Existing Annotations Review

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)

Core Functions

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:

carbohydrate binding

Directly Involved In:

glycoprotein catabolic process

Cellular Locations:

cytosol

Supporting Evidence:

file:human/FBXO27/FBXO27-uniprot.txt
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.
PMID:18203720
revealed that glycan binding requires the conserved hydrophobic pocket within the FBA domain

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:

carbohydrate binding

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

cytosol

Supporting Evidence:

file:human/FBXO27/FBXO27-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex.
PMID:18203720
All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1)

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:

carbohydrate binding

Directly Involved In:

macroautophagy

Cellular Locations:

cytosol

Supporting Evidence:

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.

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:18203720

Diversity in tissue expression, substrate binding, and SCF complex formation for a lectin family of ubiquitin ligases.

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.

PMID:32296183

A reference map of the human binary protein interactome.

HuRI binary interactome map; captures the FBXO27-SKP1 (P63208) interaction.

PMID:34445249

The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.

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.

Reactome:R-HSA-8952618

AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-8952620

NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-8955241

CAND1 binds cytosolic CRL E3 ubiquitin ligases

Reactome:R-HSA-8955289

COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes

Reactome:R-HSA-8956040

COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes

Reactome:R-HSA-8956200

MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-983140

Transfer of Ub from E2 to substrate and release of E2

Reactome:R-HSA-983147

Release of E3 from polyubiquitinated substrate

Reactome:R-HSA-983156

Polyubiquitination of substrate

Reactome:R-HSA-983157

Interaction of E3 with substrate and E2-Ub complex

file:human/FBXO27/FBXO27-deep-research-falcon.md

Falcon deep research report for human FBXO27

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.

"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**."
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.

"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."
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.

"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."
FBXO27 is a damage-triggered adaptor acting on a set of exposed glycoproteins (also VAMP3, VAMP7, GNS, PSAP, TMEM192) rather than a single substrate.

"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."
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.

"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."

Suggested Experiments

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.

Deep Research

Falcon

(FBXO27-deep-research-falcon.md)

Research report: Human **FBXO27** (UniProt **Q8NI29**) — functional annotation Falcon Edison Scientific Literature 36 citations 2 artifacts 2026-06-13T06:49:58.948476

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000018 The requested visual content can be found in the following figures: - **FBXO27 recruitment to damaged lysosomes:** Figure 2 illustr (image/png)

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Research report: Human FBXO27 (UniProt Q8NI29) — functional annotation

0) Identity verification (critical disambiguation)

The target protein is human FBXO27, also described in the literature as Fbs3 and FBG5 (consistent with UniProt Q8NI29 context). Fbs3/FBG5/FBXO27 is grouped with glycoprotein-binding “lectin-type” F-box proteins (FBA family) that recognize N-glycans on glycoproteins and act as substrate receptors for SCF ubiquitin ligases. (kumanomidou2015thestructuraldifferences pages 1-2, yoshida2018cytosolicnglycanstriggers pages 5-6)

1) Key concepts and definitions (current understanding)

1.1 SCF E3 ubiquitin ligase and F-box proteins

F-box proteins serve as interchangeable substrate-recognition adaptors in SCF (Skp1–Cullin1–F-box) E3 ubiquitin ligases. In the SCF architecture, CUL1 provides the scaffold and associates with the catalytic RING protein (RBX1), while SKP1 binds the F-box domain of the adaptor; the adaptor’s other domain(s) provide substrate specificity. Understanding the biological role of an F-box protein largely depends on identifying its substrates, and many F-box proteins historically lacked known substrates (“orphan” F-box proteins). (skaar2013mechanismsandfunction pages 1-2, skaar2013mechanismsandfunction pages 11-11)

1.2 Lectin-like F-box (FBA) family and glycan recognition

FBXO27 is part of the FBA/lectin-like family (FBXO2, FBXO6, FBXO17, FBXO27, FBXO44). These proteins contain a conserved glycan-binding “G domain” that mediates binding to glycan motifs on glycoproteins; glycan-array and mutagenesis data show that the G domain forms a hydrophobic pocket essential for glycan binding. (glenn2008diversityintissue pages 1-2, glenn2008diversityintissue pages 3-4)

1.3 Lysophagy and the endo-lysosomal damage response

Lysophagy is selective autophagy that removes damaged lysosomes. A key early step after lysosomal membrane damage is ubiquitylation of damaged-lysosome-associated proteins, enabling recruitment of autophagy receptors/adaptors and LC3-family proteins. A 2024 authoritative synthesis frames FBXO27 as one of several E3-associated factors implicated in damage-induced lysosomal ubiquitylation, but also notes redundancy and cell-type specificity in this response. (meyer2024theendolysosomaldamage pages 11-12)

2) Molecular function of FBXO27

2.1 Primary biochemical role

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. (yoshida2017ubiquitinationofexposed pages 1-2, yoshida2018cytosolicnglycanstriggers pages 5-6)

2.2 Substrate specificity: what does FBXO27 recognize?

Evidence across the lectin-F-box literature supports that FBXO27 binds N-glycans, with emphasis on high-mannose recognition (and broader N-glycan compatibility in later mechanistic work). In a conceptual synthesis, FBXO27 (with FBXO2/FBXO6) is described as recognizing the core Man3GlcNAc2 motif and preferentially binding high-mannose glycans while also engaging complex-type N-glycans—consistent with FBXO27’s ability to act on diverse glycoproteins once their luminal glycans become exposed to the cytosol during damage. (yoshida2018cytosolicnglycanstriggers pages 5-6)

A foundational experimental comparison of the FBA family supports family-level binding to high-mannose and sulfated glycoproteins, with FBXO27 showing measurable glycan-array binding in at least some array conditions and mapping binding determinants to the G domain. (glenn2008diversityintissue pages 7-9, glenn2008diversityintissue pages 3-4)

2.3 Key cellular substrates and pathways

Lysosomal membrane glycoproteins (LAMP2 and LAMP1)

A central mechanistic finding is that 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. (yoshida2017ubiquitinationofexposed pages 2-3, yoshida2017ubiquitinationofexposed pages 5-6, yoshida2017ubiquitinationofexposed pages 6-6)

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. (yoshida2017ubiquitinationofexposed pages 1-2, yoshida2017ubiquitinationofexposed pages 3-4)

