id: Q9Y679
gene_symbol: AUP1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'AUP1 (Ancient Ubiquitous Protein 1) is a conserved, ubiquitously expressed
  monotopic membrane protein that resides on the cytosolic face of the endoplasmic
  reticulum membrane and on the lipid droplet surface monolayer, inserting via an N-terminal
  hydrophobic hairpin so that both termini face the cytosol. Its principal molecular
  role is to act as an adaptor that recruits the soluble E2 ubiquitin-conjugating enzyme
  UBE2G2 (via a C-terminal G2 binding region) to ER-associated degradation (ERAD) ubiquitin
  ligase machinery, including the HRD1-SEL1L complex and the lipid-droplet/ER E3 ligases
  gp78/AMFR and TRC8/RNF139. Through this activity AUP1 couples substrate ubiquitination
  to dislocation and proteasomal degradation of misfolded ER proteins, and drives sterol-regulated
  ubiquitination and ERAD of HMGCR, INSIG1, SREBF1 and SREBF2. AUP1 also has lipid-droplet-regulatory
  functions: it binds ubiquitin through an internal CUE domain, is itself monoubiquitinated
  in a CUE-dependent manner to promote lipid droplet clustering, and its level controls
  lipid droplet abundance. Additional reported roles include hepatic VLDL/apolipoprotein
  B assembly and secretion. AUP1 is exploited by flaviviruses, whose NS4A protein relocalizes
  it to autophagosomes to trigger lipophagy.'
alternative_products:
- name: '1'
  id: Q9Y679-2
- name: '2'
  id: Q9Y679-3
  sequence_note: VSP_059683, VSP_059684
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ER membrane is the principal compartment where AUP1 acts as an ERAD E2
      adaptor; well supported by orthology and direct experiments.
    action: ACCEPT
    reason: AUP1 is a monotopic ER membrane protein with both termini in the cytosol,
      where it recruits UBE2G2 to the HRD1-SEL1L/gp78 ERAD machinery. This is a core
      localization.
    supported_by:
    - reference_id: PMID:23197321
      supporting_text: AUP1 is inserted into the membrane of the ER in a monotopic
      reference_section_type: ABSTRACT
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: ERAD participation is the core biological process of AUP1, supported by
      direct loss-of-function evidence and orthology.
    action: ACCEPT
    reason: AUP1 associates with the HRD1-SEL1L complex and recruits UBE2G2; depletion
      impairs degradation of misfolded ER proteins.
    supported_by:
    - reference_id: PMID:21857022
      supporting_text: AUP1) physically associates with
      reference_section_type: ABSTRACT
- term:
    id: GO:0005776
    label: autophagosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Autophagosome localization is only seen upon Dengue/flavivirus infection,
      when NS4A relocalizes AUP1 from lipid droplets to autophagosomes; it is not a
      constitutive localization of the normal protein.
    action: KEEP_AS_NON_CORE
    reason: This is a context-dependent (virus-induced) localization rather than the
      core ER/lipid-droplet residence of AUP1.
    supported_by:
    - reference_id: file:human/AUP1/AUP1-uniprot.txt
      supporting_text: virus infection, relocates from lipid droplets to autophagosomes.
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ER membrane is the principal site of AUP1 ERAD activity; well supported.
    action: ACCEPT
    reason: AUP1 is a monotopic ER membrane protein where it recruits UBE2G2 to the
      ERAD machinery.
    supported_by:
    - reference_id: PMID:23197321
      supporting_text: AUP1 is inserted into the membrane of the ER in a monotopic
      reference_section_type: ABSTRACT
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Lipid droplet surface localization is a core, directly demonstrated localization
      for AUP1.
    action: ACCEPT
    reason: AUP1 integrates into the LD surface monolayer in a monotopic fashion with
      both termini in the cytosol.
    supported_by:
    - reference_id: PMID:21127063
      supporting_text: integrates into the LD surface in a monotopic fashion with both
        termini facing
      reference_section_type: ABSTRACT
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: ERAD participation is the core biological process of AUP1.
    action: ACCEPT
    reason: AUP1 associates with the HRD1-SEL1L complex and recruits UBE2G2; depletion
      impairs degradation of misfolded ER proteins.
