id: Q9NYU2
gene_symbol: UGGT1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1) is a large (~173 kDa)
  soluble ER-resident enzyme that serves as the central quality control sensor and
  folding checkpoint in the calnexin/calreticulin cycle. UGGT1 recognizes
  glycoproteins with minor folding defects (preferentially molten-globule-like
  intermediates, not fully folded or completely unfolded proteins) and
  reglucosylates their N-glycans, thereby tagging them for re-engagement with the
  calnexin/calreticulin chaperone system. Its core molecular function is
  UDP-glucose:glycoprotein glucosyltransferase activity (EC 2.4.1.-), transferring
  glucose from UDP-glucose to deglucosylated high-mannose N-glycans on misfolded
  substrates. Structurally, UGGT1 has a seven-domain architecture: four N-terminal
  thioredoxin-like domains (TRXL1-TRXL4) arranged in an arc that mediate substrate
  recognition, two beta-sandwich domains (betaS1, betaS2), and the C-terminal GT24
  catalytic domain (~20% of the protein) (DOI:10.1073/pnas.1703682114). Substantial
  interdomain conformational flexibility enables UGGT1 to accommodate diverse client
  shapes and to glucosylate glycans at least ~40 angstroms from localized disordered
  regions. UGGT1 writes a site-selective "glyco-code" that determines which ER
  chaperones engage substrates and when during maturation
  (DOI:10.1016/j.molcel.2023.11.006). UGGT1-mediated reglucosylation competes with
  EDEM-family mannose trimming in a "tug-of-war" that determines whether substrates
  are retained for refolding or committed to ERAD
  (DOI:10.1101/2023.10.18.562958). UGGT1 activity is modulated by the partner
  selenoprotein SELENOF/SEP15 (DOI:10.1073/pnas.2315009121). UGGT1 is the dominant
  mammalian reglucosyltransferase (UGGT2 is ~7-30% of UGGT1 abundance in tested
  cell lines). Described as a "gatekeeper for quality control" that prevents
  transport of improperly folded glycoproteins out of the ER (PMID:10694380).
alternative_products:
- name: '1'
  id: Q9NYU2-1
- name: '2'
  id: Q9NYU2-2
  sequence_note: VSP_036508
existing_annotations:
- term:
    id: GO:0003980
    label: UDP-glucose:glycoprotein glucosyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for the core enzymatic function of UGGT1. This is the defining
      molecular function of UGGT1: it transfers glucose from UDP-glucose to
      Man9GlcNAc2 N-glycans on misfolded glycoproteins. This activity has been
      experimentally demonstrated in PMID:10694380 (27-fold increase in glucose
      transfer from UDP-glucose to denatured substrates in HUGT1-transfected cells)
      and confirmed by reglucosylation assays in PMID:40267907. The IBA annotation
      is phylogenetically well-supported and represents the core function.
    action: ACCEPT
    reason: >-
      This is the core molecular function of UGGT1, well-established experimentally
      (PMID:10694380, PMID:40267907) and phylogenetically (IBA). UGGT1 is a
      glycosyltransferase family 24 member (CAZy GT24) that catalyzes the
      reglucosylation of N-glycans on misfolded glycoproteins as part of the ER
      quality control cycle.
    supported_by:
      - reference_id: PMID:10694380
        supporting_text: >-
          Extracts from HUGT1-transfected cells displayed a 27-fold increase in the
          transfer of [(14)C]glucose from UDP-[(14)C]glucose to denatured substrates.
      - reference_id: PMID:40267907
        supporting_text: >-
          UGGT1 encodes UDP-glucose:glycoprotein glucosyltransferase 1, an enzyme
          critical for maintaining quality control of N-linked glycosylation.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for ER localization. UGGT1 contains an N-terminal signal
      peptide and a C-terminal REEL ER-retrieval motif (UniProt). Arnold et al.
      (PMID:10694380) confirmed ER localization experimentally. This IBA is
      consistent with the more specific IEA annotation to ER lumen (GO:0005788).
      While GO:0005788 (ER lumen) is more precise, GO:0005783 (endoplasmic
      reticulum) is acceptable as a broader parent term and is correctly inferred
      phylogenetically.
    action: ACCEPT
    reason: >-
      UGGT1 is an established ER-resident protein. It contains the REEL ER
      retrieval signal (UniProt), and experimental localization was confirmed in
      PMID:10694380. The IBA annotation at this level is appropriate and consistent
      with more specific ER lumen and ERGIC annotations.