3) Subcellular localization and mechanism of recruitment

3.1 Membrane association via N-myristoylation

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. (yoshida2017ubiquitinationofexposed pages 2-3, yoshida2017ubiquitinationofexposed pages 3-4)

3.2 Damage sensing: glycan exposure after rupture

Under steady-state conditions, FBXO27 is positioned on the cytosolic face of membranes and cannot access luminal glycoprotein glycans. After lysosomal membrane damage, luminal glycan chains become exposed to the cytosol; FBXO27 rapidly accumulates at these sites and drives ubiquitylation of exposed glycoproteins (especially LAMP2), promoting recruitment of LC3 and p62 and lysophagic clearance. (yoshida2017ubiquitinationofexposed pages 5-6, yoshida2018cytosolicnglycanstriggers pages 5-6)

4) Recent developments and latest research (prioritizing 2023–2024)

4.1 2024 expert synthesis: FBXO27 in the endo-lysosomal damage response

A 2024 Annual Review of Biochemistry review summarizes FBXO27 (and FBXO2) as glycan-binding F-box proteins acting as SCF substrate adaptors that contribute to damage-induced ubiquitylation; FBXO27 is specifically described as triggering ubiquitylation of luminal parts of glycosylated LAMP2 after lysosomal damage. 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. It also highlights unresolved questions, including which ligases initiate particular ubiquitin linkages (e.g., K63 chains) and what molecular cues (glycan exposure vs lipid alterations) dominate recruitment/activation in different contexts. (meyer2024theendolysosomaldamage pages 11-12)

4.2 2023 mechanistic disease-context study: cardiomyocyte autophagy and diabetic cardiomyopathy

A 2023 primary study proposes a CREG1–FBXO27–LAMP2 axis in cardiomyocytes in which CREG1 suppresses FBXO27 and thereby stabilizes LAMP2, supporting autophagy and mitigating diabetic cardiomyopathy phenotypes. In neonatal mouse cardiomyocytes, FBXO27 overexpression decreased LAMP2 protein (reported p < 0.01) and increased autophagy markers LC3II and P62, interpreted as autophagy inhibition/flux disruption; FBXO27 overexpression also reversed the pro-autophagy effect of CREG1 (p < 0.05). Pharmacologic inhibition data supported substantial proteasome involvement in LAMP2 turnover in the model (MG132 strongly increased LAMP2 in palmitate-treated cells; p < 0.01). (liu2023thecreg1fbxo27lamp2axis pages 9-10, liu2023thecreg1fbxo27lamp2axis pages 10-13, liu2023thecreg1fbxo27lamp2axis pages 1-2)

Interpretation/connection to core FBXO27 biology: these findings are consistent with the established role of FBXO27 in acting on LAMP2 (lysosomal glycoprotein) and suggest that, in cardiomyocytes, dysregulated FBXO27 levels may influence autophagy via altered LAMP2 stability. (liu2023thecreg1fbxo27lamp2axis pages 9-10, yoshida2017ubiquitinationofexposed pages 5-6)

4.3 2023 neuronal lysophagy under high glucose

In a 2023 neuronal lysophagy study (high-glucose models linked to lysosomal dysfunction), FBXO27 was evaluated among lysophagy-related factors. Importantly, silencing FBXO27 impaired clearance of galectin-3 (LGALS3) after lysosomal damage and reduced LysoTracker signal intensity, supporting a functional role for FBXO27 in lysosomal quality control in neurons under these stress conditions. (chae2023trim16mediatedlysophagysuppresses pages 10-11)

5) Current applications and real-world implementations

5.1 FBXO27 as a mechanistic handle on lysophagy

FBXO27 provides a concrete mechanistic entry point to manipulate lysophagy, because it couples a physically interpretable damage cue (exposed glycans on ruptured lysosomes) to ubiquitin signaling and autophagy recruitment. This is principally implemented in cell biology via lysosomal damage models such as LLOMe, with readouts including galectin puncta, ubiquitin accumulation, LC3 recruitment, and damaged-organelle clearance. (yoshida2017ubiquitinationofexposed pages 5-6, yoshida2017ubiquitinationofexposed media f2bb0dcd, yoshida2017ubiquitinationofexposed media 88318014)

5.2 Translational hypothesis space: cardiometabolic and neurodegenerative contexts

The cardiomyocyte study suggests that modulating the CREG1–FBXO27–LAMP2 relationship could be explored as a strategy to restore autophagy in diabetic cardiomyopathy models, although direct FBXO27-targeting therapeutics are not established. (liu2023thecreg1fbxo27lamp2axis pages 1-2, liu2023thecreg1fbxo27lamp2axis pages 9-10)

In neuronal models, FBXO27 knockdown impacts lysosomal damage handling, indicating a potential relevance for conditions where lysosomal integrity and clearance are compromised under metabolic stress (e.g., hyperglycemia-related dysfunction). (chae2023trim16mediatedlysophagysuppresses pages 10-11)

5.3 Potential biomarker associations in cancer transcriptomics

In squamous-cell lung carcinoma (SqCLC), FBXO27 was reported as upregulated across multiple datasets. While this is not a direct functional annotation, it suggests FBXO27 expression can vary in disease tissue contexts and could be explored as part of broader ubiquitin/autophagy pathway signatures. (wang2018identificationofaberrantly pages 4-6)

6) Expert opinions, limitations, and open questions

6.1 Substrate identification and “orphan” F-box context

A widely cited review emphasizes that many F-box proteins historically lacked known substrates and that identifying substrates is essential to assign biological roles. This perspective is relevant to FBXO27 because its best-supported substrates are damage-exposed lysosomal glycoproteins (notably LAMP2), while the broader substrate space across tissues and conditions remains incompletely defined. (skaar2013mechanismsandfunction pages 1-2, yoshida2017ubiquitinationofexposed pages 5-6)

6.2 Redundancy and cell-type specificity in lysosomal ubiquitylation

The 2024 expert synthesis explicitly notes FBXO27 only partially accounts for damage-induced lysosomal ubiquitylation and is not ubiquitously expressed, implying redundancy with other pathways (e.g., TRIM16-linked mechanisms) and cell-type-dependent deployment of different ubiquitin ligases/E2s in lysophagy. (meyer2024theendolysosomaldamage pages 11-12)

