RUBCN

UniProt ID: Q92622
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005769 early endosome
IBA
GO_REF:0000033 		ACCEPT
Summary: early endosome localization is supported for Rubicon endosome maturation biology.
Reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome localization fits the core negative endosome/autophagosome maturation role.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
Predominantly located in late endosomes/lysosomes
file:human/RUBCN/RUBCN-uniprot.txt
Late endosome {ECO:0000269|PubMed:19270696}
file:human/RUBCN/RUBCN-uniprot.txt
Early endosome
PMID:20974968
prevents endosome maturation through differential interactions with Rab7 and UVRAG
PMID:20974968
sequesters UVRAG from C-VPS/HOPS
GO:0005770 late endosome
IBA
GO_REF:0000033 		ACCEPT
Summary: late endosome localization is supported for Rubicon endosome maturation biology.
Reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome localization fits the core negative endosome/autophagosome maturation role.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
Predominantly located in late endosomes/lysosomes
file:human/RUBCN/RUBCN-uniprot.txt
Late endosome {ECO:0000269|PubMed:19270696}
file:human/RUBCN/RUBCN-uniprot.txt
Early endosome
PMID:20974968
prevents endosome maturation through differential interactions with Rab7 and UVRAG
PMID:20974968
sequesters UVRAG from C-VPS/HOPS
GO:0045806 negative regulation of endocytosis
IBA
GO_REF:0000033 		ACCEPT
Summary: Negative regulation of endocytosis/endocytic trafficking is a core Rubicon function.
Reason: Rubicon inhibits endosome maturation and endocytic pathway progression through Rab7 and UVRAG/PI3KC3-C2 interactions.
Supporting Evidence:
PMID:20974968
prevents endosome maturation through differential interactions with Rab7 and UVRAG
PMID:20974968
sequesters UVRAG from C-VPS/HOPS
PMID:20943950
specifically and directly interact with Rab7 via their RH domain
PMID:20943950
simultaneously binding both Rab7 and PI3-kinase
PMID:19270696
Rubicon binds only to a subpopulation of UVRAG complexes
GO:1901097 negative regulation of autophagosome maturation
IBA
GO_REF:0000033 		ACCEPT
Summary: Negative regulation of autophagosome maturation is the central RUBCN autophagy annotation.
Reason: Rubicon inhibits UVRAG-containing PI3KC3-C2 and autophagosome maturation; knockdown enhances autophagy at the maturation step.
Supporting Evidence:
PMID:19270696
Rubicon binds only to a subpopulation of UVRAG complexes
PMID:19270696
Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step
PMID:21062745
negative regulator of PI3KC3 and autophagosome maturation
file:human/RUBCN/RUBCN-uniprot.txt
negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy
PMID:21062745
interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
PMID:21062745
inhibition of PI3KC3 lipid kinase activity by Rubicon
file:human/RUBCN/RUBCN-uniprot.txt
Inhibits PIK3C3 activity
GO:1901981 phosphatidylinositol phosphate binding
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phosphatidylinositol phosphate binding is plausible but not the primary experimentally supported Rubicon function.
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.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
GO; GO:1901981; F:phosphatidylinositol phosphate binding; IBA:GO_Central
GO:0005764 lysosome
IEA
GO_REF:0000044 		ACCEPT
Summary: Lysosome localization is supported and relevant to late endosome/autophagosome maturation.
Reason: Rubicon is predominantly in late endosome/lysosome compartments and regulates delivery/fusion steps toward lysosomes.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
Lysosome {ECO:0000269|PubMed:19270696}
file:human/RUBCN/RUBCN-uniprot.txt
Predominantly located in late endosomes/lysosomes
PMID:20974968
prevents endosome maturation through differential interactions with Rab7 and UVRAG
GO:0005769 early endosome
IEA
GO_REF:0000044 		ACCEPT
Summary: early endosome localization is supported for Rubicon endosome maturation biology.
Reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome localization fits the core negative endosome/autophagosome maturation role.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
Predominantly located in late endosomes/lysosomes
file:human/RUBCN/RUBCN-uniprot.txt
Late endosome {ECO:0000269|PubMed:19270696}
file:human/RUBCN/RUBCN-uniprot.txt
Early endosome
PMID:20974968
prevents endosome maturation through differential interactions with Rab7 and UVRAG
PMID:20974968
sequesters UVRAG from C-VPS/HOPS
GO:0005770 late endosome
IEA
GO_REF:0000044 		ACCEPT
Summary: late endosome localization is supported for Rubicon endosome maturation biology.
Reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome localization fits the core negative endosome/autophagosome maturation role.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
Predominantly located in late endosomes/lysosomes
file:human/RUBCN/RUBCN-uniprot.txt
Late endosome {ECO:0000269|PubMed:19270696}
file:human/RUBCN/RUBCN-uniprot.txt
Early endosome
PMID:20974968
prevents endosome maturation through differential interactions with Rab7 and UVRAG
PMID:20974968
