id: Q92622
gene_symbol: RUBCN
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  RUBCN encodes Rubicon, a RUN/RH-domain regulator that associates with the UVRAG-containing class III
  PI3K complex II and Rab7 to inhibit PIK3C3/VPS34 activity, endosome maturation, and autophagosome
  maturation. RUBCN is a negative PI3KC3-C2/autophagosome maturation regulator rather than an
  autophagy activator. It localizes mainly to late endosome/lysosome and early endosome compartments
  and also has non-core pathogen/innate-immune interaction biology described in UniProt.
alternative_products:
- name: '1'
  id: Q92622-1
- name: '2'
  id: Q92622-2
  sequence_note: VSP_039160, VSP_039161
- name: '3'
  id: Q92622-3
  sequence_note: VSP_039471, VSP_039472, VSP_039473
existing_annotations:
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: early endosome localization is supported for Rubicon endosome maturation biology.
    action: ACCEPT
    reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome 
      localization fits the core negative endosome/autophagosome maturation role.
    additional_reference_ids:
    - PMID:19270696
    - PMID:20974968
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Predominantly located in late endosomes/lysosomes
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Late endosome {ECO:0000269|PubMed:19270696}
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Early endosome
    - reference_id: PMID:20974968
      supporting_text: prevents endosome maturation through differential interactions with Rab7 and UVRAG
    - reference_id: PMID:20974968
      supporting_text: sequesters UVRAG from C-VPS/HOPS
- term:
    id: GO:0005770
    label: late endosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: late endosome localization is supported for Rubicon endosome maturation biology.
    action: ACCEPT
    reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome 
      localization fits the core negative endosome/autophagosome maturation role.
    additional_reference_ids:
    - PMID:19270696
    - PMID:20974968
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Predominantly located in late endosomes/lysosomes
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Late endosome {ECO:0000269|PubMed:19270696}
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Early endosome
    - reference_id: PMID:20974968
      supporting_text: prevents endosome maturation through differential interactions with Rab7 and UVRAG
    - reference_id: PMID:20974968
      supporting_text: sequesters UVRAG from C-VPS/HOPS
- term:
    id: GO:0045806
    label: negative regulation of endocytosis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Negative regulation of endocytosis/endocytic trafficking is a core Rubicon function.
    action: ACCEPT
    reason: Rubicon inhibits endosome maturation and endocytic pathway progression through Rab7 and 
      UVRAG/PI3KC3-C2 interactions.
    additional_reference_ids:
    - PMID:19270696
    - PMID:20943950
    - PMID:20974968
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: PMID:20974968
      supporting_text: prevents endosome maturation through differential interactions with Rab7 and UVRAG
    - reference_id: PMID:20974968
      supporting_text: sequesters UVRAG from C-VPS/HOPS
    - reference_id: PMID:20943950
      supporting_text: specifically and directly interact with Rab7 via their RH domain
    - reference_id: PMID:20943950
      supporting_text: simultaneously binding both Rab7 and PI3-kinase
    - reference_id: PMID:19270696
      supporting_text: Rubicon binds only to a subpopulation of UVRAG complexes
- term:
    id: GO:1901097
    label: negative regulation of autophagosome maturation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Negative regulation of autophagosome maturation is the central RUBCN autophagy annotation.
    action: ACCEPT
    reason: Rubicon inhibits UVRAG-containing PI3KC3-C2 and autophagosome maturation; knockdown enhances 
      autophagy at the maturation step.
    additional_reference_ids:
    - PMID:19270696
    - PMID:21062745
    - PMID:20943950
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: PMID:19270696
      supporting_text: Rubicon binds only to a subpopulation of UVRAG complexes
    - reference_id: PMID:19270696
      supporting_text: Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step
    - reference_id: PMID:21062745
      supporting_text: negative regulator of PI3KC3 and autophagosome maturation
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy
    - reference_id: PMID:21062745
      supporting_text: interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
    - reference_id: PMID:21062745
      supporting_text: inhibition of PI3KC3 lipid kinase activity by Rubicon
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Inhibits PIK3C3 activity
- term:
    id: GO:1901981
    label: phosphatidylinositol phosphate binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phosphatidylinositol phosphate binding is plausible but not the primary experimentally supported 
      Rubicon function.
    action: KEEP_AS_NON_CORE
    reason: The local human evidence emphasizes PI3KC3/Rab7/UVRAG interaction and PI3KC3 inhibition rather 
      than direct lipid binding; retain this inherited annotation as non-core pending stronger direct support.