    supported_by:
      - reference_id: PMID:10694380
        supporting_text: >-
          HUGT1 encodes a 1555 amino acid polypeptide that, upon cleavage of an
          N-terminal signal peptide, is predicted to produce a soluble 173 kDa
          protein with the ER retrieval signal REEL.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      UGGT1 does interact with unfolded/misfolded glycoproteins, but this interaction
      represents substrate recognition for its glucosyltransferase enzymatic activity
      (GO:0003980), not an independent binding function. The N-terminal non-catalytic
      domain recognizes glycoproteins with minor folding defects (UniProt FUNCTION
      annotation, PMID:10694380), and this recognition is prerequisite to the catalytic
      reglucosylation step. This is analogous to how a kinase recognizes its protein
      substrates -- we would not annotate a kinase with "substrate protein binding"
      simply because it must bind substrates to phosphorylate them. The term GO:0051082
      is also being obsoleted (go-ontology#30962). The IBA was propagated from
      experimental annotations on UGGT1 orthologs, but the underlying experimental
      evidence reflects the same substrate-recognition mechanism.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      UGGT1 binding to unfolded proteins is incidental to its core enzymatic function
      as a UDP-glucose:glycoprotein glucosyltransferase. The protein recognizes
      misfolded glycoproteins as substrates for reglucosylation, not as an independent
      binding/chaperone function. As described in PMID:10694380, UGGT1 "operates as a
      gatekeeper for quality control by preventing transport of improperly folded
      glycoproteins out of the ER" through its glucosyltransferase activity -- the
      substrate recognition is integral to and subsumed by the enzymatic activity
      annotation GO:0003980. Additionally, GO:0051082 is being obsoleted per
      go-ontology#30962.
    supported_by:
      - reference_id: PMID:10694380
        supporting_text: >-
          UDP-glucose:glycoprotein glucosyltransferase (UGT) is a soluble protein of
          the endoplasmic reticulum (ER) that operates as a gatekeeper for quality
          control by preventing transport of improperly folded glycoproteins out of the
          ER.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: >-
      IEA annotation placing UGGT1 in the ER quality control compartment (ERQC).
      The ERQC is defined as "a subcompartment of the endoplasmic reticulum in which
      proteins with improper or incorrect folding accumulate." UGGT1 is a central
      enzyme in this compartment, acting as the folding sensor that reglucosylates
      misfolded glycoproteins for re-engagement with calnexin/calreticulin
      (PMID:10694380, PMID:40267907). The Reactome pathway R-HSA-901032 explicitly
      places UGGT1 in the ERQC. This is an appropriate and informative localization
      annotation.
    action: ACCEPT
    reason: >-
      UGGT1 is a core component of the ERQC, functioning as the folding sensor that
      determines whether glycoproteins are retained for further folding attempts.
      Reactome R-HSA-901032 explicitly models UGGT1 in this compartment. The IEA
      annotation is well-supported by the known biology of UGGT1.
    supported_by:
      - reference_id: PMID:40267907
        supporting_text: >-
          UGGT1 identifies and reglucosylates misfolded proteins, resulting in ER
          retention for re-binding to CNX/CRT to enable correct folding.
- term:
    id: GO:0097359
    label: UDP-glucosylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: >-
      IEA annotation for the biological process of UDP-glucosylation. GO:0097359 is
      defined as "the covalent attachment of a UDP-glucose residue to a substrate
      molecule." This accurately describes the process UGGT1 catalyzes: transferring
      glucose from UDP-glucose to Man9GlcNAc2 N-glycans on misfolded glycoproteins.
      The annotation is logically inferred from the MF annotation GO:0003980 and is
      correct.
    action: ACCEPT
    reason: >-
      UDP-glucosylation is the direct process outcome of UGGT1's enzymatic activity.
      The annotation is correctly inferred from the molecular function GO:0003980
      (UDP-glucose:glycoprotein glucosyltransferase activity). It accurately captures
      what UGGT1 does at the process level.
    supported_by:
      - reference_id: PMID:10694380
        supporting_text: >-
          Extracts from HUGT1-transfected cells displayed a 27-fold increase in the
          transfer of [(14)C]glucose from UDP-[(14)C]glucose to denatured substrates.
- term:
    id: GO:0003980
    label: UDP-glucose:glycoprotein glucosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for UGGT1 glucosyltransferase activity from combined automated
      methods. This is a redundant annotation for the same GO term as the IBA and IDA
      annotations, but that is acceptable. The annotation correctly identifies UGGT1's
      core enzymatic function.
    action: ACCEPT
    reason: >-
      Correct assignment of the core molecular function. While redundant with the IBA
      and IDA annotations to GO:0003980, duplicate annotations with different evidence
      codes are acceptable.
    supported_by:
      - reference_id: PMID:10694380
        supporting_text: >-
          Extracts from HUGT1-transfected cells displayed a 27-fold increase in the
          transfer of [(14)C]glucose from UDP-[(14)C]glucose to denatured substrates.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for ER lumen localization based on UniProt subcellular location
      mapping. UGGT1 is a soluble protein that resides in the ER lumen; it contains
      an N-terminal signal peptide (cleaved) and the C-terminal REEL ER retrieval
      signal (UniProt). Arnold et al. (PMID:10694380) confirmed ER localization.
      UniProt explicitly annotates SUBCELLULAR LOCATION as "Endoplasmic reticulum
      lumen." This is more specific than GO:0005783 and accurately captures where
      UGGT1 resides.
    action: ACCEPT
    reason: >-
      UGGT1 is a soluble, luminal ER protein. UniProt annotation with experimental
      evidence (PMID:10694380) and PROSITE ER-targeting motif (PRU10138) confirm
      ER lumen localization. This is the most appropriate CC annotation for UGGT1.
    supported_by:
      - reference_id: PMID:10694380
        supporting_text: >-
          HUGT1 encodes a 1555 amino acid polypeptide that, upon cleavage of an
          N-terminal signal peptide, is predicted to produce a soluble 173 kDa
          protein with the ER retrieval signal REEL.
- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for ERGIC localization based on UniProt subcellular location
      mapping. UniProt annotates UGGT1 SUBCELLULAR LOCATION as including
      "Endoplasmic reticulum-Golgi intermediate compartment" based on PROSITE
      and experimental evidence (PMID:10694380). UGGT1 cycles through the ERGIC
      as part of its ER retrieval mechanism, though its primary site of action
      is the ER lumen/ERQC. This is consistent with its ER retrieval signal
      (REEL) which would enable cycling through the ERGIC.
    action: ACCEPT
    reason: >-
      UniProt annotates UGGT1 to ERGIC, and an ISS annotation also supports this
      localization. UGGT1 contains the REEL retrieval signal which mediates cycling
      through the secretory pathway, consistent with ERGIC presence. While the
      primary functional site is the ER lumen, ERGIC presence is expected for
      ER-retrieved proteins.
    supported_by:
      - reference_id: PMID:10694380
        supporting_text: >-
          HUGT1 encodes a 1555 amino acid polypeptide that, upon cleavage of an
          N-terminal signal peptide, is predicted to produce a soluble 173 kDa
          protein with the ER retrieval signal REEL.
- term:
    id: GO:0009101
    label: glycoprotein biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation from InterPro mapping. GO:0009101 (glycoprotein biosynthetic
      process) is defined as "the chemical reactions and pathways resulting in the
      formation of glycoproteins." While UGGT1 does modify glycoproteins by adding
      glucose to their N-glycans, its role is in quality control and reglucosylation
      of already-formed glycoproteins, not in de novo glycoprotein biosynthesis.
      UGGT1 acts after the initial glycosylation and trimming steps, adding glucose
      back to N-glycans on misfolded proteins to retain them in the ER for refolding.
      This is better described as protein N-linked glycosylation (GO:0006487) or
      more specifically the ERQC pathway, rather than glycoprotein biosynthesis
      per se.
    action: MODIFY
    reason: >-
      UGGT1 does not participate in de novo glycoprotein biosynthesis. It acts
      downstream in the quality control cycle, reglucosylating N-glycans on
      misfolded glycoproteins that have already been synthesized and initially
      glycosylated. The IBA annotation to GO:0018279 (protein N-linked glycosylation
      via asparagine) is a more appropriate process term, and GO:0006487 (protein
      N-linked glycosylation) would also be suitable. GO:0009101 is misleading
      because UGGT1 does not contribute to glycoprotein biosynthesis in the usual
      sense.
    proposed_replacement_terms:
      - id: GO:0006487
        label: protein N-linked glycosylation
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation from UniProt keyword mapping for the broad parent term
      "transferase activity." UGGT1 is indeed a transferase (it transfers glucose
      from UDP-glucose to glycoprotein substrates). However, the more specific term
      GO:0003980 (UDP-glucose:glycoprotein glucosyltransferase activity) is already
      annotated via IBA, IDA, and other IEA sources. GO:0016740 is a very broad
      ancestral term that adds no information beyond what GO:0003980 provides.
    action: ACCEPT
    reason: >-
      While extremely broad, this IEA annotation is not incorrect. UGGT1 is a
      transferase. The more specific child term GO:0003980 is already captured by
      IBA and IDA annotations. It is acceptable for IEA annotations to be broader
      than what is determined by IBA or literature.
- term:
    id: GO:0016757
    label: glycosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation from UniProt keyword mapping for "glycosyltransferase activity."
      UGGT1 is a member of glycosyltransferase family 24 (CAZy GT24) and is
      classified as such in UniProt. This is a parent term of GO:0003980. While
      less specific than GO:0003980, it is correct and acceptable as an IEA
      annotation.
    action: ACCEPT
    reason: >-
      Correct parent term annotation. UGGT1 belongs to CAZy GT24 and is a
      glycosyltransferase by classification (UniProt KW-0328). The more specific
      GO:0003980 is already annotated. Broader IEA annotations are acceptable.
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation from ARBA machine learning. GO:1904380 is defined as "any
      protein alpha-1,2-demannosylation that takes place in the endoplasmic
      reticulum quality control compartment (ERQC)." UGGT1 is NOT a mannosidase
      and does NOT trim mannose residues. UGGT1 is a glucosyltransferase that adds
      glucose to N-glycans. Mannose trimming in the ERQC is carried out by ER
      mannosidase I (MAN1B1) and EDEM family members (PMID:40267907). This
      annotation is incorrect and was likely mis-assigned by the ARBA model.
    action: REMOVE
    reason: >-
      UGGT1 does not perform mannose trimming. It is a glucosyltransferase that
      adds glucose to Man9GlcNAc2 N-glycans on misfolded glycoproteins. Mannose
      trimming is carried out by distinct enzymes (ERManI/MAN1B1, EDEM1/2/3) that
      act in the ERQC pathway. While UGGT1 operates in the same pathway as the
      mannose trimming enzymes, it performs an entirely different enzymatic reaction
      (glucosylation, not demannosylation). This is an incorrect ARBA prediction.