6.3 Mechanistic gaps highlighted by primary data

The primary lysophagy work reported uncertainty about why LAMP2 is more effectively ubiquitylated than LAMP1 despite both being major lysosomal glycoproteins, and noted that LAMP2 ubiquitylation sites were not previously referenced in proteomic databases at the time—indicating incomplete understanding of substrate selection and modification topology. (yoshida2017ubiquitinationofexposed pages 5-6)

7) Relevant statistics and data highlights

7.1 Quantitative cancer expression statistics (2018)

In a SqCLC expression study, FBXO27 showed strong upregulation (EdgeR: logFC = 3.16, FC = 8.67, p = 3.62×10−35, FDR = 3.16×10−34; DESeq: logFC = 3.12, p adj = 7.98×10−18). Across study aggregation, five datasets were analyzed (4 GEO + TCGA) totaling 594 SqCLC cases and 174 non-tumor tissues. A Cox analysis reported p = 0.40 (HR 1.17; 95% CI 0.82–1.67), suggesting no strong survival association in that analysis; the authors also noted that FBXO27 did not remain in the most stringent final DEG list after adjustment. (wang2018identificationofaberrantly pages 6-7, wang2018identificationofaberrantly pages 4-6)

7.2 Quantitative mechanistic cardiomyocyte data (2023)

In cardiomyocytes, FBXO27 overexpression decreased LAMP2 (reported p < 0.01), increased LC3II and P62, and counteracted CREG1-driven pro-autophagy effects (reported p < 0.05). MG132 (proteasome inhibitor) increased LAMP2 in palmitate-treated cells (reported p < 0.01), supporting proteasome-linked turnover for LAMP2 in that model. (liu2023thecreg1fbxo27lamp2axis pages 9-10, liu2023thecreg1fbxo27lamp2axis pages 10-13)

7.3 Open Targets association statistics (curated database signal; interpret cautiously)

Open Targets lists modest disease–target associations for FBXO27 (ENSG00000161243), supported primarily by IMPC animal-model evidence and at least one GWAS credible-set evidence record linked to PubMed 37958966, with association-level scores such as ~0.236 for IgA glomerulonephritis and lower scores for other traits. These signals are not direct proof of causality but can motivate hypothesis generation. (OpenTargets Search: -FBXO27)

8) Figure-supported mechanistic evidence (visual)

The core mechanistic steps—FBXO27 recruitment to damaged lysosomes, increased LAMP2 ubiquitylation after LLOMe, and a schematic model of SCF^FBXO27-mediated lysophagy—are captured in figure regions retrieved from the 2017 PNAS study. (yoshida2017ubiquitinationofexposed media f2bb0dcd, yoshida2017ubiquitinationofexposed media 4c6e0dad, yoshida2017ubiquitinationofexposed media 88318014)

9) Consolidated evidence map

The following table summarizes major claims, evidence types, and source metadata for FBXO27.

