id: Q9P1Z2
gene_symbol: CALCOCO1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: CALCOCO1 (Calcium-binding and coiled-coil domain-containing protein 1; also known as CoCoA/coiled-coil
  coactivator and calphoglin) is a multidomain protein built from an N-terminal SKICH domain, a central
  CALCOCO1 domain with several coiled-coil segments, a disordered region, and a C-terminal UBZ1-type zinc
  finger. It is a soluble selective-autophagy cargo receptor that mediates turnover of the endoplasmic
  reticulum (reticulophagy/ER-phagy) and of the Golgi apparatus (Golgiphagy). In this role it binds membrane-associated
  ER/Golgi proteins on one side and members of the ATG8 family (LC3/GABARAP, in particular GABARAPL1 and
  GABARAPL2) on the other through LIR- and UIM/UDS-type interaction motifs, thereby tethering organelle
  fragments to the forming autophagosome. CALCOCO1 acts predominantly in the cytoplasm. Independently
  of autophagy, CALCOCO1 has a long-standing characterization as a nuclear transcriptional coactivator
  (CoCoA) that shuttles between cytoplasm and nucleus and acts as a secondary/bridging coactivator for
  nuclear receptors, the aryl hydrocarbon receptor, and the Wnt/beta-catenin (CTNNB1) and LEF1/TCF pathways,
  cooperating with p160 coactivators (GRIP1/NCOA2), p300/CBP, CARM1, and with CCAR1/MED1 (for example
  enhancing GATA1-driven transcription during erythroid differentiation). It has also been reported as
  a component of a calphoglin complex that activates inorganic pyrophosphatase and phosphoglucomutase.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator
    judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping,
    accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations of expressed fusion
    proteins in living cells
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
    Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:16344550
  title: Differential use of functional domains by coiled-coil coactivator in its synergistic coactivator
    function with beta-catenin or GRIP1.
  findings: []
- id: PMID:24245781
  title: CCAR1/CoCoA pair-mediated recruitment of the Mediator defines a novel pathway for GATA1 function.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  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:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:31971854
  title: Mass spectrometry proteomics reveals a function for mammalian CALCOCO1 in MTOR-regulated
    selective autophagy.
  full_text_unavailable: true
  findings:
  - statement: CALCOCO1 physically interacts with the ATG8-family protein MAP1LC3C, and genetic
      deletion of CALCOCO1 disrupts autophagy of the endoplasmic reticulum (reticulophagy),
      establishing CALCOCO1 as a selective-autophagy receptor in the MTOR-regulated autophagy
      axis.
  - statement: A canonical LIR motif (W47A abolishes LC3-family binding) and a non-canonical
      CLIR motif (L140A/V142A weakens MAP1LC3C binding) mediate CALCOCO1 association with
      ATG8-family proteins, with a preference for MAP1LC3C, and CALCOCO1 abundance is regulated
      by MTOR-dependent autophagy and lysosomal flux.
- id: PMID:18722177
  title: CCAR1, a key regulator of mediator complex recruitment to nuclear receptor transcription
    complexes.
  full_text_unavailable: true
  findings:
  - statement: CCAR1 cooperates with the p160 coactivator complex and CoCoA/CALCOCO1 to recruit
      the Mediator complex and RNA polymerase II to nuclear-receptor target gene promoters,
      supporting the CCAR1-CoCoA-Mediator coactivator axis.
- id: PMID:25422592
  title: Distinct, genome-wide, gene-specific selectivity patterns of four glucocorticoid receptor
    coregulators.
  full_text_unavailable: true
  findings:
  - statement: siRNA depletion of CALCOCO1 (alongside CCAR1, CCAR2, and ZNF282) shows that
      CALCOCO1 acts as a gene-selective glucocorticoid-receptor coregulator with both positive
      and negative effects on hormone-regulated genes, rather than as a global coactivator.