    supported_by:
      - reference_id: PMID:40267907
        supporting_text: >-
          A molecular marking system involving multiple ER-resident exo-mannosidases,
          including ER mannosidase I (ERManI) and EDEM family members, operates in
          tandem with this cyclical process by progressively trimming mannose residues
          from glycoproteins.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17353931
  review:
    summary: >-
      IPI annotation for "protein binding" from a large-scale IP-MS study
      (PMID:17353931, Ewing et al. 2007). This study mapped protein-protein
      interactions for 338 bait proteins using immunoprecipitation followed by
      mass spectrometry. UGGT1 was identified as a prey in this screen, but the
      study does not provide specific information about the biological significance
      of the interaction. The term "protein binding" (GO:0005515) is uninformative
      and does not tell us anything about UGGT1's actual function.
    action: REMOVE
    reason: >-
      Per curation guidelines, "protein binding" (GO:0005515) should be avoided as
      it provides no information about the actual molecular function. This annotation
      comes from a large-scale proteomics screen (PMID:17353931) that does not
      provide insight into the specific nature of the interaction. UGGT1 is known to
      interact with SELENOF (PMID:24415556) and METTL23 (PMID:23349634), but these
      are better captured by specific interaction annotations rather than the
      uninformative "protein binding" term.
- term:
    id: GO:0003980
    label: UDP-glucose:glycoprotein glucosyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:40267907
  review:
    summary: >-
      IDA annotation for UGGT1 glucosyltransferase activity from Dardas et al. 2025
      (PMID:40267907). This study identified bi-allelic UGGT1 variants causing a
      congenital disorder of glycosylation (UGGT1-CDG). The authors performed both
      cellular reglucosylation assays and in vitro catalytic activity assays using
      HPLC-based quantification of glucose transfer. Pathogenic UGGT1 variants were
      shown to impair glucosylation and catalytic activity, providing direct
      evidence for UGGT1 as a UDP-glucose:glycoprotein glucosyltransferase.
    action: ACCEPT
    reason: >-
      Strong experimental evidence from direct enzymatic assays. Dardas et al.
      (PMID:40267907) used both cellular reglucosylation assays (calreticulin
      pull-down) and in vitro catalytic activity assays (HPLC-based glucose transfer
      quantification) to demonstrate UGGT1 glucosyltransferase activity. Pathogenic
      variants showed impaired activity, confirming the enzymatic function.
    supported_by:
      - reference_id: PMID:40267907
        supporting_text: >-
          Molecular studies showed that pathogenic UGGT1 variants impair UGGT1
          glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit
          endoplasmic reticulum (ER) retention.
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901032
  review:
    summary: >-
      TAS annotation from Reactome pathway R-HSA-901032 (ER Quality Control
      Compartment). UGGT1 is correctly placed in the ERQC pathway by Reactome,
      but GO:1904380 (ER mannose trimming) specifically describes
      alpha-1,2-demannosylation. UGGT1 does not trim mannose; it adds glucose.
      UGGT1 operates in the same quality control pathway as the mannose-trimming
      enzymes but performs a distinct reaction (reglucosylation). This annotation
      is incorrect -- UGGT1 was likely erroneously associated with this process
      term because it is part of the broader ERQC pathway that includes mannose
      trimming steps.
    action: REMOVE
    reason: >-
      UGGT1 does not perform mannose trimming. GO:1904380 is defined as "any
      protein alpha-1,2-demannosylation that takes place in the ERQC." UGGT1 is
      a glucosyltransferase, not a mannosidase. While UGGT1 participates in the
      ERQC pathway alongside mannose-trimming enzymes, it catalyzes the opposite
      modification: adding glucose rather than removing mannose. This annotation
      appears to be a mis-mapping from the Reactome ERQC pathway.
    supported_by:
      - reference_id: PMID:40267907
        supporting_text: >-
          A molecular marking system involving multiple ER-resident exo-mannosidases,
          including ER mannosidase I (ERManI) and EDEM family members, operates in
          tandem with this cyclical process by progressively trimming mannose residues
          from glycoproteins. This stepwise de-mannosylation eventually reduces the
          affinity of UGGT1 for its substrate, preventing further reglucosylation
          and facilitating the extraction of misfolded proteins from the CNX cycle
- term:
    id: GO:0003980
    label: UDP-glucose:glycoprotein glucosyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-548884
  review:
    summary: >-
      TAS annotation from Reactome reaction R-HSA-548884 which models UGGT1/2
      transferring glucose from dolichyl beta-D-glucosyl phosphate to unfolded
      protein glycans. The Reactome entry states that "UGGT1 and 2 are able to
      distinguish proteins with minor folding defects in the ERQC and
      reglucosylate them." This correctly captures the core enzymatic function
      of UGGT1.
    action: ACCEPT
    reason: >-
      Correctly annotated from a well-curated Reactome reaction that specifically
      models the UGGT1 glucosyltransferase reaction. Consistent with all other
      evidence for GO:0003980.
    supported_by:
      - reference_id: Reactome:R-HSA-548884
        supporting_text: >-
          The UDP-glucose:glycoprotein glucosyltransferases 1 and 2 (UGGT1 and 2) are
          able to distinguish proteins with minor folding defects in the ERQC and
          reglucosylate them, by transferring a glucose (from dolichyl beta-D-glucosyl
          phosphate, DbGP) onto the alpha 1,3 mannose of the b (or c, not shown here)
          branch
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23349634
  review:
    summary: >-
      IPI annotation for protein binding from Cloutier et al. 2013 (PMID:23349634).
      This study identified UGGT1 as an interactor of METTL23, a lysine
      methyltransferase, by affinity purification coupled to mass spectrometry.