Claim/Aspect	Key findings	Evidence type	Source (first author, journal)	Year	URL	Citation ID(s)
Identity / synonyms	Human FBXO27 corresponds to FBG5/Fbs3; verified as a lectin-type F-box protein studied in the glycoprotein-recognition literature, matching UniProt Q8NI29 context.	Primary experiment / review	Kumanomidou, PLoS ONE; Yoshida, BioEssays	2015; 2018	https://doi.org/10.1371/journal.pone.0140366 ; https://doi.org/10.1002/bies.201700215	(kumanomidou2015thestructuraldifferences pages 1-2, yoshida2018cytosolicnglycanstriggers pages 5-6)
Domains / family	FBXO27 is part of the FBA/lectin-like F-box family; contains the canonical F-box for SKP1 binding plus a conserved glycan-binding G domain that mediates substrate recognition.	Primary experiment	Glenn, Journal of Biological Chemistry	2008	https://doi.org/10.1074/jbc.m709508200	(glenn2008diversityintissue pages 1-2, glenn2008diversityintissue pages 3-4)
Glycan specificity	Family-level assays show FBA proteins bind high-mannose and some sulfated glycoproteins; FBXO27 recognizes N-glycans, including high-mannose motifs, and can engage complex-type N-glycans in later work.	Primary experiment / review	Glenn, Journal of Biological Chemistry; Yoshida, BioEssays	2008; 2018	https://doi.org/10.1074/jbc.m709508200 ; https://doi.org/10.1002/bies.201700215	(glenn2008diversityintissue pages 7-9, yoshida2018cytosolicnglycanstriggers pages 5-6)
SCF complex role	FBXO27 functions as the interchangeable substrate-recognition subunit of an SCF ubiquitin ligase composed of SKP1-CUL1-RBX1 plus FBXO27; all FBA proteins co-precipitated canonical SCF components.	Primary experiment / review	Glenn, Journal of Biological Chemistry; Yoshida, PNAS	2008; 2017	https://doi.org/10.1074/jbc.m709508200 ; https://doi.org/10.1073/pnas.1702615114	(glenn2008diversityintissue pages 1-2, yoshida2017ubiquitinationofexposed pages 1-2, yoshida2017ubiquitinationofexposed pages 4-5)
Lysophagy mechanism	After lysosomal membrane damage (e.g., LLOMe), luminal glycans become exposed to the cytosol; membrane-bound, N-myristoylated FBXO27 is recruited, ubiquitinates exposed lysosomal glycoproteins, and promotes p62/LC3 recruitment for lysophagy.	Primary experiment / review	Yoshida, PNAS; Meyer, Annual Review of Biochemistry	2017; 2024	https://doi.org/10.1073/pnas.1702615114 ; https://doi.org/10.1146/annurev-biochem-030222-102505	(yoshida2017ubiquitinationofexposed pages 2-3, yoshida2017ubiquitinationofexposed pages 6-6, yoshida2017ubiquitinationofexposed pages 5-6, meyer2024theendolysosomaldamage pages 11-12)
Key substrates	Experimentally supported lysosomal targets include LAMP2 and LAMP1; proteomics also identified other candidate damaged-lysosome glycoproteins such as VAMP3, VAMP7, GNS, PSAP, and TMEM192. LAMP2 is highlighted as especially important for lysophagy initiation.	Primary experiment / review	Yoshida, PNAS; Yoshida, BioEssays	2017; 2018	https://doi.org/10.1073/pnas.1702615114 ; https://doi.org/10.1002/bies.201700215	(yoshida2017ubiquitinationofexposed pages 1-2, yoshida2017ubiquitinationofexposed pages 3-4, yoshida2018cytosolicnglycanstriggers pages 5-6)
Localization	FBXO27 is membrane-associated rather than purely cytosolic because of N-terminal myristoylation; this membrane targeting is required for efficient recruitment to damaged lysosomes.	Primary experiment	Yoshida, PNAS	2017	https://doi.org/10.1073/pnas.1702615114	(yoshida2017ubiquitinationofexposed pages 2-3, yoshida2017ubiquitinationofexposed pages 3-4)
Disease / cancer association	In squamous-cell lung carcinoma datasets, FBXO27 was consistently upregulated across 4 GEO datasets plus TCGA (5 datasets total; 594 tumors, 174 non-tumor tissues). One analysis reported logFC 3.16, FC 8.67, p=3.62E-35, FDR=3.16E-34, though FBXO27 did not remain among the most stringent final DEGs after adjustment. Open Targets shows modest association-level evidence, largely from animal models and one GWAS credible-set record.	Primary expression analysis / database association	Wang, J Cancer Res Clin Oncol; Open Targets	2018; 2025 platform citation	https://doi.org/10.1007/s00432-018-2653-1 ; https://platform.opentargets.org/target/ENSG00000161243	(wang2018identificationofaberrantly pages 6-7, wang2018identificationofaberrantly pages 4-6, OpenTargets Search: -FBXO27)
Cardiomyocyte autophagy / diabetic cardiomyopathy	2023 work proposed a CREG1-FBXO27-LAMP2 axis: CREG1 suppresses FBXO27, thereby stabilizing LAMP2 and supporting autophagy in cardiomyocytes. FBXO27 overexpression lowers LAMP2 and impairs autophagy markers; proteasome inhibition increases LAMP2 under pathologic conditions. In vivo, CREG1 deficiency worsened diabetic cardiomyopathy phenotypes, whereas overexpression was protective.	Primary experiment	Liu, Experimental & Molecular Medicine	2023	https://doi.org/10.1038/s12276-023-01081-2	(liu2023thecreg1fbxo27lamp2axis pages 9-10, liu2023thecreg1fbxo27lamp2axis pages 10-13, liu2023thecreg1fbxo27lamp2axis pages 1-2)
Neuronal lysophagy / high glucose	In high-glucose neuronal models, FBXO27 was evaluated among lysophagy factors. FBXO27 knockdown impaired LGALS3/galectin-3 clearance after lysosomal damage and reduced LysoTracker signal, supporting a role in neuronal lysophagy, although TRIM16 emerged as the dominant regulated factor in that study.	Primary experiment	Chae, Autophagy	2023	https://doi.org/10.1080/15548627.2023.2229659	(chae2023trim16mediatedlysophagysuppresses pages 10-11, chae2023trim16mediatedlysophagysuppresses pages 2-5)
Knowledge gaps	Earlier expert review classified many sugar-binding/orphan F-box proteins as lacking well-defined substrates; for FBXO27 specifically, later reviews note partial contribution to total lysosomal ubiquitination, likely cell-type specificity, and unresolved questions about redundancy with ligases such as TRIM16, exact recruitment cues, ubiquitin-linkage logic, and why LAMP2 is favored over LAMP1.	Review / expert analysis	Skaar, Nature Reviews Molecular Cell Biology; Meyer, Annual Review of Biochemistry; Yoshida, PNAS	2013; 2024; 2017	https://doi.org/10.1038/nrm3582 ; https://doi.org/10.1146/annurev-biochem-030222-102505 ; https://doi.org/10.1073/pnas.1702615114	(skaar2013mechanismsandfunction pages 1-2, skaar2013mechanismsandfunction pages 4-5, skaar2013mechanismsandfunction pages 11-11, yoshida2017ubiquitinationofexposed pages 5-6, meyer2024theendolysosomaldamage pages 11-12)

Table: This table consolidates the main experimentally supported and review-level findings for human FBXO27/Q8NI29, including identity, molecular function, lysophagy role, and disease relevance. It is useful as a compact evidence map for functional annotation with direct source links and citation IDs.

10) Key references (with URLs and publication dates)

Yoshida Y. et al. “Ubiquitination of exposed glycoproteins by SCF^FBXO27 directs damaged lysosomes for autophagy.” PNAS (Jul 2017). https://doi.org/10.1073/pnas.1702615114 (yoshida2017ubiquitinationofexposed pages 2-3)
Meyer H., Kravic B. “The Endo-Lysosomal Damage Response.” Annual Review of Biochemistry (Aug 2024). https://doi.org/10.1146/annurev-biochem-030222-102505 (meyer2024theendolysosomaldamage pages 11-12)
Liu D. et al. “The CREG1-FBXO27-LAMP2 axis alleviates diabetic cardiomyopathy by promoting autophagy in cardiomyocytes.” Experimental & Molecular Medicine (Sep 2023). https://doi.org/10.1038/s12276-023-01081-2 (liu2023thecreg1fbxo27lamp2axis pages 1-2)
Chae C.W. et al. “TRIM16-mediated lysophagy suppresses high-glucose-accumulated neuronal Aβ.” Autophagy (Jul 2023). https://doi.org/10.1080/15548627.2023.2229659 (chae2023trim16mediatedlysophagysuppresses pages 10-11)
Glenn K.A. et al. “Diversity in tissue expression, substrate binding, and SCF complex formation for a lectin family of ubiquitin ligases.” J Biol Chem (May 2008). https://doi.org/10.1074/jbc.m709508200 (glenn2008diversityintissue pages 1-2)
Kumanomidou T. et al. “The structural differences between… Fbs1 and… FBG3.” PLoS ONE (Oct 2015). https://doi.org/10.1371/journal.pone.0140366 (kumanomidou2015thestructuraldifferences pages 1-2)
Skaar J.R. et al. “Mechanisms and function of substrate recruitment by F-box proteins.” Nat Rev Mol Cell Biol (May 2013). https://doi.org/10.1038/nrm3582 (skaar2013mechanismsandfunction pages 1-2)
Open Targets Platform (target: FBXO27 / ENSG00000161243). https://platform.opentargets.org/target/ENSG00000161243 (access via tool context). (OpenTargets Search: -FBXO27)