    additional_reference_ids:
    - GO_REF:0000033
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: GO; GO:1901981; F:phosphatidylinositol phosphate binding; IBA:GO_Central
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Lysosome localization is supported and relevant to late endosome/autophagosome maturation.
    action: ACCEPT
    reason: Rubicon is predominantly in late endosome/lysosome compartments and regulates delivery/fusion 
      steps toward lysosomes.
    additional_reference_ids:
    - PMID:19270696
    - PMID:20974968
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Lysosome {ECO:0000269|PubMed:19270696}
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Predominantly located in late endosomes/lysosomes
    - reference_id: PMID:20974968
      supporting_text: prevents endosome maturation through differential interactions with Rab7 and UVRAG
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: early endosome localization is supported for Rubicon endosome maturation biology.
    action: ACCEPT
    reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome 
      localization fits the core negative endosome/autophagosome maturation role.
    additional_reference_ids:
    - PMID:19270696
    - PMID:20974968
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Predominantly located in late endosomes/lysosomes
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Late endosome {ECO:0000269|PubMed:19270696}
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Early endosome
    - reference_id: PMID:20974968
      supporting_text: prevents endosome maturation through differential interactions with Rab7 and UVRAG
    - reference_id: PMID:20974968
      supporting_text: sequesters UVRAG from C-VPS/HOPS
- term:
    id: GO:0005770
    label: late endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: late endosome localization is supported for Rubicon endosome maturation biology.
    action: ACCEPT
    reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome 
      localization fits the core negative endosome/autophagosome maturation role.
    additional_reference_ids:
    - PMID:19270696
    - PMID:20974968
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Predominantly located in late endosomes/lysosomes
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Late endosome {ECO:0000269|PubMed:19270696}
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Early endosome
    - reference_id: PMID:20974968
      supporting_text: prevents endosome maturation through differential interactions with Rab7 and UVRAG
    - reference_id: PMID:20974968
      supporting_text: sequesters UVRAG from C-VPS/HOPS
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20562859
  qualifier: enables
  review:
    summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN 
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG
      regulatory context, and negative autophagosome/endosome maturation terms.
    additional_reference_ids:
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: interacts directly with PI3KC3 and UVRAG
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Interacts with Rab7
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Rab7 and UVRAG compete for RUBCN binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21062745
  qualifier: enables
  review:
    summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN 
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG
      regulatory context, and negative autophagosome/endosome maturation terms.
    additional_reference_ids:
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: interacts directly with PI3KC3 and UVRAG
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Interacts with Rab7
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Rab7 and UVRAG compete for RUBCN binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22493499
  qualifier: enables
  review:
    summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN 
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG
      regulatory context, and negative autophagosome/endosome maturation terms.
    additional_reference_ids:
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: interacts directly with PI3KC3 and UVRAG
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Interacts with Rab7
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Rab7 and UVRAG compete for RUBCN binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23954414
  qualifier: enables
  review:
    summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN 
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG
      regulatory context, and negative autophagosome/endosome maturation terms.
    additional_reference_ids:
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: interacts directly with PI3KC3 and UVRAG
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Interacts with Rab7
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Rab7 and UVRAG compete for RUBCN binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24034250
  qualifier: enables
  review:
    summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN 
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG
      regulatory context, and negative autophagosome/endosome maturation terms.
    additional_reference_ids:
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: interacts directly with PI3KC3 and UVRAG
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Interacts with Rab7
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Rab7 and UVRAG compete for RUBCN binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25594178
  qualifier: enables
  review:
    summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN 
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG
      regulatory context, and negative autophagosome/endosome maturation terms.
    additional_reference_ids:
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: interacts directly with PI3KC3 and UVRAG
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Interacts with Rab7
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Rab7 and UVRAG compete for RUBCN binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN 
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG
      regulatory context, and negative autophagosome/endosome maturation terms.
    additional_reference_ids:
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: interacts directly with PI3KC3 and UVRAG
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Interacts with Rab7
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Rab7 and UVRAG compete for RUBCN binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN 
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG
      regulatory context, and negative autophagosome/endosome maturation terms.
    additional_reference_ids:
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: interacts directly with PI3KC3 and UVRAG
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Interacts with Rab7
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Rab7 and UVRAG compete for RUBCN binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34386498
  qualifier: enables
  review:
    summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN 
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG
      regulatory context, and negative autophagosome/endosome maturation terms.