    supported_by:
    - reference_id: PMID:21857022
      supporting_text: AUP1) physically associates with
      reference_section_type: ABSTRACT
- term:
    id: GO:0043130
    label: ubiquitin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: AUP1 binds ubiquitin through its internal CUE domain, a known ubiquitin-binding
      domain; this is a core molecular function underlying its ERAD and LD-clustering
      roles.
    action: ACCEPT
    reason: The CUE domain is directly demonstrated as a ubiquitin-binding domain required
      for ubiquitination and LD clustering.
    supported_by:
    - reference_id: PMID:24039768
      supporting_text: its internal CUE domain, which is a known ubiquitin-binding
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22119785
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a proteome-scale ERAD interaction
      map; uninformative as a molecular function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding does not convey AUP1's specific adaptor function;
      more informative terms (ubiquitin conjugating enzyme binding) are captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23840749
  qualifier: enables
  review:
    summary: Generic protein binding from a mu-opioid receptor membrane yeast two-hybrid
      interactome; uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput screen does not identify a
      physiologically interpretable AUP1 function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic protein binding from a binary interactome reference map; uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is too general to represent AUP1 function.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:12042322
  qualifier: located_in
  review:
    summary: Early experimental support for AUP1 ER/membrane association; consistent
      with the well-established core ER membrane localization.
    action: ACCEPT
    reason: ER membrane is a core localization for AUP1 ERAD activity.
    supported_by:
    - reference_id: file:human/AUP1/AUP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:18711132
  qualifier: located_in
  review:
    summary: AUP1 is part of the SEL1L-nucleated ER membrane ERAD complex; supports
      core ER membrane localization.
    action: ACCEPT
    reason: AUP1 was identified as a functionally important component of the SEL1L-nucleated
      ER dislocation complex.
    supported_by:
    - reference_id: PMID:18711132
      supporting_text: We identified AUP1, UBXD8, UBC6e, and OS9 as functionally important
        components of this degradation complex in mammalian cells
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:21857022
  qualifier: located_in
  review:
    summary: Direct evidence places AUP1 at the ER membrane within the HRD1-SEL1L complex.
    action: ACCEPT
    reason: ER membrane is the core compartment for AUP1 ERAD function.
    supported_by:
    - reference_id: PMID:21857022
      supporting_text: AUP1) physically associates with
      reference_section_type: ABSTRACT
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: EXP
  original_reference_id: PMID:28183703
  qualifier: located_in
  review:
    summary: AUP1 is demonstrated at the lipid droplet surface in hepatic VLDL studies;
      core localization.
    action: ACCEPT
    reason: LD surface localization is a directly demonstrated core localization of
      AUP1.
    supported_by:
    - reference_id: PMID:28183703
      supporting_text: also localizes to the surface of lipid
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9921605
  qualifier: located_in
  review:
    summary: Reactome traceable assertion of ER membrane localization is consistent
      with the established core localization.
    action: ACCEPT
    reason: ER membrane localization is well supported by direct experimental evidence.
    supported_by:
    - reference_id: file:human/AUP1/AUP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29902443
  qualifier: enables
  review:
    summary: The underlying interaction is the specific AUP1-Dengue NS4A association,
      but the GO term used is generic protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative; the meaningful (virus-specific)
      interaction is with NS4A and is not a core physiological function.
- term:
    id: GO:0005776
    label: autophagosome
  evidence_type: IDA
  original_reference_id: PMID:29902443
  qualifier: located_in
  review:
    summary: Autophagosome localization is observed only after Dengue virus infection,
      when NS4A relocalizes AUP1 from LDs.
    action: KEEP_AS_NON_CORE
    reason: A virus-induced relocalization, not the constitutive site of AUP1 action.
    supported_by:
    - reference_id: PMID:29902443
      supporting_text: relocalized
        from lipid droplets to autophagosomes upon infection
      reference_section_type: ABSTRACT
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:29902443
  qualifier: located_in
  review:
    summary: AUP1 is directly observed as a lipid droplet-localized membrane protein;
      core localization.
    action: ACCEPT
    reason: LD surface residence is the well-established core localization of AUP1.
    supported_by:
    - reference_id: PMID:29902443
      supporting_text: AUP1, a lipid droplet-localized type-III membrane
        protein
      reference_section_type: ABSTRACT
- term:
    id: GO:0009615
    label: response to virus
  evidence_type: IMP
  original_reference_id: PMID:29902443
  qualifier: involved_in
  review:
    summary: AUP1 is exploited by flaviviruses to drive virus production; this is a
      host factor role hijacked by the virus rather than an antiviral/defense function
      of AUP1.