sequesters UVRAG from C-VPS/HOPS
GO:0005515 protein binding
IPI
PMID:20562859
Network organization of the human autophagy system. 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN function.
Reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG regulatory context, and negative autophagosome/endosome maturation terms.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
interacts directly with PI3KC3 and UVRAG
file:human/RUBCN/RUBCN-uniprot.txt
Interacts with Rab7
file:human/RUBCN/RUBCN-uniprot.txt
Rab7 and UVRAG compete for RUBCN binding
GO:0005515 protein binding
IPI
PMID:21062745
The RUN domain of rubicon is important for hVps34 binding, l... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN function.
Reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG regulatory context, and negative autophagosome/endosome maturation terms.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
interacts directly with PI3KC3 and UVRAG
file:human/RUBCN/RUBCN-uniprot.txt
Interacts with Rab7
file:human/RUBCN/RUBCN-uniprot.txt
Rab7 and UVRAG compete for RUBCN binding
GO:0005515 protein binding
IPI
PMID:22493499
Receptor signaling lymphocyte-activation molecule family 1 (... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN function.
Reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG regulatory context, and negative autophagosome/endosome maturation terms.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
interacts directly with PI3KC3 and UVRAG
file:human/RUBCN/RUBCN-uniprot.txt
Interacts with Rab7
file:human/RUBCN/RUBCN-uniprot.txt
Rab7 and UVRAG compete for RUBCN binding
GO:0005515 protein binding
IPI
PMID:23954414
Beclin 2 functions in autophagy, degradation of G protein-co... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN function.
Reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG regulatory context, and negative autophagosome/endosome maturation terms.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
interacts directly with PI3KC3 and UVRAG
file:human/RUBCN/RUBCN-uniprot.txt
Interacts with Rab7
file:human/RUBCN/RUBCN-uniprot.txt
Rab7 and UVRAG compete for RUBCN binding
GO:0005515 protein binding
IPI
PMID:24034250
EGFR-mediated Beclin 1 phosphorylation in autophagy suppress... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN function.
Reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG regulatory context, and negative autophagosome/endosome maturation terms.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
interacts directly with PI3KC3 and UVRAG
file:human/RUBCN/RUBCN-uniprot.txt
Interacts with Rab7
file:human/RUBCN/RUBCN-uniprot.txt
Rab7 and UVRAG compete for RUBCN binding
GO:0005515 protein binding
IPI
PMID:25594178
A kinase-independent role for EGF receptor in autophagy init... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN function.
Reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG regulatory context, and negative autophagosome/endosome maturation terms.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
interacts directly with PI3KC3 and UVRAG
file:human/RUBCN/RUBCN-uniprot.txt
Interacts with Rab7
file:human/RUBCN/RUBCN-uniprot.txt
Rab7 and UVRAG compete for RUBCN binding
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN function.
Reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG regulatory context, and negative autophagosome/endosome maturation terms.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
interacts directly with PI3KC3 and UVRAG
file:human/RUBCN/RUBCN-uniprot.txt
Interacts with Rab7
file:human/RUBCN/RUBCN-uniprot.txt
Rab7 and UVRAG compete for RUBCN binding
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN function.
Reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG regulatory context, and negative autophagosome/endosome maturation terms.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
interacts directly with PI3KC3 and UVRAG
file:human/RUBCN/RUBCN-uniprot.txt
Interacts with Rab7
file:human/RUBCN/RUBCN-uniprot.txt
Rab7 and UVRAG compete for RUBCN binding
GO:0005515 protein binding
IPI
PMID:34386498
ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN function.
Reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG regulatory context, and negative autophagosome/endosome maturation terms.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
interacts directly with PI3KC3 and UVRAG
file:human/RUBCN/RUBCN-uniprot.txt
Interacts with Rab7
file:human/RUBCN/RUBCN-uniprot.txt
Rab7 and UVRAG compete for RUBCN binding
GO:0005515 protein binding
IPI
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human ce... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN function.
Reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG regulatory context, and negative autophagosome/endosome maturation terms.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
interacts directly with PI3KC3 and UVRAG
file:human/RUBCN/RUBCN-uniprot.txt
Interacts with Rab7
file:human/RUBCN/RUBCN-uniprot.txt
Rab7 and UVRAG compete for RUBCN binding
GO:0005515 protein binding
IPI
PMID:35512704
Systematic discovery of mutation-directed neo-protein-protei... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN function.
Reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG regulatory context, and negative autophagosome/endosome maturation terms.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
interacts directly with PI3KC3 and UVRAG
file:human/RUBCN/RUBCN-uniprot.txt
Interacts with Rab7
file:human/RUBCN/RUBCN-uniprot.txt
Rab7 and UVRAG compete for RUBCN binding
GO:0005764 lysosome
EXP
PMID:19270696
Two Beclin 1-binding proteins, Atg14L and Rubicon, reciproca... 		ACCEPT
Summary: Lysosome localization is supported and relevant to late endosome/autophagosome maturation.
Reason: Rubicon is predominantly in late endosome/lysosome compartments and regulates delivery/fusion steps toward lysosomes.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
Lysosome {ECO:0000269|PubMed:19270696}
file:human/RUBCN/RUBCN-uniprot.txt
Predominantly located in late endosomes/lysosomes
PMID:20974968
prevents endosome maturation through differential interactions with Rab7 and UVRAG
GO:0005769 early endosome
EXP
PMID:20974968
Rubicon controls endosome maturation as a Rab7 effector. 		ACCEPT
Summary: early endosome localization is supported for Rubicon endosome maturation biology.
Reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome localization fits the core negative endosome/autophagosome maturation role.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
Predominantly located in late endosomes/lysosomes
file:human/RUBCN/RUBCN-uniprot.txt
Late endosome {ECO:0000269|PubMed:19270696}
file:human/RUBCN/RUBCN-uniprot.txt
Early endosome
PMID:20974968
prevents endosome maturation through differential interactions with Rab7 and UVRAG
PMID:20974968
sequesters UVRAG from C-VPS/HOPS
GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
IDA
PMID:21062745
The RUN domain of rubicon is important for hVps34 binding, l... 		MODIFY
Summary: The PI3K/AKT pathway wording is misleading for Rubicon hVps34 inhibition.
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.
Supporting Evidence:
PMID:21062745
interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
PMID:21062745
inhibition of PI3KC3 lipid kinase activity by Rubicon
file:human/RUBCN/RUBCN-uniprot.txt
Inhibits PIK3C3 activity
PMID:21062745
negative regulator of PI3KC3 and autophagosome maturation
file:human/RUBCN/RUBCN-uniprot.txt
negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy
GO:0141039 phosphatidylinositol 3-kinase inhibitor activity
IDA
PMID:21062745
The RUN domain of rubicon is important for hVps34 binding, l... 		ACCEPT
Summary: PI3K inhibitor activity is the best molecular-function annotation for Rubicon.
Reason: Rubicon inhibits PIK3C3/VPS34 lipid kinase activity through RUN-domain-dependent interaction with hVps34.
Supporting Evidence:
PMID:21062745
interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
PMID:21062745
inhibition of PI3KC3 lipid kinase activity by Rubicon
file:human/RUBCN/RUBCN-uniprot.txt
Inhibits PIK3C3 activity
GO:1901097 negative regulation of autophagosome maturation
TAS
PMID:21118109
The role of ESCRT proteins in fusion events involving lysoso... 		ACCEPT
Summary: Negative regulation of autophagosome maturation is the central RUBCN autophagy annotation.
Reason: Rubicon inhibits UVRAG-containing PI3KC3-C2 and autophagosome maturation; knockdown enhances autophagy at the maturation step.
Supporting Evidence:
PMID:19270696
Rubicon binds only to a subpopulation of UVRAG complexes
PMID:19270696
Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step
PMID:21062745
negative regulator of PI3KC3 and autophagosome maturation
file:human/RUBCN/RUBCN-uniprot.txt
negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy
PMID:21062745
interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
PMID:21062745
inhibition of PI3KC3 lipid kinase activity by Rubicon
file:human/RUBCN/RUBCN-uniprot.txt
Inhibits PIK3C3 activity
GO:0071985 multivesicular body sorting pathway
TAS
PMID:21118109
The role of ESCRT proteins in fusion events involving lysoso... 		KEEP AS NON CORE
Summary: Multivesicular body sorting is supported as endosomal trafficking context but is not the core PN autophagy term.
Reason: Rubicon negatively regulates endocytic pathway progression and endosome maturation; retain this as a non-core endosomal trafficking branch.
Supporting Evidence:
PMID:20974968
prevents endosome maturation through differential interactions with Rab7 and UVRAG
PMID:20974968
sequesters UVRAG from C-VPS/HOPS
PMID:20943950
specifically and directly interact with Rab7 via their RH domain
PMID:20943950
simultaneously binding both Rab7 and PI3-kinase
GO:1901097 negative regulation of autophagosome maturation
IMP
PMID:21062745
The RUN domain of rubicon is important for hVps34 binding, l... 		ACCEPT
Summary: Negative regulation of autophagosome maturation is the central RUBCN autophagy annotation.
Reason: Rubicon inhibits UVRAG-containing PI3KC3-C2 and autophagosome maturation; knockdown enhances autophagy at the maturation step.
Supporting Evidence:
PMID:19270696
Rubicon binds only to a subpopulation of UVRAG complexes
PMID:19270696
Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step
