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.
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.
Parent term: macroautophagy
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0036503 ERAD pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:18203720 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. file:human/FBXO27/FBXO27-deep-research-falcon.md 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. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:18203720 It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. |
| GO:0006516 glycoprotein catabolic process | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:18203720 These differences in substrate recognition, SCF complex formation, and tissue distribution suggest that FBA proteins play diverse roles in glycoprotein quality control. file:human/FBXO27/FBXO27-uniprot.txt Able to recognize and bind denatured glycoproteins, which are modified with complex-type oligosaccharides. |
| GO:0019005 SCF ubiquitin ligase complex | IBA GO_REF:0000033 | ACCEPT | 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. 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). Supporting Evidence: PMID:18203720 All FBA family members co-immunoprecipitated components of the SCF complex file:human/FBXO27/FBXO27-uniprot.txt Part of a SCF (SKP1-cullin-F-box) protein ligase complex. |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:18203720 When an SCF complex binds a substrate protein, a ubiquitin-conjugating enzyme associates with the complex via Rbx1 and ubiquitinates the substrate protein. |
| GO:0061630 ubiquitin protein ligase activity | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:18203720 As the substrate recognition subunits of multiprotein ubiquitin ligase complexes, F-box proteins have no intrinsic catalytic activity of their own. |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning electronic assignment of cytoplasmic localization, consistent with FBXO27 acting as a cytosolic SCF substrate receptor. Reason: Correct but generic; redundant with the IBA cytoplasm and the more specific cytosol/SCF complex annotations. Supporting Evidence: PMID:18203720 It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/FBXO27/FBXO27-uniprot.txt Q8NI29; P63208: SKP1; NbExp=3; IntAct=EBI-6425694, EBI-307486; |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | 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. 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). Supporting Evidence: PMID:34445249 These SCF complexes are distinguishable by variable F-box proteins, which determine substrate specificity. |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: ComplexPortal/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. Reason: Core biological process; consistent with FBXO27 acting as the substrate receptor of an SCF complex that drives proteasomal degradation. Supporting Evidence: PMID:34445249 a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | ACCEPT | 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. Reason: Correct localization; FBXO27 functions in the cytosol as part of cytosolic CRL1/SCF complexes. Redundant with the IBA/IEA cytoplasm annotations. Supporting Evidence: PMID:18203720 It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | ACCEPT | Summary: Reactome curation of cytosolic localization within a CRL1/SCF neddylation reaction (NEDD8:AcM-UBE2M binds CRL1). Consistent with FBXO27's cytosolic SCF context. Reason: Correct localization; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: PMID:18203720 It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | ACCEPT | Summary: Reactome curation of cytosolic localization within a CRL regulation reaction (CAND1 binds cytosolic CRL E3 ligases). Consistent with FBXO27's cytosolic SCF context. Reason: Correct localization; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: PMID:18203720 It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | ACCEPT | 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. Reason: Correct localization; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: PMID:18203720 It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | ACCEPT | Summary: Reactome curation of cytosolic localization within a CRL regulation reaction (COP9 signalosome deneddylates cytosolic CRL complexes). Consistent with FBXO27's cytosolic SCF context. Reason: Correct localization; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: PMID:18203720 It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | ACCEPT | Summary: Reactome curation of cytosolic localization within a CRL1 neddylation reaction (MyrG-DCUN1D3 binds CRL1). Consistent with FBXO27's cytosolic SCF context. Reason: Correct localization; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: PMID:18203720 It is intriguing to speculate how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | ACCEPT | 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. Reason: Correct localization; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: PMID:18203720 When an SCF complex binds a substrate protein, a ubiquitin-conjugating enzyme associates with the complex via Rbx1 and ubiquitinates the substrate protein. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | ACCEPT | Summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (release of E3 from polyubiquitinated substrate). Consistent with FBXO27's cytosolic SCF context. Reason: Correct localization; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: PMID:18203720 When an SCF complex binds a substrate protein, a ubiquitin-conjugating enzyme associates with the complex via Rbx1 and ubiquitinates the substrate protein. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | ACCEPT | Summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (polyubiquitination of substrate). Consistent with FBXO27's cytosolic SCF context. Reason: Correct localization; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: PMID:18203720 When an SCF complex binds a substrate protein, a ubiquitin-conjugating enzyme associates with the complex via Rbx1 and ubiquitinates the substrate protein. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | ACCEPT | 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. Reason: Correct localization; redundant with other cytosol/cytoplasm annotations. Supporting Evidence: PMID:18203720 When an SCF complex binds a substrate protein, a ubiquitin-conjugating enzyme associates with the complex via Rbx1 and ubiquitinates the substrate protein. |
| GO:0005515 protein binding | IDA PMID:18203720 Diversity in tissue expression, substrate binding, and SCF c... | MODIFY | 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. 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 replacements: carbohydrate binding D-mannose binding Supporting Evidence: file:human/FBXO27/FBXO27-uniprot.txt Able to recognize and bind denatured glycoproteins, which are modified with complex-type oligosaccharides. PMID:18203720 revealed that glycan binding requires the conserved hydrophobic pocket within the FBA domain |
| GO:0005515 protein binding | IPI PMID:18203720 Diversity in tissue expression, substrate binding, and SCF c... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/FBXO27/FBXO27-uniprot.txt Interacts with SKP1 and CUL1. PMID:18203720 All FBA family members co-immunoprecipitated components of the SCF complex |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:18203720 Diversity in tissue expression, substrate binding, and SCF c... | ACCEPT | 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. Reason: Core cellular component with direct experimental support; FBXO27 co-precipitates the SKP1, Cullin1 and RBX1 components of the SCF complex. Supporting Evidence: PMID:18203720 All FBA family members co-immunoprecipitated components of the SCF complex PMID:18203720 All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1) |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Q: 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?
Experiment: 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.
Experiment: 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.
Experiment: 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.
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