      UniProt confirms "Interacts with METTL23" (PMID:23349634). The interaction
      was identified in the context of a study showing METTL23 preferentially
      associates with molecular chaperones. While the interaction is real, the
      term "protein binding" is uninformative.
    action: REMOVE
    reason: >-
      Per curation guidelines, "protein binding" (GO:0005515) is uninformative and
      should be avoided. The underlying data shows UGGT1 interacts with METTL23
      (a lysine methyltransferase) but this does not inform us about UGGT1's
      molecular function. The interaction may reflect METTL23's role in regulating
      chaperone/quality-control machinery rather than a core function of UGGT1.
    supported_by:
      - reference_id: PMID:23349634
        supporting_text: >-
          A common theme for most of these putative methyltransferases' interactors
          was chaperones, be they of the Hsp70 or Hsp90 variety (see METTL18,
          CAMKMT, METTL21C, METTL22, METTL23, METTL21A, and METTL21B)
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:23349634
  review:
    summary: >-
      IDA annotation for "protein-containing complex" from Cloutier et al. 2013
      (PMID:23349634). This study showed UGGT1 interacts with METTL23 by AP-MS.
      Additionally, UniProt notes that UGGT1 forms a tight complex with SELENOF
      (PMID:24415556) and is part of a large chaperone multiprotein complex
      comprising DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PDIA6, PPIB,
      SDF2L1, and UGGT1 (by similarity from UniProtKB:Q9JLA3). The term
      GO:0032991 is very generic -- it simply indicates the protein is found in
      some complex. While technically correct, it is not very informative.
    action: KEEP_AS_NON_CORE
    reason: >-
      UGGT1 is part of protein complexes (with SELENOF, with METTL23, and as
      part of a larger ER chaperone complex), so the annotation is not wrong.
      However, GO:0032991 is a very generic CC term. Participation in protein
      complexes is not a core defining feature of UGGT1 -- its core function
      is its glucosyltransferase enzymatic activity. The SELENOF complex
      enhances UGGT1 activity (PMID:24415556) but this is regulatory, not a
      core localization.
    supported_by:
      - reference_id: PMID:23349634
        supporting_text: >-
          A common theme for most of these putative methyltransferases' interactors
          was chaperones, be they of the Hsp70 or Hsp90 variety (see METTL18,
          CAMKMT, METTL21C, METTL22, METTL23, METTL21A, and METTL21B)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26808496
  review:
    summary: >-
      IPI annotation for protein binding from Liu et al. 2016 (PMID:26808496).
      This study used affinity purification of HCV E2 protein complexes from
      HCV-infected human hepatoma cells and identified UGGT1 (referred to as UGT1)
      as a novel E2 binding partner. The interaction was validated and shown to
      be functionally relevant: "gene silencing of UGT1 in human hepatoma cell
      line Huh7.5.1 markedly decreased the production of infectious HCV, indicating
      a regulatory role of UGT1 in viral lifecycle." While this is an interesting
      finding about UGGT1's role in the HCV lifecycle, the "protein binding" term
      is uninformative and this interaction reflects UGGT1's normal ER quality
      control function on the viral glycoprotein E2.
    action: REMOVE
    reason: >-
      Per curation guidelines, "protein binding" (GO:0005515) is uninformative.
      The interaction between UGGT1 and HCV E2 likely reflects UGGT1's normal
      role in glycoprotein quality control -- HCV E2 is a heavily glycosylated ER
      protein that would be subject to UGGT1's quality control function. This is
      not a novel molecular function of UGGT1 but rather evidence that UGGT1's
      normal glucosyltransferase activity acts on viral glycoproteins as substrates.
    supported_by:
      - reference_id: PMID:26808496
        supporting_text: >-
          85 cellular proteins and three viral proteins were successfully identified
          in three independent trials, among which alphafetoprotein (AFP),
          UDP-glucose: glycoprotein glucosyltransferase 1 (UGT1) and HCV NS4B were
          further validated as novel E2 binding partners.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  review:
    summary: >-
      HDA annotation for extracellular exosome localization from a proteomic
      analysis of human parotid gland exosomes (PMID:19199708). UGGT1 (referred
      to as "UDP-glucose ceramide glucosyltransferase-like 1 isoform 1") was
      identified among 491 proteins in the exosome fraction of parotid saliva
      by MudPIT mass spectrometry. However, the authors note that parotid
      exosomes "lacked endoplasmic reticulum or nuclear resident proteins,"
      suggesting ER-resident proteins should not normally be present in exosomes.
      UGGT1 is an ER-resident protein with a strong ER retention signal (REEL),
      making its presence in exosomes likely a contaminant or artifact of the
      proteomics approach.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      UGGT1 is an established ER-resident protein with a strong ER retrieval signal
      (REEL). Its detection in exosomes from parotid gland saliva (PMID:19199708)
      most likely represents contamination or low-level leakage rather than true
      exosomal localization. The authors themselves note that ER-resident proteins
      should not be present in true exosomes. High-throughput proteomics of
      exosome fractions frequently identify ER contaminants. Extracellular exosome
      is not a meaningful localization for UGGT1.
    supported_by:
      - reference_id: PMID:19199708
        supporting_text: >-
          we found that parotid exosomes lacked endoplasmic reticulum or nuclear
          resident proteins, distinguishing them from apoptotic bodies or shed
          membranes 19 , 22 , 31
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-548884
  review:
    summary: >-
      TAS annotation for ER lumen localization from Reactome reaction R-HSA-548884.