PMID:21062745
negative regulator of PI3KC3 and autophagosome maturation
file:human/RUBCN/RUBCN-uniprot.txt
negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy
PMID:21062745
interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
PMID:21062745
inhibition of PI3KC3 lipid kinase activity by Rubicon
file:human/RUBCN/RUBCN-uniprot.txt
Inhibits PIK3C3 activity
GO:0005515 protein binding
IPI
PMID:19270696
Two Beclin 1-binding proteins, Atg14L and Rubicon, reciproca... 		MARK AS OVER ANNOTATED
Summary: The interaction evidence may be real, but generic protein binding is not informative for RUBCN function.
Reason: Replace protein binding with specific PI3KC3 inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG regulatory context, and negative autophagosome/endosome maturation terms.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
interacts directly with PI3KC3 and UVRAG
file:human/RUBCN/RUBCN-uniprot.txt
Interacts with Rab7
file:human/RUBCN/RUBCN-uniprot.txt
Rab7 and UVRAG compete for RUBCN binding
GO:0005769 early endosome
IDA
PMID:19270696
Two Beclin 1-binding proteins, Atg14L and Rubicon, reciproca... 		ACCEPT
Summary: early endosome localization is supported for Rubicon endosome maturation biology.
Reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome localization fits the core negative endosome/autophagosome maturation role.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
Predominantly located in late endosomes/lysosomes
file:human/RUBCN/RUBCN-uniprot.txt
Late endosome {ECO:0000269|PubMed:19270696}
file:human/RUBCN/RUBCN-uniprot.txt
Early endosome
PMID:20974968
prevents endosome maturation through differential interactions with Rab7 and UVRAG
PMID:20974968
sequesters UVRAG from C-VPS/HOPS
GO:0005770 late endosome
IDA
PMID:19270696
Two Beclin 1-binding proteins, Atg14L and Rubicon, reciproca... 		ACCEPT
Summary: late endosome localization is supported for Rubicon endosome maturation biology.
Reason: RUBCN is an endosomal/lysosomal Rab7 and UVRAG/PI3KC3-C2 regulator; early/late endosome localization fits the core negative endosome/autophagosome maturation role.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
Predominantly located in late endosomes/lysosomes
file:human/RUBCN/RUBCN-uniprot.txt
Late endosome {ECO:0000269|PubMed:19270696}
file:human/RUBCN/RUBCN-uniprot.txt
Early endosome
PMID:20974968
prevents endosome maturation through differential interactions with Rab7 and UVRAG
PMID:20974968
sequesters UVRAG from C-VPS/HOPS
GO:0005794 Golgi apparatus
IDA NOT
PMID:19270696
Two Beclin 1-binding proteins, Atg14L and Rubicon, reciproca... 		ACCEPT
Summary: The negated Golgi colocalization annotation is supported by curated localization evidence.
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.
Supporting Evidence:
file:human/RUBCN/RUBCN-uniprot.txt
not at all in the Golgi apparatus
PMID:19270696
GFP-Rubicon was localized at the endosome/lysosome
GO:0010507 negative regulation of autophagy
IMP
PMID:19270696
Two Beclin 1-binding proteins, Atg14L and Rubicon, reciproca... 		ACCEPT
Summary: Negative regulation of autophagy is supported and core, though less specific than autophagosome maturation.
Reason: Rubicon knockdown enhances autophagy and maturation; the specific mechanism is PI3KC3-C2 inhibition and impaired autophagosome maturation.
Supporting Evidence:
PMID:19270696
Rubicon binds only to a subpopulation of UVRAG complexes
PMID:19270696
Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step
PMID:21062745
negative regulator of PI3KC3 and autophagosome maturation
file:human/RUBCN/RUBCN-uniprot.txt
negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy
PMID:21062745
interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
PMID:21062745
inhibition of PI3KC3 lipid kinase activity by Rubicon
file:human/RUBCN/RUBCN-uniprot.txt
Inhibits PIK3C3 activity
GO:0045806 negative regulation of endocytosis
IMP
PMID:19270696
Two Beclin 1-binding proteins, Atg14L and Rubicon, reciproca... 		ACCEPT
Summary: Negative regulation of endocytosis/endocytic trafficking is a core Rubicon function.
Reason: Rubicon inhibits endosome maturation and endocytic pathway progression through Rab7 and UVRAG/PI3KC3-C2 interactions.
Supporting Evidence:
PMID:20974968
prevents endosome maturation through differential interactions with Rab7 and UVRAG
PMID:20974968
sequesters UVRAG from C-VPS/HOPS
PMID:20943950
specifically and directly interact with Rab7 via their RH domain
PMID:20943950
simultaneously binding both Rab7 and PI3-kinase
PMID:19270696
Rubicon binds only to a subpopulation of UVRAG complexes
GO:0034272 phosphatidylinositol 3-kinase complex, class III, type II
IPI
PMID:19270696
Two Beclin 1-binding proteins, Atg14L and Rubicon, reciproca... 		NEW
Summary: Rubicon should be added as a PI3KC3-C2-associated regulatory subunit/context component.
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.
Supporting Evidence:
PMID:19270696
Rubicon binds only to a subpopulation of UVRAG complexes
file:human/RUBCN/RUBCN-uniprot.txt
Associates with PI3K (PI3KC3/PI3K-III/class III
file:human/RUBCN/RUBCN-uniprot.txt
complex II (PI3KC3-C2)

