study, myristoylation-defective mutants become cytosolic and fail to support normal damage-site recruitment. - statement: FBXO27 is a damage-triggered adaptor acting on a set of exposed glycoproteins (also VAMP3, VAMP7, GNS, PSAP, TMEM192) rather than a single substrate. supporting_text: Proteomics in the same framework also highlighted additional candidate glycoprotein targets associated with damaged lysosomes (e.g., VAMP3, VAMP7, GNS, PSAP, TMEM192), supporting a model where FBXO27 is a damage-triggered adaptor acting on a set of exposed glycoproteins rather than a single substrate. - statement: FBXO27 accounts for only part of damage-induced lysosomal ubiquitylation and is not ubiquitously expressed, implying cell-type specificity and redundancy with other lysophagy ligases. supporting_text: The review emphasizes **partial contribution** of FBXO27 to total lysosomal ubiquitylation and notes **non-ubiquitous expression**, suggesting **cell-type specificity** and/or redundancy among ligases. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Falcon synthesis anchored on the primary mechanistic study (Yoshida et al., PNAS 2017, SCF^FBXO27 ubiquitylation of exposed LAMP2 glycans in lysophagy), the Glenn 2008 FBA-family characterization, and a 2024 Annual Review (Meyer & Kravic). Establishes a concrete validated substrate set (LAMP2/LAMP1) and the myristoylation/damaged-lysosome-recruitment mechanism that is absent from human GOA/UniProt; cross-checked against UniProt (which records only the 2008 lectin/SCF data). LAMP2/lysophagy datapoints derive from Fbs3 mechanistic work and are surfaced as strong leads (not overriding any experimental curator annotation). core_functions: - description: Lectin substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex that binds N-linked oligosaccharides on glycoproteins via its FBA/G-domain hydrophobic pocket (Phe262-Trp263), thereby selecting glycoprotein substrates for the complex. molecular_function: id: GO:0030246 label: carbohydrate binding locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/FBXO27/FBXO27-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Able to recognize and bind denatured glycoproteins, which are modified with complex-type oligosaccharides. - reference_id: PMID:18203720 supporting_text: revealed that glycan binding requires the conserved hydrophobic pocket within the FBA domain directly_involved_in: - id: GO:0006516 label: glycoprotein catabolic process - description: Substrate receptor that integrates into the SCF complex through its F-box domain (binding SKP1 and CUL1) and delivers bound glycoproteins to the SCF machinery for poly-ubiquitination and proteasomal degradation, contributing to glycoprotein quality control. molecular_function: id: GO:0030246 label: carbohydrate binding locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/FBXO27/FBXO27-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex. - reference_id: PMID:18203720 supporting_text: All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1) directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: >- Damage-triggered lysophagy adaptor. As a membrane-associated (N-myristoylated) SCF substrate receptor, FBXO27 is recruited to ruptured lysosomes and recognizes luminal N-glycans that become exposed to the cytosol, directing SCF(FBXO27) ubiquitylation of damaged-lysosome glycoproteins (prominently LAMP2/LAMP1), which recruits autophagy adaptors (p62/SQSTM1, LC3) to promote selective autophagy of the damaged lysosome. molecular_function: id: GO:0030246 label: carbohydrate binding locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/FBXO27/FBXO27-deep-research-falcon.md supporting_text: after lysosomal membrane rupture, SCF^FBXO27 ubiquitylates **luminally glycosylated regions** of lysosomal membrane proteins, prominently **LAMP2** (and also LAMP1). In LLOMe-induced lysosomal damage models, FBXO27-dependent ubiquitylation of LAMP2 facilitates recruitment of autophagy machinery (e.g., p62 and LC3), thereby promoting lysophagy. directly_involved_in: - id: GO:0016236 label: macroautophagy proposed_new_terms: - proposed_name: lysophagy proposed_definition: The selective macroautophagy process in which a damaged or ruptured lysosome is engulfed and delivered to the autophagic machinery for degradation, typically initiated by ubiquitylation of lysosomal membrane glycoproteins whose luminal glycans become exposed to the cytosol. justification: A specific child of macroautophagy (GO:0016236) would precisely capture the validated SCF(FBXO27) role in clearing damaged lysosomes via LAMP2/LAMP1 glycan-directed ubiquitylation; currently no dedicated GO term exists for this selective-autophagy subtype, forcing use of the broad macroautophagy parent. proposed_parent: id: GO:0016236 label: macroautophagy suggested_questions: - question: What are the physiological glycoprotein substrates of FBXO27 in vivo, and do they include N-glycosylated proteins exposed on the cytosolic surface of damaged lysosomes? - question: Given that FBXO27 bound high-mannose glycans only weakly on glycan arrays, what determines its in-cell glycan/substrate selectivity relative to its paralogs FBXO2 and FBXO6? - question: Does FBXO27 contribute to a distinct branch of glycoprotein quality control (e.g. lysophagy-associated clearance) separate from the ER-associated GERAD pathway favored by FBXO2/FBXO6? suggested_experiments: - description: Perform glycoproteomic substrate-trapping (e.g. expressing the FBXO27 Phe262-Trp263 glycan-binding mutant or a dominant-negative SCF receptor) combined with affinity purification and mass spectrometry to identify endogenous N-glycosylated substrates ubiquitinated in an FBXO27-dependent manner. - description: Reconstitute SCF-FBXO27 (SKP1-CUL1-RBX1-FBXO27) in vitro with E1, an E2, and ubiquitin, and test ubiquitination of defined high-mannose glycoproteins versus deglycosylated controls to confirm glycan-dependent substrate selection and that catalysis requires the RBX1 RING subunit. - description: Induce lysosomal membrane damage (e.g. with LLOMe) in FBXO27-knockout versus wild-type cells and quantify recruitment of FBXO27 and ubiquitination of glycoproteins exposed on damaged lysosomes (e.g. LAMP2) to test a role in damaged-lysosome glycoprotein recognition, comparing wild-type FBXO27 with a myristoylation-defective (G2A) mutant and the Phe262-Trp263 glycan-pocket mutant to dissect membrane targeting versus glycan recognition.