- id: PMID:38822137
  title: YIPF3 and YIPF4 regulate autophagic turnover of the Golgi apparatus.
  full_text_unavailable: true
  findings:
  - statement: In a HeLa Golgiphagy reporter assay, knockdown of CALCOCO1 alone did not decrease
      Golgiphagy and triple knockdown with YIPF3/YIPF4 retained activity, indicating that
      CALCOCO1 is not the dominant Golgiphagy receptor in this context and that Golgi turnover
      involves redundant or context-specific receptors.
- id: PMID:39871880
  title: 'Join the club: YIPF3 and YIPF4 act as Golgiphagy receptors.'
  full_text_unavailable: true
  findings:
  - statement: Commentary framing CALCOCO1 as a soluble ER-phagy receptor with a minor Golgi-associated
      pool that can contribute to Golgiphagy through a mechanism distinct from the YIPF3/YIPF4
      transmembrane Golgiphagy receptor complex.
- id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
  title: UniProt entry Q9P1Z2 (CACO1_HUMAN)
  findings: []
- id: file:human/CALCOCO1/CALCOCO1-notes.md
  title: CALCOCO1 research notes
  findings: []
existing_annotations:
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) transfer of the historical CoCoA transcriptional coactivator activity.
      This is a real but secondary/context-dependent nuclear function rather than the current core selective-autophagy
      receptor role.
    action: KEEP_AS_NON_CORE
    reason: Coactivator activity is supported by human and ortholog experimental data (e.g. beta-catenin/TCF
      and GATA1/MED1 coactivation), so the term should be retained, but it is a secondary nuclear function
      distinct from the core autophagy-receptor activity.
    supported_by:
    - reference_id: PMID:16344550
      supporting_text: another component of the p160 nuclear receptor coactivator complex, the coiled-coil
      reference_section_type: ABSTRACT
    - reference_id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
      supporting_text: Functions as a coactivator for aryl hydrocarbon and nuclear
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: IBA transfer of a positive transcriptional regulation role, consistent with the CoCoA coactivator
      function in beta-catenin/TCF and GATA1-driven transcription.
    action: KEEP_AS_NON_CORE
    reason: Supported by experimental coactivation data but represents the secondary nuclear function
      rather than the core autophagy-receptor activity.
    supported_by: &id003
    - reference_id: PMID:16344550
      supporting_text: reduction of the endogenous CoCoA level decreased the ability of TCF/LEF and beta-catenin
        to activate transcription
      reference_section_type: ABSTRACT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear localization is consistent with the CoCoA coactivator function and with the UniProt
      note that the protein shuttles between nucleus and cytoplasm.
    action: KEEP_AS_NON_CORE
    reason: Nuclear residence is real and supports the coactivator role, but the principal compartment
      for the core autophagy-receptor activity is the cytoplasm.
    supported_by: &id005
    - reference_id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
      supporting_text: Shuttles between nucleus
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasmic localization is well supported and is the principal compartment for the selective-autophagy
      receptor activity of CALCOCO1.
    action: ACCEPT
    reason: The cytoplasm is the main site of action for the core autophagy-receptor function, and UniProt
      records cytoplasmic localization with nucleocytoplasmic shuttling.
    supported_by: &id004
    - reference_id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
      supporting_text: Cytoplasm. Nucleus. Note=Shuttles between nucleus
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a proteome-scale yeast two-hybrid map; uninformative
      as to the specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome screen does not identify a physiologically
      interpretable function for CALCOCO1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a proteome-scale interactome map; the partner list
      includes the ATG8 family member GABARAPL2 but the term itself is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is too general; the more meaningful biology (ATG8/GABARAP binding underlying
      the autophagy-receptor role) is captured in core_functions and the NEW GO:0160247/GO:0061709 recommendations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from the HuRI binary interactome; partners include GABARAPL1
      and GABARAPL2, but the GO term conveys no specific function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput screen is uninformative for curation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from the BioPlex proteome-scale interactome.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput affinity-purification screen does not establish
      a specific CALCOCO1 function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Generic protein-binding annotation from a multimodal cell-map interactome study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput dataset is uninformative as a molecular function.