Core Functions

Rubicon inhibits PIK3C3/VPS34 lipid kinase activity in the UVRAG-containing PI3KC3-C2 context and thereby negatively regulates autophagosome maturation and endosome maturation.

Molecular Function:
phosphatidylinositol 3-kinase inhibitor activity
Directly Involved In:
negative regulation of autophagosome maturation negative regulation of autophagy negative regulation of endocytosis
Cellular Locations:
late endosome lysosome early endosome
In Complex:
phosphatidylinositol 3-kinase complex, class III, type II
Supporting Evidence:
  • PMID:19270696
    Rubicon binds only to a subpopulation of UVRAG complexes
  • PMID:19270696
    Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step
  • PMID:21062745
    negative regulator of PI3KC3 and autophagosome maturation
  • file:human/RUBCN/RUBCN-uniprot.txt
    negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy
  • PMID:21062745
    interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain
  • PMID:21062745
    inhibition of PI3KC3 lipid kinase activity by Rubicon
  • file:human/RUBCN/RUBCN-uniprot.txt
    Inhibits PIK3C3 activity
  • PMID:20974968
    prevents endosome maturation through differential interactions with Rab7 and UVRAG
  • PMID:20974968
    sequesters UVRAG from C-VPS/HOPS
  • PMID:20943950
    specifically and directly interact with Rab7 via their RH domain
  • PMID:20943950
    simultaneously binding both Rab7 and PI3-kinase

