Affinage

FBXO27

F-box only protein 27 · UniProt Q8NI29

Length
283 aa
Mass
31.6 kDa
Annotated
2026-06-09
13 papers in source corpus 5 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXO27 is a glycoprotein-specific F-box protein that nucleates an SCF (SKP1/CUL1/RBX1) E3 ubiquitin ligase complex and drives lysophagy, the selective autophagic clearance of damaged lysosomes (PMID:28743755, PMID:18203720). Substrate recognition is mediated by a conserved G domain whose hydrophobic pocket, formed by two essential aromatic residues, binds high-mannose and sulfated N-glycans; mutation of these residues abolishes glycan binding (PMID:18203720). SKP1 binding is required not only for complex assembly but also to stabilize the FBXO27 conformation competent for glycoprotein capture and to prevent its aggregation, increasing its cellular concentration (PMID:21640084). Upon lysosomal membrane damage, N-myristoylation targets FBXO27 to membranes and enables its rapid accumulation at damaged lysosomes (PMID:28743755), where SCF^FBXO27 ubiquitinates glycoproteins exposed on the cytosolic face—including LAMP1, LAMP2, the SNAREs VAMP3 and VAMP7, GNS, PSAP, and TMEM192—to recruit autophagic machinery (PMID:28743755); LAMP2 ubiquitination specifically enhances this recruitment (PMID:28743755). FBXO27 levels are constrained upstream by CREG1, whose loss elevates FBXO27 and depletes LAMP2, impairing autophagy in cardiomyocytes (PMID:37658156).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2008 High

    Established the biochemical basis of FBXO27 substrate selection—how an F-box protein recognizes glycoproteins rather than peptide motifs—by mapping glycan binding to a defined G domain pocket.

    Evidence Glycan arrays and site-directed mutagenesis of G domain aromatic residues, plus co-IP of SCF components, in vitro

    PMID:18203720

    Open questions at the time
    • Did not identify physiological glycoprotein substrates in cells
    • Did not connect glycan recognition to a cellular pathway
  2. 2011 Medium

    Showed that SKP1 is not merely a scaffold adaptor but a conformational chaperone required for FBXO27 to bind glycoprotein substrates, explaining why the F-box protein is inactive in isolation.

    Evidence Co-expression/co-IP and ConA-glycoprotein binding assays with assessment of aggregation

    PMID:21640084

    Open questions at the time
    • Structural basis of SKP1-induced stabilization not resolved
    • Single lab, no in vivo substrate context
  3. 2015 Medium

    Comparative structural analysis distinguished glycan-binding from non-binding paralogs, confirming FBXO27/Fbs3 as a bona fide N-glycan recognizer within the family.

    Evidence X-ray crystallography of the Skp1-FBG3 complex with structure-based mutagenesis (FBXO27 referenced as contrast)

    PMID:26460611

    Open questions at the time
    • FBXO27's own structure not solved
    • FBXO27 glycan binding referenced, not directly re-tested here
  4. 2017 High

    Defined the physiological role of FBXO27: a lysophagy effector that senses lysosomal damage and ubiquitinates exposed lysosomal glycoproteins to trigger autophagic clearance, with N-myristoylation providing damage-responsive membrane targeting.

    Evidence Co-IP, overexpression ubiquitination screen upon lysosomal damage, mass spectrometry substrate identification, localization imaging, and autophagic recruitment assays

    PMID:28743755

    Open questions at the time
    • Endogenous loss-of-function lysophagy phenotype not fully characterized
    • N-myristoylation mechanism inferred without explicit mutagenesis
    • Relative contribution of each substrate to recruitment unclear
  5. 2023 Medium

    Placed FBXO27 within an upstream regulatory circuit, showing its abundance is controlled by CREG1 and that unrestrained FBXO27 degrades LAMP2 to impair autophagy in cardiomyocytes.

    Evidence CREG1 knockdown/overexpression in neonatal mouse cardiomyocytes with western blot and LAMP2 rescue

    PMID:37658156

    Open questions at the time
    • Mechanism by which CREG1 controls FBXO27 levels not defined
    • Tissue specificity of this regulation unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FBXO27 distinguishes damage-exposed glycans from normal lumenal glycoproteins and how substrate ubiquitination is mechanistically read by autophagy receptors remains open.
  • No structure of the FBXO27 substrate-bound complex
  • Autophagy receptor coupling to ubiquitinated substrates not defined
  • In vivo physiological requirement beyond cardiomyocytes unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005764 lysosome 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-392499 Metabolism of proteins 2
Partners
CREG1CUL1LAMP2RBX1SKP1VAMP3VAMP7
Complex memberships
SCF^FBXO27 (SKP1-CUL1-RBX1)

