Uggt1 (UGGT1; UniProt Q9JLA3) encodes the rat UDP-glucose:glycoprotein glucosyltransferase 1, a ~170 kDa endoplasmic reticulum (ER) luminal glycoprotein-folding sensor and quality-control enzyme. It transfers a single glucose residue from UDP-glucose onto deglucosylated N-linked glycans (Man7-9GlcNAc2; e.g. Man9GlcNAc2 -> Glc1Man9GlcNAc2) on glycoproteins that have not reached a native conformation. This reglucosylation regenerates the monoglucosylated tag recognized by the lectin chaperones calnexin/calreticulin, driving the calnexin/calreticulin (CNX/CRT) folding cycle: non-native clients are retained for further folding attempts and prevented from premature ER exit. UGGT1 acts as a conformation sensor, preferentially recognizing non-native glycoproteins with exposed hydrophobic surfaces, and it can delay entry of unstable/misfolded clients into glycoprotein ER-associated degradation (gpERAD), competing with EDEM/mannose-trimming pathways. Catalysis requires Ca2+ coordinated by a DxD motif. UGGT1 is the dominant cellular glucosyltransferase of this system and forms a stable complex with the selenoprotein SELENOF (SEP15), a redox-active cochaperone.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003980 UDP-glucose:glycoprotein glucosyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: This is the defining core molecular function of UGGT1. It transfers a glucose residue from UDP-glucose onto deglucosylated N-linked glycans on non-native glycoproteins, regenerating the monoglucosylated tag of the calnexin/calreticulin cycle. Falcon deep research confirms the reaction and its Ca2+/DxD-motif requirement. Reason: Core molecular function, well supported phylogenetically (IBA), by direct rat biochemistry (PMID:10764828, PMID:1533626), and by the falcon synthesis. Supporting Evidence: file:rat/Uggt1/Uggt1-deep-research-falcon.md UGGT1 is a **reglucosylating glycosyltransferase** that transfers a **glucose residue from UDP-glucose** onto **deglucosylated N-linked glycans** on glycoproteins that have not reached a native conformation. file:rat/Uggt1/Uggt1-deep-research-falcon.md UGGT1 converted **Man9GlcNAc2 → Glc1Man9GlcNAc2** on MHC I, which is the canonical “tag” for lectin-chaperone binding in the ER. file:rat/Uggt1/Uggt1-deep-research-falcon.md UGGT1 catalytic activity requires **Ca2+**, coordinated by a **DxD motif** in the catalytic site |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Manual review: endoplasmic reticulum is consistent with known biology of Uggt1. Reason: Retained as supported or plausible for this gene and evidence context. |
| GO:0051082 unfolded protein binding | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: UGGT1 is a conformation sensor that selectively recognizes and binds non-native/partially folded glycoproteins (preferring exposed hydrophobic surfaces) as the recognition step preceding reglucosylation. That recognition is real and directly assayed (GO:0051082 IDA from PMID:10764828), but it is the substrate-selection step of the glucosyltransferase rather than a standalone chaperone-like binding function, and GO:0051082 is now formally obsolete with no replacement that fits a glycoprotein quality-control sensor - so the term over-annotates the gene. Reason: Recognition/binding of non-native glycoprotein clients is real, but it is the substrate-selection step intrinsic to UGGT1's glucosyltransferase activity rather than a standalone chaperone-like binding function. GO:0051082 has been formally obsoleted in the ontology (OLS returns the label "obsolete unfolded protein binding", with the stated reason that binding terms of this kind should be replaced by an activity term such as GO:0044183 or GO:0140309); neither replacement fits a glycoprotein quality-control sensor. This restores the project-level call in projects/UNFOLDED_PROTEIN_BINDING.md, which records rat Uggt1 (Q9JLA3) as OVER_ANNOTATED for this term with no suitable replacement ("not chaperones"). The IBA is additionally stale — the current PANTHER PAINT release no longer carries an IBD for GO:0051082 in PTHR11226. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTHR11226 · UDP-glucose glycoprotein glucosyltransferase family (PAINT) SOURCE STALE OR MISSING No IBD for GO:0051082 remains in the current PTHR11226 PAINT slice (snapshot 20260528); the remaining IBDs at PTN000132051 are GO:0003980, GO:0005783, and GO:0006487 only. GO:0051082 (unfolded protein binding) has been formally obsoleted in the ontology, which likely explains its removal from PAINT. The underlying binding is real and directly assayed (PMID:10764828 IDA), so the defect is the term - it conflates conformation-sensing substrate selection by a glucosyltransferase with chaperone-like unfolded-protein binding - not the propagation path. Supporting Evidence: file:rat/Uggt1/Uggt1-deep-research-falcon.md UGGT1 is a conformation sensor: it preferentially acts on proteins that are **non-native** and can prefer clients with **exposed hydrophobic regions**, consistent with recognition of misfolded/partially folded surfaces rather than fully folded proteins. |
| GO:0097359 UDP-glucosylation | IEA GO_REF:0000108 | ACCEPT | Summary: Manual review: UDP-glucosylation is consistent with known biology of Uggt1. Reason: Retained as supported or plausible for this gene and evidence context. |
| GO:0003980 UDP-glucose:glycoprotein glucosyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Manual review: UDP-glucose:glycoprotein glucosyltransferase activity is consistent with known biology of Uggt1. Reason: Retained as supported or plausible for this gene and evidence context. |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000044 | ACCEPT | Summary: Manual review: endoplasmic reticulum lumen is consistent with known biology of Uggt1. Reason: Retained as supported or plausible for this gene and evidence context. |
| GO:0005793 endoplasmic reticulum-Golgi intermediate compartment | IEA GO_REF:0000044 | ACCEPT | Summary: Manual review: endoplasmic reticulum-Golgi intermediate compartment is consistent with known biology of Uggt1. Reason: Retained as supported or plausible for this gene and evidence context. |
| GO:0009101 glycoprotein biosynthetic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Manual review: glycoprotein biosynthetic process may be context-dependent or peripheral for Uggt1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | ACCEPT | Summary: Manual review: transferase activity is consistent with known biology of Uggt1. Reason: Retained as supported or plausible for this gene and evidence context. |
| GO:0016757 glycosyltransferase activity | IEA GO_REF:0000043 | ACCEPT | Summary: Manual review: glycosyltransferase activity is consistent with known biology of Uggt1. Reason: Retained as supported or plausible for this gene and evidence context. |
| GO:1901135 carbohydrate derivative metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Manual review: carbohydrate derivative metabolic process may be context-dependent or peripheral for Uggt1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. |
| GO:0003980 UDP-glucose:glycoprotein glucosyltransferase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: UDP-glucose:glycoprotein glucosyltransferase activity is consistent with known biology of Uggt1. Reason: Retained as supported or plausible for this gene and evidence context. |
| GO:0009306 protein secretion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: protein secretion may be context-dependent or peripheral for Uggt1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. |
| GO:0032991 protein-containing complex | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Manual review: protein-containing complex may be context-dependent or peripheral for Uggt1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. |
| GO:0005515 protein binding | IPI PMID:11278576 Association between the 15-kDa selenoprotein and UDP-glucose... | MARK AS OVER ANNOTATED | Summary: This IPI corresponds to the specific UGGT1-SELENOF (SEP15) interaction reported in PMID:11278576. The bare 'protein binding' term is uninformative; the functionally relevant partnership is a stable, high-affinity complex with the redox-active selenoprotein cochaperone SELENOF, documented in the falcon synthesis. The interaction itself is real and biologically meaningful, but GO:0005515 does not capture it. Reason: Bare protein binding is uninformative per curation guidelines. The underlying SELENOF/SEP15 interaction is captured descriptively here rather than by this generic term. Supporting Evidence: file:rat/Uggt1/Uggt1-deep-research-falcon.md UGGT1 forms a stable complex with the selenoprotein **SEP15/SELENOF**, which is proposed to act as a **redox-active cochaperone** in ER folding surveillance. |