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
PMID:19270696
Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages.
PMID:20562859
Network organization of the human autophagy system.
PMID:20974968
Rubicon controls endosome maturation as a Rab7 effector.
PMID:21062745
The RUN domain of rubicon is important for hVps34 binding, lipid kinase inhibition, and autophagy suppression.
PMID:21118109
The role of ESCRT proteins in fusion events involving lysosomes, endosomes and autophagosomes.
PMID:22493499
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.
PMID:23954414
Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism.
PMID:24034250
EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance.
PMID:25594178
A kinase-independent role for EGF receptor in autophagy initiation.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34386498
ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute Respiratory Syndrome Coronavirus-2 Replication.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:35512704
Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
PMID:20943950
Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway via a novel Rab7-binding domain.
file:human/RUBCN/RUBCN-uniprot.txt
UniProtKB record for human RUBCN
file:human/RUBCN/RUBCN-notes.md
RUBCN review notes

Suggested Questions for Experts

Q: Should RUBCN be curated as part_of GO:0034272 PI3KC3-C2, or represented only by PI3K inhibitor activity and UVRAG/Rab7 interaction context?

Suggested experts: GO autophagy editors, ComplexPortal curators

Q: Should negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction be replaced in GOA by phosphatidylinositol 3-kinase inhibitor activity for RUBCN?

Suggested experts: GO molecular function editors, GO signaling editors

Q: Should the Golgi colocalization annotation be removed given curated endosome/lysosome localization and explicit UniProt note that Rubicon is not detected at Golgi?

Suggested experts: GO cellular component editors, UniProt curators

Suggested Experiments

Experiment: 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.

Hypothesis: RUBCN requires both PI3KC3-C2 and Rab7/UVRAG interaction surfaces to inhibit autophagosome and endosome maturation.

Type: Rubicon PI3KC3-C2/Rab7 separation-of-function rescue

Experiment: 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.

Hypothesis: RUBCN occupancy marks inhibited PI3KC3-C2/Rab7 compartments and must be relieved for maturation/fusion progression.

Type: endogenous live-cell maturation imaging

📚 Additional Documentation

Notes

(RUBCN-notes.md)

RUBCN review notes

Scope

RUBCN/Rubicon is reviewed in the PN class III PI3K complex 2/autophagosome maturation branch. PN entries without PMIDs were used as context only. The central curation issue is that Rubicon is not an autophagy activator like UVRAG or Bif-1; it is an inhibitory PI3KC3-C2/Rab7/endosome maturation regulator.

Evidence synthesis

Rubicon binds a UVRAG-containing Beclin 1/Vps34 complex and inhibits late autophagy. The discovery paper reports that "Rubicon binds only to a subpopulation of UVRAG complexes" and that "Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step" [PMID:19270696, "Rubicon binds only to a subpopulation of UVRAG complexes"; PMID:19270696, "Knockdown of Rubicon caused enhancement of autophagy, especially at the maturation step"]. This supports negative regulation of autophagosome maturation and negative regulation of autophagy.

The most specific molecular function is PI3K inhibitor activity. The RUN-domain paper states that "Rubicon serves as a negative regulator of PI3KC3 and autophagosome maturation", that it "interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain", and that the RUN domain contributes to "inhibition of PI3KC3 lipid kinase activity by Rubicon" [PMID:21062745, "negative regulator of PI3KC3 and autophagosome maturation"; PMID:21062745, "interacts with the PI3KC3 catalytic subunit hVps34 via its RUN domain"; PMID:21062745, "inhibition of PI3KC3 lipid kinase activity by Rubicon"]. UniProt also summarizes: "Inhibits PIK3C3 activity" and "negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy" [file:human/RUBCN/RUBCN-uniprot.txt, "Inhibits PIK3C3 activity"; file:human/RUBCN/RUBCN-uniprot.txt, "negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy"].