    additional_reference_ids:
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: interacts directly with PI3KC3 and UVRAG
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Interacts with Rab7
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Rab7 and UVRAG compete for RUBCN binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN 
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG
      regulatory context, and negative autophagosome/endosome maturation terms.
    additional_reference_ids:
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: interacts directly with PI3KC3 and UVRAG
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Interacts with Rab7
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Rab7 and UVRAG compete for RUBCN binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35512704
  qualifier: enables
  review:
    summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN 
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG
      regulatory context, and negative autophagosome/endosome maturation terms.
    additional_reference_ids:
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: interacts directly with PI3KC3 and UVRAG
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Interacts with Rab7
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Rab7 and UVRAG compete for RUBCN binding
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: EXP
  original_reference_id: PMID:19270696
  qualifier: located_in
  review:
    summary: Lysosome localization is supported and relevant to late endosome/autophagosome maturation.
    action: ACCEPT
    reason: Rubicon is predominantly in late endosome/lysosome compartments and regulates delivery/fusion 
      steps toward lysosomes.
    additional_reference_ids:
    - PMID:19270696
    - PMID:20974968
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Lysosome {ECO:0000269|PubMed:19270696}
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Predominantly located in late endosomes/lysosomes
    - reference_id: PMID:20974968
      supporting_text: prevents endosome maturation through differential interactions with Rab7 and UVRAG
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: EXP
  original_reference_id: PMID:20974968
  qualifier: located_in
  review:
    summary: early endosome localization is supported for Rubicon endosome maturation biology.
    action: ACCEPT
    reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome 
      localization fits the core negative endosome/autophagosome maturation role.
    additional_reference_ids:
    - PMID:19270696
    - PMID:20974968
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Predominantly located in late endosomes/lysosomes
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Late endosome {ECO:0000269|PubMed:19270696}
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Early endosome
    - reference_id: PMID:20974968
      supporting_text: prevents endosome maturation through differential interactions with Rab7 and UVRAG
    - reference_id: PMID:20974968
      supporting_text: sequesters UVRAG from C-VPS/HOPS
- term:
    id: GO:0051898
    label: negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence_type: IDA
  original_reference_id: PMID:21062745
  qualifier: involved_in
  review:
    summary: The PI3K/AKT pathway wording is misleading for Rubicon hVps34 inhibition.
    action: MODIFY
    reason: The cited evidence supports inhibition of class III PI3K/VPS34 lipid kinase activity and 
      autophagosome maturation, not a general PI3K/AKT signaling pathway role.
    proposed_replacement_terms:
    - id: GO:0141039
      label: phosphatidylinositol 3-kinase inhibitor activity
    - id: GO:1901097
      label: negative regulation of autophagosome maturation
    additional_reference_ids:
    - PMID:21062745
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: PMID:21062745
      supporting_text: interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
    - reference_id: PMID:21062745
      supporting_text: inhibition of PI3KC3 lipid kinase activity by Rubicon
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Inhibits PIK3C3 activity
    - reference_id: PMID:21062745
      supporting_text: negative regulator of PI3KC3 and autophagosome maturation
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy
- term:
    id: GO:0141039
    label: phosphatidylinositol 3-kinase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:21062745
  qualifier: enables
  review:
    summary: PI3K inhibitor activity is the best molecular-function annotation for Rubicon.
    action: ACCEPT
    reason: Rubicon inhibits PIK3C3/VPS34 lipid kinase activity through RUN-domain-dependent interaction with 
      hVps34.
    additional_reference_ids:
    - PMID:21062745
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: PMID:21062745
      supporting_text: interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
    - reference_id: PMID:21062745
      supporting_text: inhibition of PI3KC3 lipid kinase activity by Rubicon
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Inhibits PIK3C3 activity
- term:
    id: GO:1901097
    label: negative regulation of autophagosome maturation
  evidence_type: TAS
  original_reference_id: PMID:21118109
  qualifier: involved_in
  review:
    summary: Negative regulation of autophagosome maturation is the central RUBCN autophagy annotation.
    action: ACCEPT
    reason: Rubicon inhibits UVRAG-containing PI3KC3-C2 and autophagosome maturation; knockdown enhances 
      autophagy at the maturation step.