    action: KEEP_AS_NON_CORE
    reason: The phenotype is virus production dependent on AUP1, a context-specific
      host-pathogen role, not a core conserved physiological function.
    supported_by:
    - reference_id: PMID:29902443
      supporting_text: Virus production was
        abolished in cells deleted for AUP1
      reference_section_type: ABSTRACT
- term:
    id: GO:0061724
    label: lipophagy
  evidence_type: IMP
  original_reference_id: PMID:29902443
  qualifier: involved_in
  review:
    summary: AUP1 is required for Dengue-induced lipophagy; demonstrated only in the
      virus-infection context.
    action: KEEP_AS_NON_CORE
    reason: Lipophagy induction is a virus-triggered process exploiting AUP1's acyltransferase
      activity, not a core constitutive function.
    supported_by:
    - reference_id: PMID:29902443
      supporting_text: exploits the acyltransferase
        activity of AUP1 to trigger lipophagy
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:23223569
  qualifier: located_in
  review:
    summary: AUP1 acts at lipid droplet-associated ER membranes; core localization.
    action: ACCEPT
    reason: AUP1 functions in sterol-regulated HMGCR ubiquitination at LD-associated
      ER membranes.
    supported_by:
    - reference_id: PMID:23223569
      supporting_text: lipid droplet-associated ER membranes
      reference_section_type: ABSTRACT
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:23223569
  qualifier: located_in
  review:
    summary: AUP1 is a lipid droplet-associated protein recruiting Ubc7/UBE2G2 there;
      core localization.
    action: ACCEPT
    reason: LD localization is directly demonstrated and required for AUP1's sterol-regulated
      ERAD role.
    supported_by:
    - reference_id: PMID:23223569
      supporting_text: Aup1 recruits the ubiquitin-conjugating enzyme Ubc7 to
      reference_section_type: ABSTRACT
- term:
    id: GO:0031624
    label: ubiquitin conjugating enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:23223569
  qualifier: enables
  review:
    summary: AUP1 binds and recruits the E2 ubiquitin-conjugating enzyme Ubc7/UBE2G2;
      this is a core molecular function.
    action: ACCEPT
    reason: AUP1 recruits Ubc7 (UBE2G2) to lipid droplets and facilitates its binding
      to gp78 and Trc8, central to its adaptor role.
    supported_by:
    - reference_id: PMID:23223569
      supporting_text: Aup1 recruits the ubiquitin-conjugating enzyme Ubc7 to
      reference_section_type: ABSTRACT
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:23223569
  qualifier: enables
  review:
    summary: AUP1 binds the E3 ubiquitin ligases gp78/AMFR and Trc8/RNF139, bridging
      them to the E2; core molecular function.
    action: ACCEPT
    reason: AUP1 facilitates binding of Ubc7 to both gp78 and Trc8, directly demonstrating
      ligase association.
    supported_by:
    - reference_id: PMID:23223569
      supporting_text: facilitates its binding to both gp78 and Trc8
      reference_section_type: ABSTRACT
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:23223569
  qualifier: involved_in
  review:
    summary: AUP1 is required for sterol-regulated ERAD of HMGCR, INSIG1, and SREBF1/2;
      core process.
    action: ACCEPT
    reason: AUP1 knockdown blunts sterol-accelerated ubiquitination and ERAD of HMGCR
      and other sterol-pathway substrates.
    supported_by:
    - reference_id: PMID:23223569
      supporting_text: RNAi-mediated knockdown of Aup1 blunts sterol-accelerated ubiquitination
      reference_section_type: ABSTRACT
- term:
    id: GO:1990044
    label: protein localization to lipid droplet
  evidence_type: IMP
  original_reference_id: PMID:23223569
  qualifier: involved_in
  review:
    summary: AUP1 recruits/localizes the E2 Ubc7 to lipid droplets, supporting a role
      in protein localization to the LD.
    action: ACCEPT
    reason: AUP1 recruits Ubc7 to lipid droplets, a directly demonstrated protein-targeting
      function at the LD.
    supported_by:
    - reference_id: PMID:23223569
      supporting_text: Aup1 recruits the ubiquitin-conjugating enzyme Ubc7 to
      reference_section_type: ABSTRACT
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:21857022
  qualifier: located_in
  review:
    summary: ER localization (parent of ER membrane) consistent with core ER membrane
      residence.