      UGGT1 is modeled in Reactome as a soluble ER lumen protein that catalyzes
      the reglucosylation of misfolded glycoproteins. This is consistent with
      UniProt's annotation of SUBCELLULAR LOCATION as "Endoplasmic reticulum lumen"
      and with the experimental evidence from PMID:10694380 showing ER localization
      and the presence of an ER retrieval signal (REEL).
    action: ACCEPT
    reason: >-
      UGGT1 is a well-established ER lumen protein. Reactome correctly places it
      in the ER lumen for its reglucosylation reaction. Consistent with the IEA
      annotation from UniProt and experimental evidence (PMID:10694380).
    supported_by:
      - reference_id: PMID:10694380
        supporting_text: >-
          HUGT1 encodes a 1555 amino acid polypeptide that, upon cleavage of an
          N-terminal signal peptide, is predicted to produce a soluble 173 kDa
          protein with the ER retrieval signal REEL.
- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation for ERGIC localization transferred from experimentally-verified
      orthologs by curator judgment. UniProt annotates UGGT1 to the ERGIC based on
      both PROSITE ER-targeting rules and experimental evidence (PMID:10694380).
      The ISS annotation is consistent with the IEA annotation to the same term and
      with the known biology of UGGT1 as a protein that cycles through the early
      secretory pathway via its REEL retrieval signal.
    action: ACCEPT
    reason: >-
      Consistent with the IEA annotation and UniProt subcellular location data.
      UGGT1 contains the REEL retrieval signal enabling cycling through the ERGIC.
      The ISS transfer from orthologs is well-supported.
    supported_by:
      - reference_id: PMID:10694380
        supporting_text: >-
          HUGT1 encodes a 1555 amino acid polypeptide that, upon cleavage of an
          N-terminal signal peptide, is predicted to produce a soluble 173 kDa
          protein with the ER retrieval signal REEL.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:10694380
  review:
    summary: >-
      The IDA annotation to GO:0051082 from PMID:10694380 reflects the experimental
      observation that UGGT1 selectively recognizes and acts upon misfolded/unfolded
      glycoproteins. Arnold et al. (2000) demonstrated that HUGT1 (UGGT1) extracts
      show a 27-fold increase in transfer of [14C]glucose from UDP-[14C]glucose to
      denatured substrates. The assay measured glucosyltransferase activity toward
      denatured substrates, not an independent binding activity. UGGT1's interaction
      with unfolded glycoproteins is substrate recognition intrinsic to its
      glucosyltransferase catalytic cycle: the N-terminal domain senses folding
      defects, and the C-terminal catalytic domain then reglucosylates the substrate.
      UniProt describes the FUNCTION as "Recognizes glycoproteins with minor folding
      defects. Reglucosylates single N-glycans near the misfolded part of the protein."
      This is an enzymatic activity, not a standalone binding function. The term
      GO:0051082 is also being obsoleted (go-ontology#30962).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The experimental evidence in PMID:10694380 demonstrates glucosyltransferase
      activity (glucose transfer to denatured substrates), which inherently requires
      substrate recognition/binding. Annotating this as "unfolded protein binding"
      separately from the glucosyltransferase activity is an over-annotation -- it
      conflates enzymatic substrate recognition with an independent molecular function.
      UGGT1 is not a chaperone that simply binds and holds unfolded proteins; it is an
      enzyme that recognizes misfolded glycoprotein substrates and catalytically
      reglucosylates them. The core molecular function is fully captured by GO:0003980
      (UDP-glucose:glycoprotein glucosyltransferase activity). Furthermore, GO:0051082
      is being obsoleted per go-ontology#30962.
    supported_by:
      - reference_id: PMID:10694380
        supporting_text: >-
          UDP-glucose:glycoprotein glucosyltransferase (UGT) is a soluble protein of
          the endoplasmic reticulum (ER) that operates as a gatekeeper for quality
          control by preventing transport of improperly folded glycoproteins out of the
          ER.
      - reference_id: PMID:10694380
        supporting_text: >-
          Extracts from HUGT1-transfected cells displayed a 27-fold increase in the
          transfer of [(14)C]glucose from UDP-[(14)C]glucose to denatured substrates.
- term:
    id: GO:0003980
    label: UDP-glucose:glycoprotein glucosyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:10694380
  review:
    summary: >-
      IDA annotation for the core enzymatic activity from the foundational
      characterization paper by Arnold et al. 2000 (PMID:10694380). This study
      cloned HUGT1 (UGGT1), expressed it in COS-1 cells, and demonstrated a 27-fold
      increase in glucose transfer from UDP-glucose to denatured glycoprotein
      substrates. Site-directed mutagenesis of highly conserved residues (D1452A,
      Q1453A, D1454A, L1455A, P1456A, N1457A) in the catalytic domain identified
      four residues essential for catalytic function. This is the primary
      experimental evidence establishing UGGT1 as a UDP-glucose:glycoprotein
      glucosyltransferase.
    action: ACCEPT
    reason: >-
      Foundational direct assay evidence for UGGT1's core molecular function.