    additional_reference_ids:
    - PMID:19270696
    - PMID:21062745
    - PMID:20943950
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: PMID:19270696
      supporting_text: Rubicon binds only to a subpopulation of UVRAG complexes
    - reference_id: PMID:19270696
      supporting_text: Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step
    - reference_id: PMID:21062745
      supporting_text: negative regulator of PI3KC3 and autophagosome maturation
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy
    - reference_id: PMID:21062745
      supporting_text: interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
    - reference_id: PMID:21062745
      supporting_text: inhibition of PI3KC3 lipid kinase activity by Rubicon
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Inhibits PIK3C3 activity
- term:
    id: GO:0071985
    label: multivesicular body sorting pathway
  evidence_type: TAS
  original_reference_id: PMID:21118109
  qualifier: involved_in
  review:
    summary: Multivesicular body sorting is supported as endosomal trafficking context but is not the core PN 
      autophagy term.
    action: KEEP_AS_NON_CORE
    reason: Rubicon negatively regulates endocytic pathway progression and endosome maturation; retain this as
      a non-core endosomal trafficking branch.
    additional_reference_ids:
    - PMID:20943950
    - PMID:20974968
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: PMID:20974968
      supporting_text: prevents endosome maturation through differential interactions with Rab7 and UVRAG
    - reference_id: PMID:20974968
      supporting_text: sequesters UVRAG from C-VPS/HOPS
    - reference_id: PMID:20943950
      supporting_text: specifically and directly interact with Rab7 via their RH domain
    - reference_id: PMID:20943950
      supporting_text: simultaneously binding both Rab7 and PI3-kinase
- term:
    id: GO:1901097
    label: negative regulation of autophagosome maturation
  evidence_type: IMP
  original_reference_id: PMID:21062745
  qualifier: involved_in
  review:
    summary: Negative regulation of autophagosome maturation is the central RUBCN autophagy annotation.
    action: ACCEPT
    reason: Rubicon inhibits UVRAG-containing PI3KC3-C2 and autophagosome maturation; knockdown enhances 
      autophagy at the maturation step.
    additional_reference_ids:
    - PMID:19270696
    - PMID:21062745
    - PMID:20943950
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: PMID:19270696
      supporting_text: Rubicon binds only to a subpopulation of UVRAG complexes
    - reference_id: PMID:19270696
      supporting_text: Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step
    - reference_id: PMID:21062745
      supporting_text: negative regulator of PI3KC3 and autophagosome maturation
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy
    - reference_id: PMID:21062745
      supporting_text: interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
    - reference_id: PMID:21062745
      supporting_text: inhibition of PI3KC3 lipid kinase activity by Rubicon
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Inhibits PIK3C3 activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19270696
  qualifier: enables
  review:
    summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN 
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG
      regulatory context, and negative autophagosome/endosome maturation terms.
    additional_reference_ids:
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: interacts directly with PI3KC3 and UVRAG
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Interacts with Rab7
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Rab7 and UVRAG compete for RUBCN binding
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IDA
  original_reference_id: PMID:19270696
  qualifier: located_in
  review:
    summary: early endosome localization is supported for Rubicon endosome maturation biology.
    action: ACCEPT
    reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome 
      localization fits the core negative endosome/autophagosome maturation role.
    additional_reference_ids:
    - PMID:19270696
    - PMID:20974968
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Predominantly located in late endosomes/lysosomes
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Late endosome {ECO:0000269|PubMed:19270696}
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Early endosome
    - reference_id: PMID:20974968
      supporting_text: prevents endosome maturation through differential interactions with Rab7 and UVRAG
    - reference_id: PMID:20974968
      supporting_text: sequesters UVRAG from C-VPS/HOPS
- term:
    id: GO:0005770
    label: late endosome
  evidence_type: IDA
  original_reference_id: PMID:19270696
  qualifier: located_in
  review:
    summary: late endosome localization is supported for Rubicon endosome maturation biology.
    action: ACCEPT
    reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome 
      localization fits the core negative endosome/autophagosome maturation role.
    additional_reference_ids:
    - PMID:19270696
    - PMID:20974968
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Predominantly located in late endosomes/lysosomes
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Late endosome {ECO:0000269|PubMed:19270696}
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Early endosome
    - reference_id: PMID:20974968
      supporting_text: prevents endosome maturation through differential interactions with Rab7 and UVRAG
    - reference_id: PMID:20974968
      supporting_text: sequesters UVRAG from C-VPS/HOPS
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:19270696
  qualifier: colocalizes_with
  negated: true
  review:
    summary: The negated Golgi colocalization annotation is supported by curated localization evidence.
