CALCOCO2

id: Q13137
gene_symbol: CALCOCO2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: CALCOCO2 (NDP52) is a selective autophagy receptor/adaptor that
  couples cargo marked by galectin-8 or ubiquitin-associated signals to the
  autophagy machinery. The strongest supported biology is in xenophagy and
  mitophagy, where CALCOCO2 helps recruit LC3/GABARAP and ULK-complex machinery
  to pathogen-containing compartments or damaged mitochondria and can also
  promote late autophagosome maturation/flux. Older annotations centered on PML
  body or nuclear-domain biology are not supported by later localization work and
  should be kept separate from the core selective-autophagy role.
alternative_products:
- name: '1'
  id: Q13137-1
- name: '2'
  id: Q13137-2
  sequence_note: VSP_044728
- name: '3'
  id: Q13137-3
  sequence_note: VSP_046766
- name: '4'
  id: Q13137-4
  sequence_note: VSP_046767
- name: '5'
  id: Q13137-5
  sequence_note: VSP_047414
existing_annotations:
- term:
    id: GO:0005776
    label: autophagosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Phylogenetic inference to autophagosome localization is consistent
      with direct experimental work placing CALCOCO2/NDP52 on pathogen-containing
      autophagosomes during selective autophagy.
    action: ACCEPT
    reason: Autophagosome localization is part of the core receptor/adaptor role
      of CALCOCO2 in selective autophagy.
    supported_by:
    - reference_id: PMID:25771791
      supporting_text: NDP52 also promotes the maturation of autophagosomes via
        its interaction with LC3A, LC3B, and/or GABARAPL2 through a distinct
        LC3-interacting region, and with MYOSIN VI.
- term:
    id: GO:0016605
    label: PML body
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: The legacy NDP52/PML-body story was revised by later localization
      work that found mainly cytoplasmic staining and no convincing ND/PML-body
      localization.
    action: REMOVE
    reason: Later direct evidence argues that CALCOCO2 is not a PML-body protein;
      the earlier assignment is likely an overinterpretation of early antibody
      staining.
    supported_by:
    - reference_id: PMID:9230084
      supporting_text: Our NDP52-specific sera revealed mainly cytoplasmic
        staining but no ND pattern, neither in untreated nor in IFN-treated
        cells.
- term:
    id: GO:0098792
    label: xenophagy
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Xenophagy is a well-supported core CALCOCO2 function, and the IBA is
      reinforced by direct human-cell studies on antibacterial autophagy.
    action: ACCEPT
    reason: CALCOCO2/NDP52 is a canonical selective-autophagy receptor for
      cytosol-exposed intracellular bacteria.
    supported_by:
    - reference_id: PMID:22246324
      supporting_text: By recruiting NDP52 (also known as CALCOCO2), galectin 8
        activates antibacterial autophagy.
    - reference_id: PMID:25771791
      supporting_text: complete xenophagy is selectively regulated by a single
        autophagy receptor, which initially orchestrates bacteria targeting to
        autophagosomes and subsequently ensures pathogen degradation by
        regulating pathogen-containing autophagosome maturation.
- term:
    id: GO:1901098
    label: positive regulation of autophagosome maturation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: CALCOCO2 promotes maturation of pathogen-containing autophagosomes
      after initial cargo capture.
    action: KEEP_AS_NON_CORE
    reason: This is a supported downstream role within xenophagy, but it is more
      contextual than the core cargo-adaptor activity itself.
    supported_by:
    - reference_id: PMID:25771791
      supporting_text: NDP52 also promotes the maturation of autophagosomes via
        its interaction with LC3A, LC3B, and/or GABARAPL2 through a distinct
        LC3-interacting region, and with MYOSIN VI.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  review:
    summary: This is an early large-scale human interactome entry rather than a
      mechanistically informative CALCOCO2 function annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from a proteome-scale interaction map is too
      nonspecific to retain once CALCOCO2's receptor-level autophagy function is
      known.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18330356
  review:
    summary: This annotation derives from normalized yeast two-hybrid resource
      development rather than a focused CALCOCO2 functional study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from broad interaction-library screening is
      not an informative CALCOCO2 molecular function term.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18985028
  review:
    summary: The paper is a host-virus interaction network study and does not
      establish a specific CALCOCO2 molecular function beyond generic binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: The selective-autophagy receptor role is the biologically meaningful
      function to retain; generic host-virus network binding is too broad.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  review:
    summary: This is a high-throughput interactome methodology paper rather than
      a focused functional analysis of CALCOCO2.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from large-scale interactome generation is too
      nonspecific for curated GO retention.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21903422
  review:
    summary: The study places CALCOCO2 in an antiviral innate-immunity network
      linked to autophagy, but the resulting GO term is still only generic
      protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: The network context is interesting, but a protein binding annotation
      does not capture the receptor/adaptor function that matters for GO.