Rubicon also controls endosome maturation as a Rab7 effector. One paper states that Rubicon "prevents endosome maturation through differential interactions with Rab7 and UVRAG" and that it "sequesters UVRAG from C-VPS/HOPS" [PMID:20974968, "prevents endosome maturation through differential interactions with Rab7 and UVRAG"; PMID:20974968, "sequesters UVRAG from C-VPS/HOPS"]. A Rab7-domain paper reports that Rubicon and PLEKHM1 "specifically and directly interact with Rab7 via their RH domain" and that Rubicon uniquely regulates membrane trafficking by "simultaneously binding both Rab7 and PI3-kinase" [PMID:20943950, "specifically and directly interact with Rab7 via their RH domain"; PMID:20943950, "simultaneously binding both Rab7 and PI3-kinase"]. This supports negative regulation of endocytosis/endosome maturation and a non-core multivesicular body sorting context.

Subcellular location should be endosome/lysosome, not Golgi. UniProt states that Rubicon is "Predominantly located in late endosomes/lysosomes" and "not at all in the Golgi apparatus" [file:human/RUBCN/RUBCN-uniprot.txt, "Predominantly located in late endosomes/lysosomes"; file:human/RUBCN/RUBCN-uniprot.txt, "not at all in the Golgi apparatus"]. Therefore the negated NOT colocalizes_with Golgi apparatus row should be accepted; a positive Golgi annotation would not be supported.

Generic protein binding rows are mostly over-annotations. The useful annotations are PI3K inhibitor activity, PI3KC3-C2 association, Rab7/UVRAG regulatory context, and negative regulation of autophagosome/endosome maturation. Protein binding by itself loses the function.

Falcon

Falcon deep research was run for RUBCN on 2026-06-02 but timed out after 600 seconds, and no RUBCN-deep-research-falcon.md report was produced. This review therefore uses the local GOA, UniProt, cached publication files, and the additional notes above.

Description cleanup note

The YAML description field was revised to keep it as a standalone biological summary. Project-specific curation framing moved here instead.

  • Moved out of the YAML description: the prior wording framed RUBCN in the Proteostasis Network context as a negative PI3KC3-C2/autophagosome maturation regulator rather than an autophagy activator, with UniProt pathogen/innate-immune interaction biology treated as non-core for the GOA rows.

Pn Notes

(RUBCN-pn-notes.md)

RUBCN PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q92622
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-pr-1217 (PR 1217)
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • 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.
  • Existing/core annotation action counts: ACCEPT: 17; KEEP_AS_NON_CORE: 2; MARK_AS_OVER_ANNOTATED: 12; MODIFY: 1; NEW: 1

PN Consistency Summary

  • Consistency: Mostly consistent, with one nuance. Review + notes correctly emphasize Rubicon as a NEGATIVE regulator of PI3KC3-C2/autophagosome maturation (inhibits VPS34; PMID:19270696, 21062745). PN Notes say only "Member of class III PI3K complex 2 that binds to UVRAG and inhibits activity" — captures the inhibitory role. The PN component-membership framing (treating Rubicon as a structural C2 subunit) is the contestable point: Rubicon binds only a subpopulation of UVRAG complexes and is often described as an associated regulator rather than a stoichiometric core subunit. Flag, not a contradiction.
  • PN story / NEW pressure: PN asserts GO:0034272 membership that is absent from GOA (new_to_goa). Review adds GO:0034272 part_of as action NEW (PMID:28306502... actually RUBCN cites discovery/RUN-domain papers) — matching the PN projection. Term verified real. Review also proposes PI3K inhibitor / negative-regulation MF terms beyond PN. Verdict: ADD GO:0034272 (review already did) — aligned with PN.
  • Evidence alignment: PN cites Annual Review, a cardiovascular-autophagy review, and PMID:19270696 (Matsunaga). Review uses primary PMID:19270696, 21062745 (RUN domain/PI3KC3 inhibition), 20974968, 20943950 (Rab7 RH-domain). PMID:19270696 shared.
  • Verdict: Consistent; NEW GO:0034272 matches PN projection (verified, new_to_goa). Open question whether part_of vs "associated inhibitory regulator" is the right relation for a subpopulation binder — already flagged in the review's suggested_questions; no edits required.