    action: ACCEPT
    reason: AUP1 is an ER protein within the HRD1-SEL1L complex; the more specific
      ER membrane term is preferred but this is correct.
    supported_by:
    - reference_id: PMID:21857022
      supporting_text: AUP1) physically associates with
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:21127063
  qualifier: located_in
  review:
    summary: Direct evidence of AUP1 at the ER membrane; core localization.
    action: ACCEPT
    reason: ER membrane residence is a core localization for AUP1.
    supported_by:
    - reference_id: file:human/AUP1/AUP1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:23197321
  qualifier: located_in
  review:
    summary: AUP1 inserts into the ER membrane in monotopic hairpin fashion; core localization.
    action: ACCEPT
    reason: Directly demonstrated monotopic ER membrane insertion.
    supported_by:
    - reference_id: PMID:23197321
      supporting_text: AUP1 is inserted into the membrane of the ER in a monotopic
      reference_section_type: ABSTRACT
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:21857022
  qualifier: located_in
  review:
    summary: AUP1 localizes to lipid droplets and its level controls LD abundance;
      core localization.
    action: ACCEPT
    reason: LD localization is directly demonstrated and central to AUP1's LD-regulatory
      function.
    supported_by:
    - reference_id: PMID:21127063
      supporting_text: ancient ubiquitous protein 1 (AUP1) localizes to LDs
      reference_section_type: ABSTRACT
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:23197321
  qualifier: located_in
  review:
    summary: AUP1 is transported to the LD hemi-membrane in monotopic fashion; core
      localization.
    action: ACCEPT
    reason: Monotopic topology is directly shown to be required for LD targeting.
    supported_by:
    - reference_id: PMID:23197321
      supporting_text: subsequently transported to the hemi-membrane of LDs
      reference_section_type: ABSTRACT
- term:
    id: GO:0031624
    label: ubiquitin conjugating enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:21857022
  qualifier: enables
  review:
    summary: AUP1 recruits the soluble E2 UBE2G2 in ER quality control; core molecular
      function.
    action: ACCEPT
    reason: One of AUP1's functions in ER quality control is to recruit the soluble
      E2 ubiquitin-conjugating enzyme UBE2G2.
    supported_by:
    - reference_id: PMID:21127063
      supporting_text: binds to Ube2g2
      reference_section_type: ABSTRACT
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:21857022
  qualifier: involved_in
  review:
    summary: AUP1 depletion impairs degradation of misfolded ER proteins; core process.
    action: ACCEPT
    reason: Loss-of-function evidence directly supports AUP1 in ERAD.
    supported_by:
    - reference_id: PMID:21857022
      supporting_text: AUP1) physically associates with
      reference_section_type: ABSTRACT
- term:
    id: GO:0140042
    label: lipid droplet formation
  evidence_type: IMP
  original_reference_id: PMID:21857022
  qualifier: involved_in
  review:
    summary: AUP1 expression level affects the abundance of cellular lipid droplets;
      a core LD-regulatory function, though regulation of abundance/clustering is the
      better-supported framing than de novo formation.
    action: KEEP_AS_NON_CORE
    reason: The data show AUP1 controls LD abundance/clustering rather than directly
      catalyzing LD biogenesis; retained as a supported but secondary LD-regulatory
      role.
    supported_by:
    - reference_id: PMID:21857022
      supporting_text: AUP1) in lipid droplet accumulation
      reference_section_type: TITLE
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:21127063
  qualifier: located_in
  review:
    summary: AUP1 integrates into the LD surface monolayer; core localization.
    action: ACCEPT
    reason: Directly demonstrated monotopic LD surface localization.
    supported_by:
    - reference_id: PMID:21127063
      supporting_text: integrates into the LD surface in a monotopic fashion with both
        termini facing
      reference_section_type: ABSTRACT
- term:
    id: GO:0031624
    label: ubiquitin conjugating enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:21127063
  qualifier: enables
  review:
    summary: AUP1 binds the E2 UBE2G2 via its C-terminal G2BR; core molecular function.
    action: ACCEPT
    reason: AUP1, by means of its G2BR domain, binds Ube2g2, providing a direct molecular
      link to the ubiquitination machinery.