    supported_by:
    - reference_id: PMID:21903422
      supporting_text: At least four proteins (CALCOCO2, ATG7, ATG9A, and
        RB1CC1) appear to connect the HI5 to autophagy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  review:
    summary: This annotation comes from a proteome-scale liver interaction map,
      not a mechanistic CALCOCO2 study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from large network studies is too broad to
      keep as a meaningful CALCOCO2 annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: This is another broad human interactome resource entry.
    action: MARK_AS_OVER_ANNOTATED
    reason: The annotation adds little biological meaning compared with the
      receptor/adaptor function supported by targeted selective-autophagy papers.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  review:
    summary: The study focuses on interaction perturbations in human genetic
      disorders, not on a specific CALCOCO2 molecular activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is too uninformative here for GO curation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  review:
    summary: This annotation comes from a large-scale alternative-splicing
      interactome analysis.
    action: MARK_AS_OVER_ANNOTATED
    reason: It does not resolve a CALCOCO2-specific molecular function beyond
      broad interaction capacity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: BioPlex-scale interaction data identified CALCOCO2-associated
      partners, but not a specific curated function.
    action: MARK_AS_OVER_ANNOTATED
    reason: A generic protein binding term from co-complex mapping is too broad
      relative to the selective-autophagy receptor function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29892012
  review:
    summary: This is an interaction-perturbation framework paper rather than a
      primary CALCOCO2 functional study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding does not capture CALCOCO2 biology in a GO-useful
      way.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  review:
    summary: The paper surveys how genetic variation disrupts protein
      interactions across the population scale.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is too indirect and nonspecific to retain as a curated CALCOCO2
      molecular function annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: This entry comes from a reference human binary interactome map.
    action: MARK_AS_OVER_ANNOTATED
    reason: A broad protein binding term from a large binary-interaction resource
      is not the right level of function for CALCOCO2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32707033
  review:
    summary: This annotation reflects kinase-network association rather than a
      focused mechanistic CALCOCO2 activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from interaction-network expansion is too
      nonspecific for retained GO curation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: Cell-line-specific interactome remodeling identifies CALCOCO2
      partners but not a specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The receptor/adaptor function should be curated directly instead of
      keeping a generic protein binding term from proteome-scale maps.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34524948
  review:
    summary: The macroautophagy proximity interactome places CALCOCO2 in pathway
      neighborhoods, but the GO term retained here is only generic protein
      binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: This dataset is pathway-relevant, but the specific function to retain
      is selective-autophagy cargo adaptor activity rather than generic binding.
- term:
    id: GO:0000421
    label: autophagosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: UniProt-based subcellular mapping is consistent with CALCOCO2 acting
      at autophagosomal membranes through LC3/GABARAP-family interactions.
    action: KEEP_AS_NON_CORE
    reason: This is a plausible mechanistic localization, but the strongest direct
      cellular-component evidence is the broader autophagosome term.
    supported_by:
    - reference_id: PMID:25771791
      supporting_text: NDP52 also promotes the maturation of autophagosomes via
        its interaction with LC3A, LC3B, and/or GABARAPL2 through a distinct
        LC3-interacting region, and with MYOSIN VI.
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: UniProt lists cytoskeleton association, but I did not review the
      underlying primary publication supporting that specific localization.
    action: UNDECIDED
    reason: This may reflect a context-dependent association rather than a stable
      core localization, and the key supporting paper was not available in the
      local cache.
    supported_by:
    - reference_id: file:human/CALCOCO2/CALCOCO2-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Perinuclear cytoplasmic localization is consistent with the reviewed
      UniProt entry and with older direct microscopy.
    action: KEEP_AS_NON_CORE
    reason: This is a supported but contextual localization that should not be
      confused with the core autophagy-adaptor role.
    supported_by:
    - reference_id: file:human/CALCOCO2/CALCOCO2-uniprot.txt
      supporting_text: Cytoplasm, perinuclear region
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Cytosolic localization is consistent with CALCOCO2 acting as a
      cytosolic receptor for damaged vesicles, bacteria, and mitochondria.