| GO:0005788 endoplasmic reticulum lumen | IDA PMID:11535823 Immunolocalization of UDP-glucose:glycoprotein glucosyltrans... | ACCEPT | Summary: UGGT1 is a soluble ER luminal enzyme bearing a C-terminal ER-retention motif; the ER lumen is where it carries out reglucosylation as part of the CNX/CRT quality-control cycle. This is the core site of action, supported by direct immunolocalization (PMID:11535823) and the falcon synthesis. Reason: Core subcellular localization, directly observed (IDA) and consistent with the falcon synthesis describing UGGT1 as an ER-resident luminal enzyme. Supporting Evidence: file:rat/Uggt1/Uggt1-deep-research-falcon.md UGGT1 is described across multiple mammalian studies as **ER-localized/ER-resident** and operating in the **ER lumen** as part of ER protein quality control and early secretory pathway surveillance. |
| GO:0005793 endoplasmic reticulum-Golgi intermediate compartment | IDA PMID:11535823 Immunolocalization of UDP-glucose:glycoprotein glucosyltrans... | ACCEPT | Summary: Manual review: endoplasmic reticulum-Golgi intermediate compartment is consistent with known biology of Uggt1. Reason: Retained as supported or plausible for this gene and evidence context. |
| GO:0051082 unfolded protein binding | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Same call as the IBA/IDA unfolded protein binding rows. Recognition and binding of non-native glycoprotein clients is real and conserved - the ISO transfer from human UGGT1 is sound and the donor carries its own IDA - but the obsolete term casts a glucosyltransferase's substrate selection as chaperone-like unfolded-protein binding, so it over-annotates the gene. Reason: Same call as the IBA and IDA rows for this obsolete term. The ISO transfer is consistent with the conserved folding-sensor mechanism, but the term itself is obsolete and characterises UGGT1 as a chaperone-like binder rather than a glycoprotein quality-control sensor, per projects/UNFOLDED_PROTEIN_BINDING.md. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q9NYU2 · human UGGT1 SUPPORTS SOURCE BUT NOT TARGET The rat ISO names human UGGT1 as its donor (WITH/FROM UniProtKB Q9NYU2 in the rat GOA record), and the donor annotation is experimentally grounded rather than weak - the human record carries GO:0051082 by IDA (PMID:10694380) alongside the IBA. The defect is therefore in the term, not in the propagation path or the source evidence. GO:0051082 is obsolete, and it conflates conformation-sensing substrate selection by a glucosyltransferase with chaperone-like unfolded-protein binding. The same call is recorded for the human gene in projects/UNFOLDED_PROTEIN_BINDING.md. Supporting Evidence: file:rat/Uggt1/Uggt1-deep-research-falcon.md UGGT1 preferentially acts on **non-native/partially folded glycoproteins** and prefers proteins with **exposed hydrophobic regions** over folded proteins. |
| GO:0051082 unfolded protein binding | IDA PMID:10764828 Cloning and characterization of mammalian UDP-glucose glycop... | MARK AS OVER ANNOTATED | Summary: Direct-assay evidence that UGGT1 binds non-native protein substrates. The binding itself is not in doubt and the falcon synthesis corroborates the conformation-sensing recognition activity; but that recognition is the substrate-selection step of the glucosyltransferase mechanism, and the obsolete GO:0051082 frames it as chaperone-like unfolded-protein binding, so the term over-annotates the gene even on this, the strongest of the three rows. Reason: The direct experimental evidence (IDA) for binding of non-native protein clients is not in doubt, and this row is the strongest of the three. It is kept rather than removed for that reason. The term is nonetheless obsolete, and it frames a glycoprotein quality-control sensor as a chaperone-like binder, so it is marked over-annotated in line with projects/UNFOLDED_PROTEIN_BINDING.md. The underlying recognition step is retained in core_functions as part of the glucosyltransferase activity (GO:0003980) that it serves. Supporting Evidence: file:rat/Uggt1/Uggt1-deep-research-falcon.md UGGT1 is a conformation sensor: it preferentially acts on proteins that are **non-native** and can prefer clients with **exposed hydrophobic regions** |