Full Consistency Review

  • UniProt: Q92622 · batch: proteostasis-pr-1217 · review status: COMPLETE
  • PN placement: ALP|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct|Class 3 PI3K complex 2 component ; PN-node mapping: type leaf mapped, ok_for_propagation_to_go → GO:0034272 (class III PI3K complex, type II), goa_status new_to_goa; ancestors GO:0035032 / GO:0016236 context_only.
  • Consistency: Mostly consistent, with one nuance. Review + notes correctly emphasize Rubicon as a NEGATIVE regulator of PI3KC3-C2/autophagosome maturation (inhibits VPS34; PMID:19270696, 21062745). PN Notes say only "Member of class III PI3K complex 2 that binds to UVRAG and inhibits activity" — captures the inhibitory role. The PN component-membership framing (treating Rubicon as a structural C2 subunit) is the contestable point: Rubicon binds only a subpopulation of UVRAG complexes and is often described as an associated regulator rather than a stoichiometric core subunit. Flag, not a contradiction.
  • PN story / NEW pressure: PN asserts GO:0034272 membership that is absent from GOA (new_to_goa). Review adds GO:0034272 part_of as action NEW (PMID:28306502... actually RUBCN cites discovery/RUN-domain papers) — matching the PN projection. Term verified real. Review also proposes PI3K inhibitor / negative-regulation MF terms beyond PN. Verdict: ADD GO:0034272 (review already did) — aligned with PN.
  • Mapping strategy: This gene supports (does not change) the existing C2-component → GO:0034272 mapping. Caveat: because Rubicon associates with only a UVRAG subpopulation and inhibits the complex, part_of GO:0034272 is defensible but borderline vs. an "associated regulator" reading; the review itself raises this as a suggested question. Ancestors correctly held too_broad. PN-projected term coincides with review (not broader/narrower).
  • Evidence alignment: PN cites Annual Review, a cardiovascular-autophagy review, and PMID:19270696 (Matsunaga). Review uses primary PMID:19270696, 21062745 (RUN domain/PI3KC3 inhibition), 20974968, 20943950 (Rab7 RH-domain). PMID:19270696 shared.
  • Verdict: Consistent; NEW GO:0034272 matches PN projection (verified, new_to_goa). Open question whether part_of vs "associated inhibitory regulator" is the right relation for a subpopulation binder — already flagged in the review's suggested_questions; no edits required.

PN Dossier Context

  • review_batch: proteostasis-pr-1217
  • review_yaml: genes/human/RUBCN/RUBCN-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Autophagy-Lysosome Pathway | Autophagosome closure maturation and lysosome fusion | Class 3 PI3K complex 2, direct | Class 3 PI3K complex 2 component

  • UniProt: Q92622
  • In branches: ALP
  • Notes: Member of class III PI3K complex 2 that binds to UVRAG and inhibits activity
  • PN references (titles):
    • Mammalian Autophagy: How Does It Work? | Annual Review of Biochemistry (annualreviews.org)
    • role of autophagy in cardiovascular pathology | Cardiovascular Research | Oxford Academic (oup.com)
    • Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages | Nature Cell Biology
  • PN-node mapping records (path + ancestors):
    • [type] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct|Class 3 PI3K complex 2 component
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0034272 phosphatidylinositol 3-kinase complex, class III, type II]
      rationale: This PN type denotes component membership in the direct class III PI3K complex 2 module used during autophagosome maturation and lysosome fusion. The corresponding GO complex term is the right propagation target.
    • [group] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct
      status=context_only scope=too_broad_to_propagate GO=[GO:0035032 phosphatidylinositol 3-kinase complex, class III]
      rationale: Reviewed as a class-III PI3K complex context or regulator bucket. This node is useful for curator interpretation, but it should not project cellular-component membership; only explicit complex-component leaves propagate to GO complex terms.
    • [class] Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion
      status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
      rationale: This class is a late macroautophagy context, but the subtree mixes docking, fusion, localization, membrane-composition, and unknown late-stage roles. The class-level relation is useful for display while propagation is restricted to narrower mechanism nodes.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (1)

  • GO:0034272 phosphatidylinositol 3-kinase complex, class III, type II | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagosome closure maturation and lysosome fusion|Class 3 PI3K complex 2, direct|Class 3 PI3K complex 2 component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
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.