    action: ACCEPT
    reason: Cytosolic localization is a core prerequisite for CALCOCO2's
      selective-autophagy receptor function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23022382
  review:
    summary: This paper defines the functionally important CALCOCO2-LC3C
      interaction required for antibacterial autophagy.
    action: MODIFY
    reason: Generic protein binding is too vague; the biology is better captured
      as autophagy cargo adaptor activity.
    proposed_replacement_terms:
    - id: GO:0160247
      label: autophagy cargo adaptor activity
    supported_by:
    - reference_id: PMID:23022382
      supporting_text: the selectivity of the autophagy receptor NDP52 for LC3C
        is crucial for innate immunity
- term:
    id: GO:0098792
    label: xenophagy
  evidence_type: IMP
  original_reference_id: PMID:23022382
  review:
    summary: Direct perturbation experiments support CALCOCO2/NDP52 as required
      for antibacterial autophagy.
    action: ACCEPT
    reason: This is a core selective-autophagy process for CALCOCO2.
    supported_by:
    - reference_id: PMID:23022382
      supporting_text: LC3C is required for antibacterial autophagy
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34389544
  review:
    summary: Structural and biochemical work dissects CALCOCO2 interactions with
      RB1CC1, NAP1, TBK1, and ATG8-family machinery during selective autophagy
      initiation.
    action: MODIFY
    reason: The underlying biology is receptor/adaptor function in selective
      autophagy, not generic protein binding.
    proposed_replacement_terms:
    - id: GO:0160247
      label: autophagy cargo adaptor activity
    supported_by:
    - reference_id: PMID:34389544
      supporting_text: NDP52 (also known as CALCOCO2) is a crucial
        multifunctional autophagy receptor in mammals
- term:
    id: GO:0016605
    label: PML body
  evidence_type: IDA
  original_reference_id: PMID:7540613
  review:
    summary: The original NDP52/PML-body assignment does not hold up against the
      later direct re-evaluation of localization.
    action: REMOVE
    reason: Better evidence indicates CALCOCO2 is mainly cytoplasmic and not a
      bona fide PML-body component.
    supported_by:
    - reference_id: PMID:9230084
      supporting_text: These data imply that NDP52 forms homodimers but no
        heterodimers with Sp100 and PML, lacks autoantigenicity in PBC,
        localizes mainly in the cytoplasm, and is associated with the nucleus,
        but not with NDs.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22246324
  review:
    summary: The galectin-8 study shows a specific CALCOCO2 interaction that
      activates antibacterial autophagy.
    action: MODIFY
    reason: The mechanistically meaningful function is selective-autophagy cargo
      adaptor activity, not generic protein binding.
    proposed_replacement_terms:
    - id: GO:0160247
      label: autophagy cargo adaptor activity
    supported_by:
    - reference_id: PMID:22246324
      supporting_text: We found in a LUMIER assay that galectin-8 and NDP52
        interacted specifically
    - reference_id: PMID:22246324
      supporting_text: By recruiting NDP52 (also known as CALCOCO2), galectin 8
        activates antibacterial autophagy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23245322
  review:
    summary: The LRSAM1 study places CALCOCO2/NDP52 in ubiquitin-dependent
      antibacterial autophagy and documents a direct CALCOCO2-LRSAM1 interaction.
    action: MODIFY
    reason: The biologically useful curation target is CALCOCO2's cargo-adaptor
      role in selective autophagy rather than generic protein binding.
    proposed_replacement_terms:
    - id: GO:0160247
      label: autophagy cargo adaptor activity
    supported_by:
    - reference_id: PMID:23245322
      supporting_text: The ubiquitinated coat is bound by ubiquitin interacting
        autophagy adaptor proteins (e.g., NDP52 and p62), resulting in
        recruitment of autophagic machinery
    - reference_id: PMID:23245322
      supporting_text: We observed an interaction between LRSAM1 and NDP52, but
        not GABARAPL2, LC3, or p62
- term:
    id: GO:0005776
    label: autophagosome
  evidence_type: IDA
  original_reference_id: PMID:25771791
  review:
    summary: CALCOCO2/NDP52 is directly implicated at pathogen-containing
      autophagosomes during antibacterial autophagy.
    action: ACCEPT
    reason: This is core subcellular biology for CALCOCO2's validated
      selective-autophagy role.
    supported_by:
    - reference_id: PMID:25771791
      supporting_text: complete xenophagy is selectively regulated by a single
        autophagy receptor, which initially orchestrates bacteria targeting to
        autophagosomes and subsequently ensures pathogen degradation by
        regulating pathogen-containing autophagosome maturation.