References

(kumanomidou2015thestructuraldifferences pages 1-2): Taichi Kumanomidou, Kazuya Nishio, Kenji Takagi, Tomomi Nakagawa, Atsuo Suzuki, Takashi Yamane, Fuminori Tokunaga, Kazuhiro Iwai, Arisa Murakami, Yukiko Yoshida, Keiji Tanaka, and Tsunehiro Mizushima. The structural differences between a glycoprotein specific f-box protein fbs1 and its homologous protein fbg3. PLoS ONE, 10:e0140366, Oct 2015. URL: https://doi.org/10.1371/journal.pone.0140366, doi:10.1371/journal.pone.0140366. This article has 24 citations and is from a peer-reviewed journal.
(yoshida2018cytosolicnglycanstriggers pages 5-6): Yukiko Yoshida and Keiji Tanaka. Cytosolic n-glycans: triggers for ubiquitination directing proteasomal and autophagic degradation: molecular systems for monitoring cytosolic n-glycans as signals for unwanted proteins and organelles. BioEssays : news and reviews in molecular, cellular and developmental biology, Feb 2018. URL: https://doi.org/10.1002/bies.201700215, doi:10.1002/bies.201700215. This article has 19 citations.
(skaar2013mechanismsandfunction pages 1-2): Jeffrey R. Skaar, Julia K. Pagan, and Michele Pagano. Mechanisms and function of substrate recruitment by f-box proteins. Nature Reviews Molecular Cell Biology, 14:369-381, May 2013. URL: https://doi.org/10.1038/nrm3582, doi:10.1038/nrm3582. This article has 818 citations and is from a domain leading peer-reviewed journal.
(skaar2013mechanismsandfunction pages 11-11): Jeffrey R. Skaar, Julia K. Pagan, and Michele Pagano. Mechanisms and function of substrate recruitment by f-box proteins. Nature Reviews Molecular Cell Biology, 14:369-381, May 2013. URL: https://doi.org/10.1038/nrm3582, doi:10.1038/nrm3582. This article has 818 citations and is from a domain leading peer-reviewed journal.
(glenn2008diversityintissue pages 1-2): Kevin A. Glenn, Rick F. Nelson, Hsiang M. Wen, Adam J. Mallinger, and Henry L. Paulson. Diversity in tissue expression, substrate binding, and scf complex formation for a lectin family of ubiquitin ligases*. Journal of Biological Chemistry, 283:12717-12729, May 2008. URL: https://doi.org/10.1074/jbc.m709508200, doi:10.1074/jbc.m709508200. This article has 106 citations and is from a domain leading peer-reviewed journal.
(glenn2008diversityintissue pages 3-4): Kevin A. Glenn, Rick F. Nelson, Hsiang M. Wen, Adam J. Mallinger, and Henry L. Paulson. Diversity in tissue expression, substrate binding, and scf complex formation for a lectin family of ubiquitin ligases*. Journal of Biological Chemistry, 283:12717-12729, May 2008. URL: https://doi.org/10.1074/jbc.m709508200, doi:10.1074/jbc.m709508200. This article has 106 citations and is from a domain leading peer-reviewed journal.
(meyer2024theendolysosomaldamage pages 11-12): Hemmo Meyer and Bojana Kravic. The endo-lysosomal damage response. Aug 2024. URL: https://doi.org/10.1146/annurev-biochem-030222-102505, doi:10.1146/annurev-biochem-030222-102505. This article has 67 citations and is from a domain leading peer-reviewed journal.
(yoshida2017ubiquitinationofexposed pages 1-2): Yukiko Yoshida, Sayaka Yasuda, Toshiharu Fujita, Maho Hamasaki, Arisa Murakami, Junko Kawawaki, Kazuhiro Iwai, Yasushi Saeki, Tamotsu Yoshimori, Noriyuki Matsuda, and Keiji Tanaka. Ubiquitination of exposed glycoproteins by scffbxo27 directs damaged lysosomes for autophagy. Proceedings of the National Academy of Sciences, 114:8574-8579, Jul 2017. URL: https://doi.org/10.1073/pnas.1702615114, doi:10.1073/pnas.1702615114. This article has 153 citations and is from a highest quality peer-reviewed journal.
(glenn2008diversityintissue pages 7-9): Kevin A. Glenn, Rick F. Nelson, Hsiang M. Wen, Adam J. Mallinger, and Henry L. Paulson. Diversity in tissue expression, substrate binding, and scf complex formation for a lectin family of ubiquitin ligases*. Journal of Biological Chemistry, 283:12717-12729, May 2008. URL: https://doi.org/10.1074/jbc.m709508200, doi:10.1074/jbc.m709508200. This article has 106 citations and is from a domain leading peer-reviewed journal.
(yoshida2017ubiquitinationofexposed pages 2-3): Yukiko Yoshida, Sayaka Yasuda, Toshiharu Fujita, Maho Hamasaki, Arisa Murakami, Junko Kawawaki, Kazuhiro Iwai, Yasushi Saeki, Tamotsu Yoshimori, Noriyuki Matsuda, and Keiji Tanaka. Ubiquitination of exposed glycoproteins by scffbxo27 directs damaged lysosomes for autophagy. Proceedings of the National Academy of Sciences, 114:8574-8579, Jul 2017. URL: https://doi.org/10.1073/pnas.1702615114, doi:10.1073/pnas.1702615114. This article has 153 citations and is from a highest quality peer-reviewed journal.
(yoshida2017ubiquitinationofexposed pages 5-6): Yukiko Yoshida, Sayaka Yasuda, Toshiharu Fujita, Maho Hamasaki, Arisa Murakami, Junko Kawawaki, Kazuhiro Iwai, Yasushi Saeki, Tamotsu Yoshimori, Noriyuki Matsuda, and Keiji Tanaka. Ubiquitination of exposed glycoproteins by scffbxo27 directs damaged lysosomes for autophagy. Proceedings of the National Academy of Sciences, 114:8574-8579, Jul 2017. URL: https://doi.org/10.1073/pnas.1702615114, doi:10.1073/pnas.1702615114. This article has 153 citations and is from a highest quality peer-reviewed journal.
(yoshida2017ubiquitinationofexposed pages 6-6): Yukiko Yoshida, Sayaka Yasuda, Toshiharu Fujita, Maho Hamasaki, Arisa Murakami, Junko Kawawaki, Kazuhiro Iwai, Yasushi Saeki, Tamotsu Yoshimori, Noriyuki Matsuda, and Keiji Tanaka. Ubiquitination of exposed glycoproteins by scffbxo27 directs damaged lysosomes for autophagy. Proceedings of the National Academy of Sciences, 114:8574-8579, Jul 2017. URL: https://doi.org/10.1073/pnas.1702615114, doi:10.1073/pnas.1702615114. This article has 153 citations and is from a highest quality peer-reviewed journal.
(yoshida2017ubiquitinationofexposed pages 3-4): Yukiko Yoshida, Sayaka Yasuda, Toshiharu Fujita, Maho Hamasaki, Arisa Murakami, Junko Kawawaki, Kazuhiro Iwai, Yasushi Saeki, Tamotsu Yoshimori, Noriyuki Matsuda, and Keiji Tanaka. Ubiquitination of exposed glycoproteins by scffbxo27 directs damaged lysosomes for autophagy. Proceedings of the National Academy of Sciences, 114:8574-8579, Jul 2017. URL: https://doi.org/10.1073/pnas.1702615114, doi:10.1073/pnas.1702615114. This article has 153 citations and is from a highest quality peer-reviewed journal.