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Chromatin localization transferred by Ensembl Compara from the mouse ortholog; consistent
      with the coactivator (CoCoA) role and promoter association by ChIP, but it is a secondary nuclear
      function.
    action: KEEP_AS_NON_CORE
    reason: Promoter/chromatin association is supported for the coactivator function but is not the core
      autophagy-receptor activity.
    supported_by: &id001
    - reference_id: PMID:16344550
      supporting_text: CoCoA associated specifically with the promoters
      reference_section_type: ABSTRACT
- term:
    id: GO:0003682
    label: chromatin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Chromatin binding transferred from the mouse ortholog; consistent with the promoter association
      of the CoCoA coactivator, but a secondary nuclear function.
    action: KEEP_AS_NON_CORE
    reason: Supported by ChIP promoter-association data for the coactivator role; not the core autophagy-receptor
      activity.
    supported_by: *id001
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated (multi-method IEA) assignment of transcription coactivator activity, consistent
      with the experimentally supported CoCoA role.
    action: KEEP_AS_NON_CORE
    reason: Redundant with the IBA/ISS/IMP coactivator annotations; supported but secondary to the core
      autophagy-receptor activity.
    supported_by: &id002
    - reference_id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
      supporting_text: Functions as a coactivator for aryl hydrocarbon and nuclear
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Very broad signal transduction term transferred from the mouse ortholog; too general to be
      informative for CALCOCO1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Signal transduction is an over-broad parent term that does not capture either the coactivator
      or the autophagy-receptor function.
- term:
    id: GO:0030518
    label: nuclear receptor-mediated steroid hormone signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Steroid-hormone nuclear-receptor signaling transferred from the mouse ortholog; consistent
      with the CoCoA coactivator role for nuclear receptors such as the androgen receptor, but a secondary
      function.
    action: KEEP_AS_NON_CORE
    reason: The coactivator function for nuclear receptors is supported, but this pathway is secondary
      to the core autophagy-receptor activity.
    supported_by: *id002
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated ortholog transfer of positive regulation of Pol II transcription; redundant with
      the IBA/ISS coactivator annotations.
    action: KEEP_AS_NON_CORE
    reason: Supported by experimental coactivation data but is a secondary nuclear function.
    supported_by: *id003
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct (immunofluorescence/HPA) evidence for cytosolic localization, consistent with the
      cytoplasmic site of action of the autophagy-receptor function.
    action: ACCEPT
    reason: Cytosolic localization is directly observed and matches the principal compartment for the
      core selective-autophagy receptor activity.
    supported_by: *id004
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence/orthology transfer of positive regulation of Pol II transcription; consistent with
      the CoCoA coactivator role.
    action: KEEP_AS_NON_CORE
    reason: Supported but redundant with other coactivator annotations and secondary to the core autophagy-receptor
      function.
    supported_by: *id003
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:24245781
  qualifier: enables
  review:
    summary: This annotation reads as direct sequence-specific DNA binding, but CALCOCO1/CoCoA is a coactivator
      recruited to promoters via transcription factors such as GATA1 rather than a sequence-specific DNA-binding
      protein; the ChIP signal reflects promoter occupancy through protein-protein interactions.
    action: MODIFY
    reason: CALCOCO1 lacks a sequence-specific DNA-binding domain and is recruited to the gamma-globin
      promoter via GATA1/CCAR1/MED1; the evidence supports a transcription coregulator/coactivator role
      rather than direct cis-regulatory DNA binding.
    proposed_replacement_terms:
    - id: GO:0003712
      label: transcription coregulator activity
    supported_by:
    - reference_id: PMID:24245781
      supporting_text: GATA1, MED1, CCAR1, and CoCoA were all recruited onto the
      reference_section_type: RESULTS
    - reference_id: PMID:24245781
      supporting_text: the GATA1 CF domain serves as a docking surface for multiple coactivators, including
        CoCoA, CCAR1, and MED1
      reference_section_type: RESULTS
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IMP
  original_reference_id: PMID:24245781
  qualifier: enables
  review:
    summary: Human experimental (IMP) support for the coactivator function; CoCoA cooperates with CCAR1
      to enhance GATA1/MED1-driven gamma-globin transcription, and CoCoA knockdown reduces GATA1 target
      gene expression.