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 FBXO27 is a glycoprotein-specific F-box protein that forms an SCF (SKP1/CUL1/F-box) ubiquitin ligase complex (SCF^FBXO27) and ubiquitinates glycoproteins exposed on damaged lysosomal membranes, including SNARE proteins VAMP3 and VAMP7, and lysosomal proteins LAMP1, LAMP2, GNS, PSAP, and TMEM192, to recruit autophagic machinery and induce lysophagy. Co-immunoprecipitation, overexpression-based ubiquitination screen upon lysosomal damage, identification of substrates by mass spectrometry, functional autophagic machinery recruitment assays Proceedings of the National Academy of Sciences of the United States of America High 28743755
2017 FBXO27 undergoes N-myristoylation, which localizes it to membranes and enables rapid accumulation around damaged lysosomes upon lysosomal damage. Localization experiments (imaging of FBXO27 at damaged lysosomes), identification of N-myristoylation as membrane-targeting signal Proceedings of the National Academy of Sciences of the United States of America Medium 28743755
2017 Ubiquitination of LAMP2 by SCF^FBXO27 upon lysosomal damage enhances autophagic machinery recruitment to damaged lysosomes. Overexpression of FBXO27, ubiquitination assay of LAMP2, autophagic machinery recruitment assay Proceedings of the National Academy of Sciences of the United States of America Medium 28743755
2008 FBXO27 (as part of the FBA family) binds high-mannose and sulfated glycoproteins through a conserved G domain; two aromatic amino acids forming a hydrophobic pocket in the G domain are necessary for high-affinity glycan binding, as demonstrated by site-directed mutagenesis. FBXO27 co-precipitates components of the canonical SCF complex (Skp1, Cullin1, Rbx1). Glycan arrays, site-directed mutagenesis of G domain aromatic residues, co-immunoprecipitation of SCF complex components The Journal of biological chemistry High 18203720
2011 Skp1 binding to FBXO27 (Fbg5) stabilizes its conformation, enabling glycoprotein substrate binding; when expressed alone, Fbg5 does not bind N-glycoproteins, but co-expression with Skp1 facilitates ConA-reactive glycoprotein binding. Skp1 also increases FBXO27 cellular concentration by preventing aggregate formation. Co-expression and co-immunoprecipitation, ConA-glycoprotein binding assay, assessment of aggregate formation Biochemical and biophysical research communications Medium 21640084
2015 Crystal structure of the Skp1-FBG3 (FBXO44) complex determined at 2.6 Å resolution revealed why FBG3 lacks carbohydrate-binding activity despite homology to FBXO27/Fbs3: distinct hydrogen bond networks in four loops (β2-β3, β5-β6, β7-β8, β9-β10) prevent formation of the carbohydrate-binding pocket present in Fbs1/FBXO2. By contrast, FBXO27 (Fbs3/FBG5) is confirmed to recognize N-glycans of glycoproteins. X-ray crystallography of Skp1-FBG3 complex, structure-based mutational analysis PloS one Medium 26460611
2023 CREG1 inhibits FBXO27 protein expression, thereby preventing FBXO27-mediated degradation of LAMP2 protein; loss of CREG1 leads to increased FBXO27 expression and reduced LAMP2 levels, impairing autophagy in cardiomyocytes. Knockdown and overexpression of CREG1 in neonatal mouse cardiomyocytes, western blotting for FBXO27 and LAMP2 protein levels, rescue experiments with LAMP2 overexpression Experimental & molecular medicine Medium 37658156

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles. Autophagy 347 32048886
2017 Ubiquitination of exposed glycoproteins by SCFFBXO27 directs damaged lysosomes for autophagy. Proceedings of the National Academy of Sciences of the United States of America 117 28743755
2008 Diversity in tissue expression, substrate binding, and SCF complex formation for a lectin family of ubiquitin ligases. The Journal of biological chemistry 67 18203720
2023 TRIM16-mediated lysophagy suppresses high-glucose-accumulated neuronal Aβ. Autophagy 32 37357416
2023 The CREG1-FBXO27-LAMP2 axis alleviates diabetic cardiomyopathy by promoting autophagy in cardiomyocytes. Experimental & molecular medicine 32 37658156
2002 A new subfamily of structurally related human F-box proteins. Gene 31 12383498
2011 Skp1 stabilizes the conformation of F-box proteins. Biochemical and biophysical research communications 27 21640084
2021 Non-coding RNAs and related molecules associated with form-deprivation myopia in mice. Journal of cellular and molecular medicine 19 34841657
2015 The Structural Differences between a Glycoprotein Specific F-Box Protein Fbs1 and Its Homologous Protein FBG3. PloS one 15 26460611
2025 Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survival. Autophagy 13 39744815
2024 Role for the F-box proteins in heart diseases. Pharmacological research 5 39577754
2022 Caveolin-1 rs1997623 variant and adult metabolic syndrome-Assessing the association in three ethnic cohorts of Arabs, South Asians and South East Asians. Frontiers in genetics 5 36338969
2025 Endoplasmic reticulum stress and unfolded protein response play roles in recurrent pregnancy loss: A bioinformatics study. Journal of reproductive immunology 4 39923360

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