- term:
    id: GO:0098792
    label: xenophagy
  evidence_type: IMP
  original_reference_id: PMID:25771791
  review:
    summary: Perturbation evidence shows CALCOCO2 controls both targeting and
      maturation steps in pathogen-selective autophagy.
    action: ACCEPT
    reason: Xenophagy is a primary, literature-supported CALCOCO2 process.
    supported_by:
    - reference_id: PMID:25771791
      supporting_text: complete xenophagy is selectively regulated by a single
        autophagy receptor, which initially orchestrates bacteria targeting to
        autophagosomes and subsequently ensures pathogen degradation by
        regulating pathogen-containing autophagosome maturation.
- term:
    id: GO:1901098
    label: positive regulation of autophagosome maturation
  evidence_type: IMP
  original_reference_id: PMID:25771791
  review:
    summary: This paper specifically supports CALCOCO2 as a regulator of late
      pathogen-containing autophagosome maturation.
    action: KEEP_AS_NON_CORE
    reason: The term is valid, but it captures a later step downstream of the core
      receptor/adaptor function.
    supported_by:
    - reference_id: PMID:25771791
      supporting_text: NDP52 also promotes the maturation of autophagosomes via
        its interaction with LC3A, LC3B, and/or GABARAPL2 through a distinct
        LC3-interacting region, and with MYOSIN VI.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    summary: Membrane-proteome detection is compatible with transient association
      during autophagy, but the term itself is overly broad for CALCOCO2.
    action: MARK_AS_OVER_ANNOTATED
    reason: More informative and biologically grounded locations are autophagosome,
      cytosol, and perinuclear cytoplasm; CALCOCO2 is not best described as a
      generic membrane component.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: The remaining species were largely involved in cellular
        processes and molecular functions that could be predicted to be
        transiently associated with membranes.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:9230084
  review:
    summary: Later localization work found CALCOCO2/NDP52 to be mainly
      cytoplasmic, not a nuclear-dot protein.
    action: ACCEPT
    reason: Cytoplasmic localization is strongly supported and is fundamental to
      the selective-autophagy receptor role.
    supported_by:
    - reference_id: PMID:9230084
      supporting_text: Our NDP52-specific sera revealed mainly cytoplasmic
        staining but no ND pattern, neither in untreated nor in IFN-treated
        cells.
- term:
    id: GO:0034341
    label: response to type II interferon
  evidence_type: IDA
  original_reference_id: PMID:9230084
  review:
    summary: The localization study explicitly reported only marginal induction by
      IFN-gamma and no clear interferon-driven relocalization phenotype.
    action: REMOVE
    reason: The evidence does not justify a robust biological-process annotation to
      response to type II interferon.
    supported_by:
    - reference_id: PMID:9230084
      supporting_text: NDP52 mRNA and protein levels were only marginally
        enhanced by IFN gamma and not enhanced at all by IFN beta.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:9230084
  review:
    summary: CALCOCO2/NDP52 homodimerization was directly demonstrated.
    action: KEEP_AS_NON_CORE
    reason: This is a valid molecular feature but is not the main function to
      foreground relative to selective-autophagy adaptor biology.
    supported_by:
    - reference_id: PMID:9230084
      supporting_text: NDP52 homodimerization but no heterodimerization with
        Sp100 or PML could be demonstrated.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:9230084
  review:
    summary: Perinuclear cytoplasmic staining is compatible with the broader
      cytoplasmic localization described in the revised localization study.
    action: KEEP_AS_NON_CORE
    reason: This is a supported but contextual sublocalization rather than a core
      statement about CALCOCO2 function.
    supported_by:
    - reference_id: file:human/CALCOCO2/CALCOCO2-uniprot.txt
      supporting_text: Cytoplasm, perinuclear region
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12869526
  review:
    summary: A direct HCAP1/GEMIN4 interaction was reported, but the annotation
      remains generic and peripheral to CALCOCO2's established biology.
    action: MARK_AS_OVER_ANNOTATED
    reason: This isolated interaction does not define a useful GO molecular
      function for CALCOCO2 compared with the well-supported autophagy adaptor
      role.
    supported_by:
    - reference_id: PMID:12869526
      supporting_text: Then, the interaction between HCAP1 and NDP52 was
        confirmed by GST pull-down assay and a coimmunoprecipitation experiment.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:7540613
  review:
    summary: Later work supports nucleus association in fractions, but not
      PML-body localization or a nucleus-centered function.
    action: KEEP_AS_NON_CORE
    reason: Nuclear association is not the main CALCOCO2 biology, but a minor or
      contextual localization cannot be excluded.
    supported_by:
    - reference_id: PMID:9230084
      supporting_text: In subcellular fractionation experiments, NDP52 was found
        in cytoplasmic and nuclear fractions.