(liu2023thecreg1fbxo27lamp2axis pages 9-10): Dan Liu, Ruinan Xing, Quanyu Zhang, Xiaoxiang Tian, Yanping Qi, Haixu Song, Yanxia Liu, Haibo Yu, Xiaolin Zhang, Quanmin Jing, Chenghui Yan, and Yaling Han. The creg1-fbxo27-lamp2 axis alleviates diabetic cardiomyopathy by promoting autophagy in cardiomyocytes. Experimental & Molecular Medicine, 55:2025-2038, Sep 2023. URL: https://doi.org/10.1038/s12276-023-01081-2, doi:10.1038/s12276-023-01081-2. This article has 36 citations and is from a peer-reviewed journal.
(liu2023thecreg1fbxo27lamp2axis pages 10-13): Dan Liu, Ruinan Xing, Quanyu Zhang, Xiaoxiang Tian, Yanping Qi, Haixu Song, Yanxia Liu, Haibo Yu, Xiaolin Zhang, Quanmin Jing, Chenghui Yan, and Yaling Han. The creg1-fbxo27-lamp2 axis alleviates diabetic cardiomyopathy by promoting autophagy in cardiomyocytes. Experimental & Molecular Medicine, 55:2025-2038, Sep 2023. URL: https://doi.org/10.1038/s12276-023-01081-2, doi:10.1038/s12276-023-01081-2. This article has 36 citations and is from a peer-reviewed journal.
(liu2023thecreg1fbxo27lamp2axis pages 1-2): Dan Liu, Ruinan Xing, Quanyu Zhang, Xiaoxiang Tian, Yanping Qi, Haixu Song, Yanxia Liu, Haibo Yu, Xiaolin Zhang, Quanmin Jing, Chenghui Yan, and Yaling Han. The creg1-fbxo27-lamp2 axis alleviates diabetic cardiomyopathy by promoting autophagy in cardiomyocytes. Experimental & Molecular Medicine, 55:2025-2038, Sep 2023. URL: https://doi.org/10.1038/s12276-023-01081-2, doi:10.1038/s12276-023-01081-2. This article has 36 citations and is from a peer-reviewed journal.
(chae2023trim16mediatedlysophagysuppresses pages 10-11): Chang Woo Chae, Jee Hyeon Yoon, Jae Ryong Lim, Ji Yong Park, Ji Hyeon Cho, Young Hyun Jung, Gee Euhn Choi, Hyun Jik Lee, and Ho Jae Han. Trim16-mediated lysophagy suppresses high-glucose-accumulated neuronal aβ. Autophagy, 19:2752-2768, Jul 2023. URL: https://doi.org/10.1080/15548627.2023.2229659, doi:10.1080/15548627.2023.2229659. This article has 37 citations and is from a domain leading peer-reviewed journal.
(yoshida2017ubiquitinationofexposed media f2bb0dcd): Yukiko Yoshida, Sayaka Yasuda, Toshiharu Fujita, Maho Hamasaki, Arisa Murakami, Junko Kawawaki, Kazuhiro Iwai, Yasushi Saeki, Tamotsu Yoshimori, Noriyuki Matsuda, and Keiji Tanaka. Ubiquitination of exposed glycoproteins by scffbxo27 directs damaged lysosomes for autophagy. Proceedings of the National Academy of Sciences, 114:8574-8579, Jul 2017. URL: https://doi.org/10.1073/pnas.1702615114, doi:10.1073/pnas.1702615114. This article has 153 citations and is from a highest quality peer-reviewed journal.
(yoshida2017ubiquitinationofexposed media 88318014): Yukiko Yoshida, Sayaka Yasuda, Toshiharu Fujita, Maho Hamasaki, Arisa Murakami, Junko Kawawaki, Kazuhiro Iwai, Yasushi Saeki, Tamotsu Yoshimori, Noriyuki Matsuda, and Keiji Tanaka. Ubiquitination of exposed glycoproteins by scffbxo27 directs damaged lysosomes for autophagy. Proceedings of the National Academy of Sciences, 114:8574-8579, Jul 2017. URL: https://doi.org/10.1073/pnas.1702615114, doi:10.1073/pnas.1702615114. This article has 153 citations and is from a highest quality peer-reviewed journal.
(wang2018identificationofaberrantly pages 4-6): Kai Wang, Xiao Qu, Shaorui Liu, Xudong Yang, Fenglong Bie, Yu Wang, Cuicui Huang, and Jiajun Du. Identification of aberrantly expressed f-box proteins in squamous-cell lung carcinoma. Journal of Cancer Research and Clinical Oncology, 144:1509-1521, May 2018. URL: https://doi.org/10.1007/s00432-018-2653-1, doi:10.1007/s00432-018-2653-1. This article has 33 citations and is from a peer-reviewed journal.
(wang2018identificationofaberrantly pages 6-7): Kai Wang, Xiao Qu, Shaorui Liu, Xudong Yang, Fenglong Bie, Yu Wang, Cuicui Huang, and Jiajun Du. Identification of aberrantly expressed f-box proteins in squamous-cell lung carcinoma. Journal of Cancer Research and Clinical Oncology, 144:1509-1521, May 2018. URL: https://doi.org/10.1007/s00432-018-2653-1, doi:10.1007/s00432-018-2653-1. This article has 33 citations and is from a peer-reviewed journal.
(OpenTargets Search: -FBXO27): Open Targets Query (-FBXO27, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(yoshida2017ubiquitinationofexposed media 4c6e0dad): Yukiko Yoshida, Sayaka Yasuda, Toshiharu Fujita, Maho Hamasaki, Arisa Murakami, Junko Kawawaki, Kazuhiro Iwai, Yasushi Saeki, Tamotsu Yoshimori, Noriyuki Matsuda, and Keiji Tanaka. Ubiquitination of exposed glycoproteins by scffbxo27 directs damaged lysosomes for autophagy. Proceedings of the National Academy of Sciences, 114:8574-8579, Jul 2017. URL: https://doi.org/10.1073/pnas.1702615114, doi:10.1073/pnas.1702615114. This article has 153 citations and is from a highest quality peer-reviewed journal.
(yoshida2017ubiquitinationofexposed pages 4-5): Yukiko Yoshida, Sayaka Yasuda, Toshiharu Fujita, Maho Hamasaki, Arisa Murakami, Junko Kawawaki, Kazuhiro Iwai, Yasushi Saeki, Tamotsu Yoshimori, Noriyuki Matsuda, and Keiji Tanaka. Ubiquitination of exposed glycoproteins by scffbxo27 directs damaged lysosomes for autophagy. Proceedings of the National Academy of Sciences, 114:8574-8579, Jul 2017. URL: https://doi.org/10.1073/pnas.1702615114, doi:10.1073/pnas.1702615114. This article has 153 citations and is from a highest quality peer-reviewed journal.
(chae2023trim16mediatedlysophagysuppresses pages 2-5): Chang Woo Chae, Jee Hyeon Yoon, Jae Ryong Lim, Ji Yong Park, Ji Hyeon Cho, Young Hyun Jung, Gee Euhn Choi, Hyun Jik Lee, and Ho Jae Han. Trim16-mediated lysophagy suppresses high-glucose-accumulated neuronal aβ. Autophagy, 19:2752-2768, Jul 2023. URL: https://doi.org/10.1080/15548627.2023.2229659, doi:10.1080/15548627.2023.2229659. This article has 37 citations and is from a domain leading peer-reviewed journal.
(skaar2013mechanismsandfunction pages 4-5): Jeffrey R. Skaar, Julia K. Pagan, and Michele Pagano. Mechanisms and function of substrate recruitment by f-box proteins. Nature Reviews Molecular Cell Biology, 14:369-381, May 2013. URL: https://doi.org/10.1038/nrm3582, doi:10.1038/nrm3582. This article has 818 citations and is from a domain leading peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