    action: KEEP_AS_NON_CORE
    reason: This is well-supported human experimental evidence for the coactivator function, but it is
      a secondary/context-dependent nuclear role distinct from the core autophagy-receptor activity.
    supported_by:
    - reference_id: PMID:24245781
      supporting_text: Recombinant GATA1, CCAR1, CoCoA and MED1(1-602) formed a
      reference_section_type: ABSTRACT
    - reference_id: PMID:24245781
      supporting_text: the GATA1 CF domain serves as a docking surface for multiple coactivators, including
        CoCoA, CCAR1, and MED1
      reference_section_type: RESULTS
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: located_in
  review:
    summary: Direct evidence (expressed fusion protein) for nuclear localization, consistent with the
      nucleocytoplasmic shuttling and the CoCoA coactivator role.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is directly observed and supports the coactivator function, but the cytoplasm
      is the principal site for the core autophagy-receptor activity.
    supported_by: *id005
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IMP
  original_reference_id: PMID:16344550
  qualifier: involved_in
  review:
    summary: CoCoA enhances beta-catenin/TCF-LEF and androgen-receptor transcriptional activation, and
      its knockdown reduces target-gene transcription; supports a positive transcriptional regulation
      role.
    action: KEEP_AS_NON_CORE
    reason: Supported human experimental evidence for the coactivator function, but secondary to the core
      autophagy-receptor activity.
    supported_by: *id003
- term:
    id: GO:0003712
    label: transcription coregulator activity
  evidence_type: IDA
  original_reference_id: PMID:16344550
  qualifier: enables
  review:
    summary: Direct evidence that CoCoA acts as a transcriptional coregulator/coactivator synergizing
      with beta-catenin for AR and TCF/LEF targets.
    action: KEEP_AS_NON_CORE
    reason: Well-supported molecular function for the historical CoCoA role; secondary to the core autophagy-receptor
      activity.
    supported_by:
    - reference_id: PMID:16344550
      supporting_text: directly binds to and cooperates
      reference_section_type: ABSTRACT
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IMP
  original_reference_id: PMID:16344550
  qualifier: enables
  review:
    summary: IMP support for transcription coactivator activity via CoCoA cooperation with beta-catenin
      for AR and TCF/LEF target genes.
    action: KEEP_AS_NON_CORE
    reason: Well-supported coactivator function; secondary to the core autophagy-receptor activity.
    supported_by:
    - reference_id: PMID:16344550
      supporting_text: cooperates synergistically with
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16344550
  qualifier: enables
  review:
    summary: The underlying evidence is a specific direct interaction of CoCoA with beta-catenin (CTNNB1),
      which is better captured by the more informative beta-catenin binding term that is also annotated
      from this same paper.
    action: MODIFY
    reason: Bare protein binding is uninformative; the specific, supported interaction is with beta-catenin,
      for which a dedicated GO term exists.
    proposed_replacement_terms:
    - id: GO:0008013
      label: beta-catenin binding
    supported_by:
    - reference_id: PMID:16344550
      supporting_text: directly binds to and cooperates
      reference_section_type: ABSTRACT
- term:
    id: GO:0008013
    label: beta-catenin binding
  evidence_type: IPI
  original_reference_id: PMID:16344550
  qualifier: enables
  review:
    summary: Direct interaction between CoCoA and beta-catenin (CTNNB1) underpins its synergistic coactivator
      function in the Wnt/beta-catenin and androgen-receptor pathways.
    action: KEEP_AS_NON_CORE
    reason: Specific and well-supported binding for the coactivator role, but part of the secondary nuclear
      function rather than the core autophagy-receptor activity.
    supported_by:
    - reference_id: PMID:16344550
      supporting_text: directly binds to and cooperates
      reference_section_type: ABSTRACT
- term:
    id: GO:0043565
    label: sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:16344550
  qualifier: enables
  review:
    summary: CoCoA is a coactivator recruited to promoters via DNA-bound transcription factors such as
      TCF/LEF and beta-catenin rather than a sequence-specific DNA-binding protein; the ChIP promoter
      association reflects recruitment, not intrinsic DNA-sequence recognition.