      Arnold et al. (PMID:10694380) performed definitive enzymatic assays
      (radiolabeled glucose transfer) and site-directed mutagenesis confirming
      the glucosyltransferase activity. This is the gold-standard IDA evidence.
    supported_by:
      - reference_id: PMID:10694380
        supporting_text: >-
          Extracts from HUGT1-transfected cells displayed a 27-fold increase in the
          transfer of [(14)C]glucose from UDP-[(14)C]glucose to denatured substrates.
      - reference_id: PMID:10694380
        supporting_text: >-
          Site-directed alanine mutagenesis within a highly conserved region of HUGT1
          identified four residues that are essential for catalytic function.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:10694380
  review:
    summary: >-
      IDA annotation for ER localization from Arnold et al. 2000 (PMID:10694380).
      The study showed that UGGT1 (HUGT1) is localized to the ER, consistent with
      its signal peptide, ER retrieval signal (REEL), and function as an ER-resident
      quality control enzyme. The study expressed HUGT1 in COS-1 cells and obtained
      protein localized to the ER for enzymatic activity assays.
    action: ACCEPT
    reason: >-
      Direct experimental evidence of ER localization from the characterization
      study (PMID:10694380). The more specific GO:0005788 (ER lumen) is also
      annotated, but GO:0005783 is acceptable as the parent term confirmed by
      this IDA.
    supported_by:
      - reference_id: PMID:10694380
        supporting_text: >-
          HUGT1 encodes a 1555 amino acid polypeptide that, upon cleavage of an
          N-terminal signal peptide, is predicted to produce a soluble 173 kDa
          protein with the ER retrieval signal REEL.
- term:
    id: GO:0051084
    label: "'de novo' post-translational protein folding"
  evidence_type: TAS
  original_reference_id: PMID:10694380
  review:
    summary: >-
      TAS annotation for "de novo post-translational protein folding"
      (GO:0051084), defined as "the process of assisting in the correct
      noncovalent folding of newly formed polypeptides or folding intermediates."
      UGGT1 does participate in the protein folding quality control cycle by
      reglucosylating misfolded glycoproteins so they can re-engage with
      calnexin/calreticulin for further folding attempts (PMID:10694380,
      PMID:40267907). However, UGGT1 itself is not a chaperone that directly
      assists in protein folding. It is an enzyme that tags misfolded proteins
      for re-entry into the calnexin/calreticulin chaperone cycle. The term
      implies direct folding assistance, which is misleading for UGGT1. A
      more accurate process annotation would be one reflecting its role in
      protein quality control in the ER or N-linked glycosylation.
    action: MODIFY
    reason: >-
      UGGT1 does not directly fold proteins. It is an enzyme (glucosyltransferase)
      that acts as a folding sensor, recognizing misfolded glycoproteins and
      reglucosylating them so they can re-bind calnexin/calreticulin for another
      round of folding. The actual folding is performed by the calnexin/calreticulin
      chaperone system. "De novo post-translational protein folding" implies direct
      chaperone activity, which is inaccurate for UGGT1. A better process term
      would be GO:0006487 (protein N-linked glycosylation) or GO:0097359
      (UDP-glucosylation), which more accurately reflect UGGT1's enzymatic role
      in the quality control cycle.
    proposed_replacement_terms:
      - id: GO:0006487
        label: protein N-linked glycosylation
    additional_reference_ids:
      - PMID:40267907
    supported_by:
      - reference_id: PMID:40267907
        supporting_text: >-
          UGGT1 identifies and reglucosylates misfolded proteins, resulting in ER
          retention for re-binding to CNX/CRT to enable correct folding.
      - reference_id: PMID:10694380
        supporting_text: >-
          UDP-glucose:glycoprotein glucosyltransferase (UGT) is a soluble protein of
          the endoplasmic reticulum (ER) that operates as a gatekeeper for quality
          control by preventing transport of improperly folded glycoproteins out of the
          ER.
core_functions:
- description: >-
    UGGT1 catalyzes the reglucosylation of N-glycans on misfolded glycoproteins
    in the ER lumen, serving as the central folding sensor and checkpoint of the
    calnexin/calreticulin quality control cycle. Its seven-domain architecture
    (TRXL1-4, betaS1-2, GT24 catalytic domain) provides interdomain
    conformational flexibility that enables recognition of diverse
    molten-globule-like folding intermediates and glucosylation of glycans at
    variable distances from misfolded regions (DOI:10.1073/pnas.1703682114).
    UGGT1 writes a site-selective "glyco-code" that programs which ER chaperones
    engage substrates at specific glycosylation sites
    (DOI:10.1016/j.molcel.2023.11.006). This reglucosylation competes with
    EDEM-family mannose trimming in a "tug-of-war" that determines substrate
    fate between refolding and ERAD commitment
    (DOI:10.1101/2023.10.18.562958). UGGT1 also promotes substrate solubility
    by maintaining misfolded glycoproteins in the lectin-chaperone cycle,
    reducing insoluble aggregation (DOI:10.1091/mbc.e13-02-0101). Activity is
    modulated by the partner selenoprotein SELENOF/SEP15, which affects a
    subset of UGGT1 clients (DOI:10.1073/pnas.2315009121).
  molecular_function:
    id: GO:0003980
    label: UDP-glucose:glycoprotein glucosyltransferase activity
  directly_involved_in:
    - id: GO:0006487
      label: protein N-linked glycosylation
    - id: GO:0097359
      label: UDP-glucosylation
  locations:
    - id: GO:0005788
      label: endoplasmic reticulum lumen
    - id: GO:0044322
      label: endoplasmic reticulum quality control compartment
  supported_by:
    - reference_id: PMID:10694380
      supporting_text: >-
        Extracts from HUGT1-transfected cells displayed a 27-fold increase in the
        transfer of [(14)C]glucose from UDP-[(14)C]glucose to denatured substrates.