meyer2024theendolysosomaldamage pages 11-12
yoshida2018cytosolicnglycanstriggers pages 5-6
wang2018identificationofaberrantly pages 4-6
yoshida2017ubiquitinationofexposed pages 5-6
yoshida2017ubiquitinationofexposed pages 2-3
glenn2008diversityintissue pages 1-2
kumanomidou2015thestructuraldifferences pages 1-2
skaar2013mechanismsandfunction pages 1-2
skaar2013mechanismsandfunction pages 11-11
glenn2008diversityintissue pages 3-4
yoshida2017ubiquitinationofexposed pages 1-2
glenn2008diversityintissue pages 7-9
yoshida2017ubiquitinationofexposed pages 6-6
yoshida2017ubiquitinationofexposed pages 3-4
wang2018identificationofaberrantly pages 6-7
yoshida2017ubiquitinationofexposed pages 4-5
skaar2013mechanismsandfunction pages 4-5
https://doi.org/10.1371/journal.pone.0140366
https://doi.org/10.1002/bies.201700215
https://doi.org/10.1074/jbc.m709508200
https://doi.org/10.1073/pnas.1702615114
https://doi.org/10.1146/annurev-biochem-030222-102505
https://doi.org/10.1007/s00432-018-2653-1
https://platform.opentargets.org/target/ENSG00000161243
https://doi.org/10.1038/s12276-023-01081-2
https://doi.org/10.1080/15548627.2023.2229659
https://doi.org/10.1038/nrm3582
https://doi.org/10.1371/journal.pone.0140366,
https://doi.org/10.1002/bies.201700215,
https://doi.org/10.1038/nrm3582,
https://doi.org/10.1074/jbc.m709508200,
https://doi.org/10.1146/annurev-biochem-030222-102505,
https://doi.org/10.1073/pnas.1702615114,
https://doi.org/10.1038/s12276-023-01081-2,
https://doi.org/10.1080/15548627.2023.2229659,
https://doi.org/10.1007/s00432-018-2653-1,

📚 Additional Documentation

Pn Notes

(FBXO27-pn-notes.md)

FBXO27 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q8NI29
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FBXO27/FBXO27-ai-review.yaml
AIGR review HTML: missing - genes/human/FBXO27/FBXO27-ai-review.html
Gene notes: missing - genes/human/FBXO27/FBXO27-notes.md
GOA TSV: present - genes/human/FBXO27/FBXO27-goa.tsv
UniProt record: present - genes/human/FBXO27/FBXO27-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FBXO27.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FBXO27.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/FBXO27/FBXO27-deep-research-falcon.md

AIGR Review Snapshot

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/core annotation action counts: ACCEPT: 16; KEEP_AS_NON_CORE: 6; MODIFY: 1