    action: MODIFY
    reason: CALCOCO1 has no sequence-specific DNA-binding domain; the supported activity is transcription
      coregulator/coactivator function with promoter association mediated by protein-protein interactions.
    proposed_replacement_terms:
    - id: GO:0003712
      label: transcription coregulator activity
    supported_by: *id001
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IDA
  original_reference_id: PMID:16344550
  qualifier: involved_in
  review:
    summary: Broad positive-regulation-of-gene-expression term supported by the coactivator activity of
      CoCoA on beta-catenin/TCF-LEF and AR target genes; more specifically captured by the positive regulation
      of Pol II transcription annotations.
    action: KEEP_AS_NON_CORE
    reason: Supported but broad; redundant with the more specific transcription-regulation terms and secondary
      to the core autophagy-receptor activity.
    supported_by: *id003
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence/orthology transfer of transcription coactivator activity, consistent with the experimentally
      supported CoCoA role.
    action: KEEP_AS_NON_CORE
    reason: Redundant with the IBA/IEA/IMP coactivator annotations; supported but secondary to the core
      autophagy-receptor activity.
    supported_by: *id002
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Very broad signal transduction term transferred by orthology; too general to be informative
      for CALCOCO1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-broad parent term that does not capture the coactivator or autophagy-receptor function.
- term:
    id: GO:0030518
    label: nuclear receptor-mediated steroid hormone signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Orthology transfer of steroid-hormone nuclear-receptor signaling, consistent with the CoCoA
      coactivator role for nuclear receptors such as the androgen receptor.
    action: KEEP_AS_NON_CORE
    reason: Supported for the coactivator function but secondary to the core autophagy-receptor activity.
    supported_by:
    - reference_id: PMID:16344550
      supporting_text: the androgen receptor (AR), a nuclear
      reference_section_type: ABSTRACT
- term:
    id: GO:0160247
    label: autophagy cargo adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:31971854
  qualifier: enables
  review:
    summary: CALCOCO1 acts as an autophagy cargo adaptor/receptor, binding ATG8-family proteins and linking ER cargo to the autophagy machinery.
    action: NEW
    reason: The PN review showed that the proposed reticulophagy/Golgiphagy receptor MF requests duplicate an existing GO term. GO:0160247 captures the cargo-adaptor activity without minting a bespoke receptor term.
    supported_by:
    - reference_id: PMID:31971854
      supporting_text: CALCOCO1 physically interacts with MAP1LC3C, a key protein in the machinery of autophagy
      reference_section_type: ABSTRACT
    - reference_id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
      supporting_text: 'Q9H0R8: GABARAPL1'
      reference_section_type: DATABASE_ENTRY
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IMP
  original_reference_id: PMID:31971854
  qualifier: involved_in
  review:
    summary: Genetic deletion of CALCOCO1 disrupts autophagy of the endoplasmic reticulum, supporting a specific reticulophagy process annotation.
    action: NEW
    reason: PN correctly projected the ER-phagy node to existing GO:0061709. This is more precise than generic selective autophagy and avoids treating the Golgi-associated report as a broad propagating assertion.
    supported_by:
    - reference_id: PMID:31971854
      supporting_text: Genetic deletion of CALCOCO1 disrupted autophagy of the endoplasmic reticulum (reticulophagy)
      reference_section_type: ABSTRACT
core_functions:
- description: CALCOCO1 acts as a soluble selective-autophagy cargo receptor that bridges organelle membrane
    proteins of the endoplasmic reticulum and Golgi to ATG8-family proteins (LC3/GABARAP, notably GABARAPL1
    and GABARAPL2) via LIR- and UIM/UDS-type motifs, driving reticulophagy (ER-phagy) and Golgiphagy.