    - reference_id: PMID:40267907
      supporting_text: >-
        Molecular studies showed that pathogenic UGGT1 variants impair UGGT1
        glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit
        endoplasmic reticulum (ER) retention.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10694380
  title: Two homologues encoding human UDP-glucose:glycoprotein glucosyltransferase
    differ in mRNA expression and enzymatic activity.
  findings: []
- id: PMID:17353931
  title: Large-scale mapping of human protein-protein interactions by mass spectrometry.
  findings: []
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein
    identification technology (MudPIT).
  findings: []
- id: PMID:23349634
  title: A newly uncovered group of distantly related lysine methyltransferases preferentially
    interact with molecular chaperones to regulate their activity.
  findings: []
- id: PMID:24415556
  title: Both isoforms of human UDP-glucose:glycoprotein glucosyltransferase are
    enzymatically active.
  findings: []
- id: PMID:26808496
  title: Comparative Proteomics Reveals Important Viral-Host Interactions in HCV-Infected
    Human Liver Cells.
  findings: []
- id: PMID:40267907
  title: Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation.
  findings: []
- id: Reactome:R-HSA-548884
  title: UGGT1,2 transfers glucose from DbGP to (un)folded protein:(GlcNAc)2 (Man)8b
  findings: []
- id: Reactome:R-HSA-901032
  title: ER Quality Control Compartment (ERQC)
  findings: []
- id: DOI:10.1073/pnas.1703682114
  title: Interdomain conformational flexibility underpins the activity of UGGT, the
    eukaryotic glycoprotein secretion checkpoint.
  findings:
  - statement: >-
      UGGT1 has a seven-domain topology with four N-terminal thioredoxin-like
      domains (TRXL1-4) arranged in an arc, two beta-sandwich domains, and a
      C-terminal GT24 catalytic domain
  - statement: >-
      Interdomain conformational flexibility is required for activity;
      engineered interdomain disulfides that rigidify UGGT reduce catalytic
      function
- id: DOI:10.1016/j.molcel.2023.11.006
  title: ER chaperones use a protein folding and quality control glyco-code.
  findings:
  - statement: >-
      UGGT1-mediated reglucosylation writes a programmable glyco-code that
      determines which ER chaperones engage substrates at specific
      glycosylation sites
  - statement: >-
      UGGT1 deletion reduces monoglucosylated AAT by more than half; UGGT1/2
      double deletion abolishes glucosylation
  - statement: >-
      UGGT preferentially modifies particular glycosylation sites (e.g., AAT
      N247 more than N83), supporting positional logic in the glyco-code
- id: DOI:10.1101/2023.10.18.562958
  title: UGGT1-mediated reglucosylation of N-glycan competes with ER-associated degradation
    of unstable and misfolded glycoproteins.
  findings:
  - statement: >-
      UGGT1 delays degradation of misfolded glycoproteins in a tug-of-war
      between reglucosylation/refolding and EDEM-mediated mannose trimming
      that commits substrates to ERAD
  - statement: >-
      UGGT2 protein levels are ~6.9% (HCT116) and ~29.8% (HeLa) of UGGT1,
      establishing UGGT1 as the dominant mammalian reglucosyltransferase
- id: DOI:10.1073/pnas.2315009121
  title: Insights into the interaction between UGGT, the gatekeeper of folding in the
    ER, and its partner, the selenoprotein SEP15.
  findings:
  - statement: >-
      AlphaFold-multimer predicts a specific UGGT1/SEP15 complex with SEP15
      selenocysteine positioned proximal to UGGT1 catalytic region
  - statement: >-
      About 27% of expressed SEP15 co-occurs with UGGT1; interface mutants
      reduce binding to ~3.8-6.5%
  - statement: >-
      SEP15 affects a subset of UGGT1 clients rather than globally shifting
      all UGGT activity (26 proteins with significantly altered glucosylation
      in SELENOF-null cells)
- id: DOI:10.1091/mbc.e13-02-0101
  title: UDP-glucose:glycoprotein glucosyltransferase (UGGT1) promotes substrate solubility
    in the endoplasmic reticulum.
  findings:
  - statement: >-
      UGGT1 enzymatic activity increases the soluble fraction of misfolded
      alpha-1 antitrypsin variants and reduces insoluble aggregation,
      maintaining ER solubility of folding intermediates through
      monoglucosylation and lectin-chaperone cycling
- id: DOI:10.7554/eLife.63997
  title: Quantitative glycoproteomics reveals cellular substrate selectivity of the
    ER protein quality control sensors UGGT1 and UGGT2.
  findings:
  - statement: >-
      UGGT1 preferentially modifies large, complex glycoproteins (often
      membrane/plasma-membrane targeted), while UGGT2 preferentially modifies
      smaller soluble/lysosomal proteins