PN Consistency Summary

Consistency: Good, with a deliberate divergence. As an FBA/FBG lectin F-box, the review (correctly) does NOT make GO:1990756 the core MF; instead core MF = GO:0030246 carbohydrate binding (+ proposed GO:0005537 D-mannose binding), with GO:0006516 glycoprotein catabolic process and lysophagy as core BP. Deep research (Yoshida/Fbs3 lysophagy of LAMP2/LAMP1), UniProt (2008 lectin/SCF data), and GOA agree. The contributes_to GO:0061630 IBA is reasonably kept non-core. No internal contradictions.
PN story / NEW pressure: PN's generic GO:1990756 adaptor target does NOT match this gene's informative MF (glycan binding) — a known special case the prompt flagged. Review adds the lysophagy/damaged-lysosome-glycoprotein role (LAMP2/LAMP1, p62/LC3, N-myristoylation) absent from GOA. KEY ISSUE: review proposes "lysophagy" as a NEW term, but GO:0062093 lysophagy already exists (verified; child of GO:0016236 macroautophagy, def. "selective autophagy…damaged lysosome…by macroautophagy"). So this is ALREADY CAPTURED in GO, not new. Also GO:0097466 "ubiquitin-dependent glycoprotein ERAD pathway" exists as a more specific option than the ERAD IBA.
Evidence alignment: PN cites only "15340381 / rev". Review anchored on PMID:18203720 (FBA lectin family, full text) + Falcon (Yoshida PNAS lysophagy) + PMID:34445249. PN reference disjoint from review's; review evidence is far richer and substrate-validated.
Verdict: CONSISTENT (with lectin caveat); ONE FIX — replace the proposed-new "lysophagy" with existing GO:0062093.

Full Consistency Review

UniProt: Q8NI29 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE (well-developed; SPECIAL CASE — lectin F-box)
PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|FBA (aux domain IPR007397) ; PN-node mapping: group=mapped GO:1990756; subtype/type/branch=no_mapping; class=context_only (GO:0061630).
Consistency: Good, with a deliberate divergence. As an FBA/FBG lectin F-box, the review (correctly) does NOT make GO:1990756 the core MF; instead core MF = GO:0030246 carbohydrate binding (+ proposed GO:0005537 D-mannose binding), with GO:0006516 glycoprotein catabolic process and lysophagy as core BP. Deep research (Yoshida/Fbs3 lysophagy of LAMP2/LAMP1), UniProt (2008 lectin/SCF data), and GOA agree. The contributes_to GO:0061630 IBA is reasonably kept non-core. No internal contradictions.
PN story / NEW pressure: PN's generic GO:1990756 adaptor target does NOT match this gene's informative MF (glycan binding) — a known special case the prompt flagged. Review adds the lysophagy/damaged-lysosome-glycoprotein role (LAMP2/LAMP1, p62/LC3, N-myristoylation) absent from GOA. KEY ISSUE: review proposes "lysophagy" as a NEW term, but GO:0062093 lysophagy already exists (verified; child of GO:0016236 macroautophagy, def. "selective autophagy…damaged lysosome…by macroautophagy"). So this is ALREADY CAPTURED in GO, not new. Also GO:0097466 "ubiquitin-dependent glycoprotein ERAD pathway" exists as a more specific option than the ERAD IBA.
Mapping strategy: Node mapping is fine for the family, but PN's GO:1990756 over-reaches/under-describes FBXO27 specifically — glycan binding is the real MF. Reviewer already handled this at the gene level (MODIFY protein-binding → carbohydrate binding). No node change needed; flag FBXO27 as the lectin exception to the GO:1990756 default.
Evidence alignment: PN cites only "15340381 / rev". Review anchored on PMID:18203720 (FBA lectin family, full text) + Falcon (Yoshida PNAS lysophagy) + PMID:34445249. PN reference disjoint from review's; review evidence is far richer and substrate-validated.
Verdict: CONSISTENT (with lectin caveat); ONE FIX — replace the proposed-new "lysophagy" with existing GO:0062093.
Recommended edits: [YAML] In FBXO27-ai-review.yaml, replace the proposed_new_terms "lysophagy" entry with a reference to existing GO:0062093 lysophagy (verified real), and set core_function #3 directly_involved_in to GO:0062093 (more specific than GO:0016236 macroautophagy). [YAML] Optionally MODIFY the ERAD IBA (GO:0036503) toward GO:0097466 ubiquitin-dependent glycoprotein ERAD pathway if retained.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/FBXO27/FBXO27-ai-review.yaml
PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | FBA

UniProt: Q8NI29
In branches: UPS
Signature domains: IPR001810
Auxiliary domains: IPR007397
PN references (titles):
- 15340381 / rev
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|FBA
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
  status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
  rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor

Note

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.

📄 View Raw YAML

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.

FBXO27

Gene Description

Proposed New Ontology Terms

lysophagy

Existing Annotations Review

Core Functions

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.

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human FBXO27 (UniProt Q8NI29) — functional annotation

0) Identity verification (critical disambiguation)

1) Key concepts and definitions (current understanding)

1.1 SCF E3 ubiquitin ligase and F-box proteins

1.2 Lectin-like F-box (FBA) family and glycan recognition

1.3 Lysophagy and the endo-lysosomal damage response

2) Molecular function of FBXO27

2.1 Primary biochemical role

2.2 Substrate specificity: what does FBXO27 recognize?

2.3 Key cellular substrates and pathways

Lysosomal membrane glycoproteins (LAMP2 and LAMP1)

3) Subcellular localization and mechanism of recruitment

3.1 Membrane association via N-myristoylation

3.2 Damage sensing: glycan exposure after rupture

4) Recent developments and latest research (prioritizing 2023–2024)

4.1 2024 expert synthesis: FBXO27 in the endo-lysosomal damage response

4.2 2023 mechanistic disease-context study: cardiomyocyte autophagy and diabetic cardiomyopathy

4.3 2023 neuronal lysophagy under high glucose

5) Current applications and real-world implementations

5.1 FBXO27 as a mechanistic handle on lysophagy

5.2 Translational hypothesis space: cardiometabolic and neurodegenerative contexts

5.3 Potential biomarker associations in cancer transcriptomics

6) Expert opinions, limitations, and open questions

6.1 Substrate identification and “orphan” F-box context

6.2 Redundancy and cell-type specificity in lysosomal ubiquitylation

6.3 Mechanistic gaps highlighted by primary data

7) Relevant statistics and data highlights

7.1 Quantitative cancer expression statistics (2018)

7.2 Quantitative mechanistic cardiomyocyte data (2023)

7.3 Open Targets association statistics (curated database signal; interpret cautiously)

8) Figure-supported mechanistic evidence (visual)

9) Consolidated evidence map

10) Key references (with URLs and publication dates)

Artifacts

Citations

📚 Additional Documentation

Pn Notes

FBXO27 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | FBA

Projected GO annotations (1)

Note

📄 View Raw YAML