    This receptor/adaptor activity is supported by direct interactions with the ATG8 family in the UniProt
    interaction record and by recent autophagy literature. The ER-phagy arm is captured by reticulophagy
    plus the general autophagy cargo-adaptor MF; the Golgi-associated role remains context-dependent and
    should not drive a new MF term request.
  molecular_function:
    id: GO:0160247
    label: autophagy cargo adaptor activity
  supported_by:
  - reference_id: file:human/CALCOCO1/CALCOCO1-uniprot.txt
    supporting_text: 'Q9H0R8: GABARAPL1'
    reference_section_type: DATABASE_ENTRY
  - reference_id: file:human/CALCOCO1/CALCOCO1-notes.md
    supporting_text: selective-autophagy receptor that functions in reticulophagy (ER-phagy)
    reference_section_type: OTHER
  - reference_id: PMID:31971854
    full_text_unavailable: true
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005829
    label: cytosol
  directly_involved_in:
  - id: GO:0061709
    label: reticulophagy
- description: CALCOCO1/CoCoA functions as a secondary/bridging transcriptional coactivator in the nucleus,
    cooperating with beta-catenin (CTNNB1) and the p160 coactivator complex (GRIP1/NCOA2, p300/CBP, CARM1)
    and with CCAR1/MED1 to enhance transcription by nuclear receptors, the aryl hydrocarbon receptor,
    and the Wnt/beta-catenin (TCF/LEF) and GATA1 pathways. It is recruited to target promoters through
    protein-protein interactions rather than sequence-specific DNA binding.
  supported_by:
  - reference_id: PMID:16344550
    supporting_text: directly binds to and cooperates
    reference_section_type: ABSTRACT
  - reference_id: PMID:24245781
    supporting_text: the GATA1 CF domain serves as a docking surface for multiple coactivators, including
      CoCoA, CCAR1, and MED1
    reference_section_type: RESULTS
  molecular_function:
    id: GO:0003713
    label: transcription coactivator activity
  directly_involved_in:
  - id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  locations:
  - id: GO:0005634
    label: nucleus
proposed_new_terms: []
suggested_questions:
- question: Which ER and Golgi membrane proteins does CALCOCO1 recognize as cargo, and what are the precise
    LIR/UDS motifs that mediate ATG8-family (LC3/GABARAP) binding?
- question: How is CALCOCO1 partitioned between its cytoplasmic autophagy-receptor function and its nuclear
    coactivator (CoCoA) function, and is the nucleocytoplasmic shuttling regulated by autophagy or stress
    signaling?
- question: Is the historical calphoglin activity (activation of inorganic pyrophosphatase and phosphoglucomutase)
    a genuine independent function of CALCOCO1, or an artifact of the original complex preparation?
suggested_experiments:
- description: Map the CALCOCO1 LIR/UDS motifs by mutagenesis and quantify binding to each ATG8-family
    member (LC3A/B/C, GABARAP, GABARAPL1, GABARAPL2) using isothermal titration calorimetry or pulldown,
    and test whether motif mutants abolish reticulophagy/Golgiphagy in cells.
  hypothesis: CALCOCO1 engages GABARAP-subfamily ATG8 proteins through defined LIR/UDS motifs that are
    required for ER-phagy and Golgiphagy.
  experiment_type: biochemical interaction mapping and cell-based autophagy flux assay
- description: Use CALCOCO1 knockout and rescue (wild-type vs ATG8-binding-deficient mutant) cells with
    ER- and Golgi-targeted autophagy flux reporters to quantify the contribution of CALCOCO1 to reticulophagy
    and Golgiphagy under basal and stress conditions.
  hypothesis: Loss of CALCOCO1 selectively impairs ER-phagy and Golgiphagy without affecting bulk autophagy.
  experiment_type: genetic loss-of-function with organelle-specific autophagy reporters
- description: Determine the subcellular distribution and functional separability of the autophagy-receptor
    versus coactivator roles by domain-swap and localization mutants, testing reticulophagy flux and TCF/LEF
    or GATA1 reporter activity in parallel.
  hypothesis: The cytoplasmic autophagy-receptor function and the nuclear coactivator function are mediated
    by distinct domains and can be uncoupled.
  experiment_type: structure-function and dual-readout reporter assays