    supported_by:
    - reference_id: PMID:21127063
      supporting_text: by means of its G2BR
      reference_section_type: ABSTRACT
- term:
    id: GO:0034389
    label: lipid droplet organization
  evidence_type: IDA
  original_reference_id: PMID:24039768
  qualifier: involved_in
  review:
    summary: Monoubiquitinated AUP1 on the LD surface induces lipid droplet clustering;
      a core LD-regulatory function.
    action: ACCEPT
    reason: AUP1 induces LD cluster formation in a CUE/monoubiquitination-dependent
      manner.
    supported_by:
    - reference_id: PMID:24039768
      supporting_text: the lipid droplet protein AUP1 induces cluster formation
      reference_section_type: ABSTRACT
- term:
    id: GO:1990044
    label: protein localization to lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:21127063
  qualifier: involved_in
  review:
    summary: AUP1 brings the AUP1-Ube2g2 complex to lipid droplets, localizing the
      E2 to the LD; supported.
    action: ACCEPT
    reason: AUP1 provides the molecular link recruiting Ube2g2 to lipid droplets.
    supported_by:
    - reference_id: PMID:21127063
      supporting_text: presence of the AUP1-Ube2g2 complex at LDs
      reference_section_type: ABSTRACT
- term:
    id: GO:0030970
    label: retrograde protein transport, ER to cytosol
  evidence_type: IMP
  original_reference_id: PMID:25660456
  qualifier: involved_in
  review:
    summary: AUP1 is required for dislocation (retrotranslocation) of the ERAD substrate
      NHK from the ER to the cytosol; core process tied to its ERAD adaptor role.
    action: ACCEPT
    reason: AUP1 was identified as an ERAD component essential for dislocation of NHK,
      i.e. ER-to-cytosol retrograde transport.
    supported_by:
    - reference_id: PMID:25660456
      supporting_text: dislocation, also known as retrotranslocation
      reference_section_type: ABSTRACT
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:18570454
  qualifier: located_in
  review:
    summary: High-throughput exosome proteomics localization; inconsistent with AUP1's
      monotopic ER/LD membrane topology and not a functionally meaningful localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is a mass-spectrometry co-purification hit, not evidence for a functional
      extracellular/exosomal role for an ER/LD membrane protein.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: Generic membrane from a high-throughput membrane proteome; too unspecific
      to be informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific ER membrane and lipid droplet localizations are captured by
      other annotations; the bare membrane term adds no information.
core_functions:
- description: Acts as a substrate-adaptor/scaffold that recruits the soluble E2 ubiquitin-conjugating
    enzyme UBE2G2 to ER-associated degradation ubiquitin ligase machinery, coupling
    substrate ubiquitination to dislocation and proteasomal degradation of misfolded
    ER proteins.
  supported_by:
  - reference_id: PMID:21857022
    supporting_text: AUP1) physically associates with
    reference_section_type: ABSTRACT
  - reference_id: PMID:21127063
    supporting_text: by means of its G2BR
    reference_section_type: ABSTRACT
  molecular_function:
    id: GO:0031624
    label: ubiquitin conjugating enzyme binding
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
- description: Drives sterol-regulated ubiquitination and ERAD of HMGCR and related
    sterol-pathway substrates by recruiting the E2 Ubc7/UBE2G2 to lipid droplet-associated
    ER membranes and bridging it to the E3 ligases gp78/AMFR and Trc8/RNF139.
  supported_by:
  - reference_id: PMID:23223569
    supporting_text: facilitates its binding to both gp78 and Trc8
    reference_section_type: ABSTRACT
  molecular_function:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
- description: Binds ubiquitin through its internal CUE domain and, when monoubiquitinated,
    drives lipid droplet clustering, thereby regulating lipid droplet organization
    and abundance.
  supported_by:
  - reference_id: PMID:24039768
    supporting_text: the lipid droplet protein AUP1 induces cluster formation
    reference_section_type: ABSTRACT
  molecular_function:
    id: GO:0043130
    label: ubiquitin binding
  directly_involved_in:
  - id: GO:0034389
    label: lipid droplet organization
proposed_new_terms: []
suggested_questions:
- question: Does AUP1 have an intrinsic enzymatic (acyltransferase) activity, and if
    so what is its physiological substrate? The flavivirus study refers to an AUP1
    acyltransferase domain whose activity is required for lipophagy, but a defined
    enzymatic function and substrate are not established outside the infection context.
suggested_experiments:
- description: Define the substrate repertoire of AUP1-dependent ERAD genome-wide (e.g.
    proximity labeling or quantitative degradomics in AUP1-knockout vs wild-type cells)
    to distinguish core ERAD clients from sterol-pathway-specific and lipid-droplet-specific
    roles.