    action: ACCEPT
    reason: This is a NOT annotation. Primary Rubicon localization is endosome/lysosome, and UniProt explicitly
      notes that Rubicon is not detected in the Golgi apparatus.
    additional_reference_ids:
    - PMID:19270696
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: not at all in the Golgi apparatus
    - reference_id: PMID:19270696
      supporting_text: GFP-Rubicon was localized at the endosome/lysosome
- term:
    id: GO:0010507
    label: negative regulation of autophagy
  evidence_type: IMP
  original_reference_id: PMID:19270696
  qualifier: involved_in
  review:
    summary: Negative regulation of autophagy is supported and core, though less specific than autophagosome 
      maturation.
    action: ACCEPT
    reason: Rubicon knockdown enhances autophagy and maturation; the specific mechanism is PI3KC3-C2 
      inhibition and impaired autophagosome maturation.
    additional_reference_ids:
    - PMID:19270696
    - PMID:21062745
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: PMID:19270696
      supporting_text: Rubicon binds only to a subpopulation of UVRAG complexes
    - reference_id: PMID:19270696
      supporting_text: Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step
    - reference_id: PMID:21062745
      supporting_text: negative regulator of PI3KC3 and autophagosome maturation
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy
    - reference_id: PMID:21062745
      supporting_text: interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
    - reference_id: PMID:21062745
      supporting_text: inhibition of PI3KC3 lipid kinase activity by Rubicon
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Inhibits PIK3C3 activity
- term:
    id: GO:0045806
    label: negative regulation of endocytosis
  evidence_type: IMP
  original_reference_id: PMID:19270696
  qualifier: involved_in
  review:
    summary: Negative regulation of endocytosis/endocytic trafficking is a core Rubicon function.
    action: ACCEPT
    reason: Rubicon inhibits endosome maturation and endocytic pathway progression through Rab7 and 
      UVRAG/PI3KC3-C2 interactions.
    additional_reference_ids:
    - PMID:19270696
    - PMID:20943950
    - PMID:20974968
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: PMID:20974968
      supporting_text: prevents endosome maturation through differential interactions with Rab7 and UVRAG
    - reference_id: PMID:20974968
      supporting_text: sequesters UVRAG from C-VPS/HOPS
    - reference_id: PMID:20943950
      supporting_text: specifically and directly interact with Rab7 via their RH domain
    - reference_id: PMID:20943950
      supporting_text: simultaneously binding both Rab7 and PI3-kinase
    - reference_id: PMID:19270696
      supporting_text: Rubicon binds only to a subpopulation of UVRAG complexes
- term:
    id: GO:0034272
    label: phosphatidylinositol 3-kinase complex, class III, type II
  evidence_type: IPI
  original_reference_id: PMID:19270696
  qualifier: part_of
  review:
    summary: Rubicon should be added as a PI3KC3-C2-associated regulatory subunit/context component.
    action: NEW
    reason: RUBCN associates with the UVRAG-containing class III PI3K complex II and directly interacts with 
      PIK3C3 and UVRAG; this is the specific complex context missing from GOA.
    additional_reference_ids:
    - PMID:19270696
    - PMID:21062745
    - file:human/RUBCN/RUBCN-uniprot.txt
    - file:human/RUBCN/RUBCN-notes.md
    supported_by:
    - reference_id: PMID:19270696
      supporting_text: Rubicon binds only to a subpopulation of UVRAG complexes
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: Associates with PI3K (PI3KC3/PI3K-III/class III
    - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
      supporting_text: complex II (PI3KC3-C2)
references:
- 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:19270696
  title: Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different 
    stages.
  findings: []
- id: PMID:20562859
  title: Network organization of the human autophagy system.
  findings: []
- id: PMID:20974968
  title: Rubicon controls endosome maturation as a Rab7 effector.
  findings: []
- id: PMID:21062745
  title: The RUN domain of rubicon is important for hVps34 binding, lipid kinase inhibition, and autophagy 
    suppression.
  findings: []
- id: PMID:21118109
  title: The role of ESCRT proteins in fusion events involving lysosomes, endosomes and autophagosomes.
  findings: []
- id: PMID:22493499
  title: Receptor signaling lymphocyte-activation molecule family 1 (Slamf1) regulates membrane fusion and 
    NADPH oxidase 2 (NOX2) activity by recruiting a Beclin-1/Vps34/ultraviolet radiation resistance-associated
    gene (UVRAG) complex.