| GO:0005515 protein binding | IPI PMID:10764828 Cloning and characterization of mammalian UDP-glucose glycop... | MARK AS OVER ANNOTATED | Summary: Manual review: protein binding is too generic or over-extended for Uggt1. Reason: Marked over-annotated because more specific terms capture the biology more accurately. |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000121 | ACCEPT | Summary: Manual review: endoplasmic reticulum is consistent with known biology of Uggt1. Reason: Retained as supported or plausible for this gene and evidence context. |
| GO:0003980 UDP-glucose:glycoprotein glucosyltransferase activity | IDA PMID:10764828 Cloning and characterization of mammalian UDP-glucose glycop... | ACCEPT | Summary: Manual review: UDP-glucose:glycoprotein glucosyltransferase activity is consistent with known biology of Uggt1. Reason: Retained as supported or plausible for this gene and evidence context. |
| GO:0051084 'de novo' post-translational protein folding | TAS PMID:10764828 Cloning and characterization of mammalian UDP-glucose glycop... | KEEP AS NON CORE | Summary: Manual review: 'de novo' post-translational protein folding may be context-dependent or peripheral for Uggt1. Reason: Kept as non-core to preserve potentially valid context-specific annotation without elevating it to core function. |
| GO:0003980 UDP-glucose:glycoprotein glucosyltransferase activity | TAS PMID:10764828 Cloning and characterization of mammalian UDP-glucose glycop... | ACCEPT | Summary: Manual review: UDP-glucose:glycoprotein glucosyltransferase activity is consistent with known biology of Uggt1. Reason: Retained as supported or plausible for this gene and evidence context. |
| GO:0003980 UDP-glucose:glycoprotein glucosyltransferase activity | IDA PMID:12518055 UDP-Glc:glycoprotein glucosyltransferase recognizes structur... | ACCEPT | Summary: Manual review: UDP-glucose:glycoprotein glucosyltransferase activity is consistent with known biology of Uggt1. Reason: Retained as supported or plausible for this gene and evidence context. |
| GO:0006457 protein folding | TAS PMID:12518055 UDP-Glc:glycoprotein glucosyltransferase recognizes structur... | MODIFY | Summary: UGGT1 contributes to protein folding indirectly, by reglucosylating non-native glycoproteins so they re-engage the calnexin/calreticulin lectin chaperones for additional folding rounds and avoid premature ER exit. The generic 'protein folding' term captures this only at a high level; the precise role is the glycan-dependent quality-control/folding cycle described in the falcon synthesis. Replaced by the compartment-specific GO:0034975 (protein folding in endoplasmic reticulum), which states the same involvement at the right scope. Reason: UGGT1 does not directly fold proteins; it drives the lectin-chaperone folding cycle in the ER lumen. The generic 'protein folding' term is broad relative to that mechanism and is not compartment-specific; GO:0034975 (protein folding in endoplasmic reticulum) states the same involvement at the right scope and is the term this review carries in core_functions. Proposed replacements: protein folding in endoplasmic reticulum Supporting Evidence: file:rat/Uggt1/Uggt1-deep-research-falcon.md When a glycoprotein carries a **monoglucosylated N-glycan** it can bind CNX/CRT; after deglucosylation, a protein that is still non-native can be **reglucosylated by UGGT1**, enabling additional rounds of CNX/CRT-assisted folding and preventing premature ER exit. |
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Download this section (compressed HTML)Q: Does rat UGGT1 reglucosylation actively delay glycoprotein ERAD in vivo, and how is the balance between refolding and degradation set in rat tissues?
Q: Is the UGGT1-SELENOF (SEP15) complex required for full reglucosylation activity or substrate selectivity in rat liver ER, where UGGT1 was first purified?
Experiment: Measure rat UGGT1 reglucosylation activity on defined non-native glycoprotein substrates (e.g. M9-BODIPY) in liver ER fractions with and without Ca2+ chelation and DxD-motif mutation, to dissociate client binding from catalysis.
Experiment: Use SELENOF/SEP15 knockdown in a rat hepatocyte model to test whether loss of the cochaperone alters the set of glycoproteins reglucosylated by UGGT1 and shifts client fate toward gpERAD.
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