- description: Reconstitute AUP1-UBE2G2-gp78/Trc8 ubiquitination in vitro with defined
    components to test whether AUP1 is a passive scaffold or actively stimulates E2/E3
    activity.
- description: Test whether AUP1-dependent ERAD of endogenous polytopic membrane clients
    such as NKCC2/SLC12A1 and NCC/SLC12A3 requires the G2BR-UBE2G2 interaction and
    the CUE domain, to determine whether physiological substrate handling uses the
    same module that maintains UBE2G2 levels and recruits it to the ER membrane.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  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: PMID:12042322
  title: Ancient ubiquitous protein 1 binds to the conserved membrane-proximal sequence
    of the cytoplasmic tail of the integrin alpha subunits that plays a crucial role
    in the inside-out signaling of alpha IIbbeta 3.
  findings: []
- id: PMID:18570454
  title: Proteomic analysis of exosomes from human neural stem cells by flow field-flow
    fractionation and nanoflow liquid chromatography-tandem mass spectrometry.
  findings: []
- id: PMID:18711132
  title: SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:21127063
  title: Ancient ubiquitous protein 1 (AUP1) localizes to lipid droplets and binds
    the E2 ubiquitin conjugase G2 (Ube2g2) via its G2 binding region.
  findings: []
- id: PMID:21857022
  title: Dual role of ancient ubiquitous protein 1 (AUP1) in lipid droplet accumulation
    and endoplasmic reticulum (ER) protein quality control.
  findings: []
- id: PMID:22119785
  title: Defining human ERAD networks through an integrative mapping strategy.
  findings: []
- id: PMID:23197321
  title: Monotopic topology is required for lipid droplet targeting of ancient ubiquitous
    protein 1.
  findings: []
- id: PMID:23223569
  title: Ancient ubiquitous protein-1 mediates sterol-induced ubiquitination of 3-hydroxy-3-methylglutaryl
    CoA reductase in lipid droplet-associated endoplasmic reticulum membranes.
  findings: []
- id: PMID:23840749
  title: 'MOR is not enough: identification of novel mu-opioid receptor interacting
    proteins using traditional and modified membrane yeast two-hybrid screens.'
  findings: []
- id: PMID:24039768
  title: Monoubiquitination of ancient ubiquitous protein 1 promotes lipid droplet
    clustering.
  findings: []
- id: PMID:25660456
  title: Identification of ERAD components essential for dislocation of the null Hong
    Kong variant of α-1-antitrypsin (NHK).
  findings: []
- id: PMID:28183703
  title: AUP1 (Ancient Ubiquitous Protein 1) Is a Key Determinant of Hepatic Very-Low-Density
    Lipoprotein Assembly and Secretion.
  findings: []
- id: PMID:29902443
  title: Flaviviruses Exploit the Lipid Droplet Protein AUP1 to Trigger Lipophagy
    and Drive Virus Production.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:34879065
  title: A structurally conserved site in AUP1 binds the E2 enzyme UBE2G2 and is essential
    for ER-associated degradation.
  full_text_unavailable: true
  findings:
  - statement: The 27-residue G2BR of AUP1 binds the backside of the ERAD E2 enzyme
      UBE2G2 with low-nanomolar affinity; this interaction maintains cellular UBE2G2
      levels by preventing its rapid degradation, recruits UBE2G2 to the ER membrane,
      and allosterically activates ubiquitination in conjunction with ERAD E3 ligases.
- id: PMID:38474353
  title: AUP1 Regulates the Endoplasmic Reticulum-Associated Degradation and Polyubiquitination
    of NKCC2.
  full_text_unavailable: true
  findings:
  - statement: AUP1 interacts with the ER-resident form of the kidney Na-K-2Cl cotransporter
      NKCC2 (SLC12A1) and with the ER lectin OS9, enhances NKCC2 ER retention and ERAD
      in a proteasome- and mannosidase-dependent manner, and is required for NKCC2
      polyubiquitination; AUP1 also downregulates the related cotransporter NCC, indicating
      a broader role in ERAD of sodium-dependent chloride cotransporters relevant to
      antenatal Bartter syndrome type 1.
- id: Reactome:R-HSA-9921605
  title: NS4A binds AUP1
  findings: []