  findings: []
- id: PMID:23954414
  title: Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism.
  findings: []
- id: PMID:24034250
  title: EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor 
    chemoresistance.
  findings: []
- id: PMID:25594178
  title: A kinase-independent role for EGF receptor in autophagy initiation.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:34386498
  title: ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute Respiratory Syndrome Coronavirus-2 
    Replication.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:35512704
  title: Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
  findings: []
- id: PMID:20943950
  title: Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway via a novel Rab7-binding 
    domain.
  findings: []
- id: file:human/RUBCN/RUBCN-uniprot.txt
  title: UniProtKB record for human RUBCN
  findings: []
- id: file:human/RUBCN/RUBCN-notes.md
  title: RUBCN review notes
  findings: []
core_functions:
- molecular_function:
    id: GO:0141039
    label: phosphatidylinositol 3-kinase inhibitor activity
  description: Rubicon inhibits PIK3C3/VPS34 lipid kinase activity in the UVRAG-containing PI3KC3-C2 context 
    and thereby negatively regulates autophagosome maturation and endosome maturation.
  directly_involved_in:
  - id: GO:1901097
    label: negative regulation of autophagosome maturation
  - id: GO:0010507
    label: negative regulation of autophagy
  - id: GO:0045806
    label: negative regulation of endocytosis
  locations:
  - id: GO:0005770
    label: late endosome
  - id: GO:0005764
    label: lysosome
  - id: GO:0005769
    label: early endosome
  in_complex:
    id: GO:0034272
    label: phosphatidylinositol 3-kinase complex, class III, type II
  supported_by:
  - reference_id: PMID:19270696
    supporting_text: Rubicon binds only to a subpopulation of UVRAG complexes
  - reference_id: PMID:19270696
    supporting_text: Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step
  - reference_id: PMID:21062745
    supporting_text: negative regulator of PI3KC3 and autophagosome maturation
  - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
    supporting_text: negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy
  - reference_id: PMID:21062745
    supporting_text: interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
  - reference_id: PMID:21062745
    supporting_text: inhibition of PI3KC3 lipid kinase activity by Rubicon
  - reference_id: file:human/RUBCN/RUBCN-uniprot.txt
    supporting_text: Inhibits PIK3C3 activity
  - reference_id: PMID:20974968
    supporting_text: prevents endosome maturation through differential interactions with Rab7 and UVRAG
  - reference_id: PMID:20974968
    supporting_text: sequesters UVRAG from C-VPS/HOPS
  - reference_id: PMID:20943950
    supporting_text: specifically and directly interact with Rab7 via their RH domain
  - reference_id: PMID:20943950
    supporting_text: simultaneously binding both Rab7 and PI3-kinase
proposed_new_terms: []
suggested_questions:
- question: Should RUBCN be curated as part_of GO:0034272 PI3KC3-C2, or represented only by PI3K inhibitor 
    activity and UVRAG/Rab7 interaction context?
  experts:
  - GO autophagy editors
  - ComplexPortal curators
- question: Should negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction 
    be replaced in GOA by phosphatidylinositol 3-kinase inhibitor activity for RUBCN?
  experts:
  - GO molecular function editors
  - GO signaling editors
- question: Should the Golgi colocalization annotation be removed given curated endosome/lysosome localization
    and explicit UniProt note that Rubicon is not detected at Golgi?
  experts:
  - GO cellular component editors
  - UniProt curators
suggested_experiments:
- description: Use RUBCN knockout/rescue with RUN-domain hVps34-binding mutants and RH-domain Rab7-binding 
    mutants to measure PI3KC3 lipid kinase activity, Rab7 activation, EGFR/endosome maturation, and 
    autophagosome-lysosome fusion.
  experiment_type: Rubicon PI3KC3-C2/Rab7 separation-of-function rescue
  hypothesis: RUBCN requires both PI3KC3-C2 and Rab7/UVRAG interaction surfaces to inhibit autophagosome and 
    endosome maturation.
- description: Perform live-cell imaging of tagged endogenous RUBCN, UVRAG, Rab7, and HOPS markers during 
    starvation and endocytic cargo maturation to test whether RUBCN leaves endosomal/autophagosomal sites 
    before fusion competence.
  experiment_type: endogenous live-cell maturation imaging
  hypothesis: RUBCN occupancy marks inhibited PI3KC3-C2/Rab7 compartments and must be relieved for 
    maturation/fusion progression.