- term:
    id: GO:0016032
    label: viral process
  evidence_type: TAS
  original_reference_id: PMID:7540613
  review:
    summary: Virus-associated redistribution observations do not establish
      CALCOCO2 as directly involved in viral process in a GO-curatable way.
    action: REMOVE
    reason: The evidence is observational and predates the clearer selective
      autophagy receptor framework for CALCOCO2.
    supported_by:
    - reference_id: PMID:7540613
      supporting_text: Molecular characterization of NDP52, a novel protein of
        the nuclear domain 10, which is redistributed upon virus infection and
        interferon treatment.
- term:
    id: GO:0160247
    label: autophagy cargo adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:23022382
  review:
    summary: CALCOCO2/NDP52 is a selective-autophagy receptor that recognizes
      cargo-associated signals and recruits autophagy machinery through LC3/GABARAP-
      and ULK-complex-linked interactions.
    action: NEW
    reason: This is the most specific molecular-function term capturing the core
      CALCOCO2 biology that is currently missing from GOA.
    supported_by:
    - reference_id: PMID:22246324
      supporting_text: By recruiting NDP52 (also known as CALCOCO2), galectin 8
        activates antibacterial autophagy.
    - reference_id: PMID:23022382
      supporting_text: the selectivity of the autophagy receptor NDP52 for LC3C
        is crucial for innate immunity
    - reference_id: PMID:26266977
      supporting_text: Once recruited to mitochondria, NDP52 and optineurin
        recruit the autophagy factors ULK1, DFCP1 and WIPI1 to focal spots
        proximal to mitochondria
- term:
    id: GO:0000423
    label: mitophagy
  evidence_type: IMP
  original_reference_id: PMID:26266977
  review:
    summary: CALCOCO2/NDP52 is directly required for PINK1/Parkin-linked
      mitophagy and recruits upstream autophagy-initiation factors to damaged
      mitochondria.
    action: NEW
    reason: This PN-aligned process assignment is strongly supported in the
      literature and is currently absent from the local GOA seed.
    supported_by:
    - reference_id: PMID:26266977
      supporting_text: two receptors previously linked to xenophagy, NDP52 and
        optineurin, are the primary receptors for PINK1- and parkin-mediated
        mitophagy.
    - reference_id: PMID:30853401
      supporting_text: ectopic placement of NDP52 on mitochondria or peroxisomes
        is sufficient to initiate selective autophagy by focally localizing and
        activating the ULK1 complex.
- term:
    id: GO:0061909
    label: autophagosome-lysosome fusion
  evidence_type: IMP
  original_reference_id: PMID:34382418
  review:
    summary: CALCOCO2 also has a supported late-stage role in promoting
      autophagosome-lysosome fusion and mitophagy flux.
    action: NEW
    reason: The evidence supports a contextual late-autophagy function that is
      distinct from, and secondary to, the core cargo-adaptor role.
    supported_by:
    - reference_id: PMID:34382418
      supporting_text: NDP52 promoted mitophagy flux through the recruitment of
        Ras-associated protein RAB7 (RAB7) and TANK-binding kinase 1 (TBK1).
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: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: file:human/CALCOCO2/CALCOCO2-uniprot.txt
  title: UniProtKB reviewed entry for human CALCOCO2 (Q13137)
  findings:
  - statement: Reviewed UniProt entry places CALCOCO2 in the cytoplasm,
      perinuclear cytoplasm, cytoskeleton, and autophagosome-related compartments
    supporting_text: Cytoplasm, perinuclear region
- id: PMID:12869526
  title: HCC-associated protein HCAP1, a variant of GEMIN4, interacts with zinc-finger
    proteins.
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:18330356
  title: Construction and characterization of a normalized yeast two-hybrid library
    derived from a human protein-coding clone collection.
  findings: []
- id: PMID:18985028
  title: Hepatitis C virus infection protein network.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
- id: PMID:21903422
  title: Mapping a dynamic innate immunity protein interaction network regulating
    type I interferon production.
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:22246324
  title: Galectin 8 targets damaged vesicles for autophagy to defend cells against
    bacterial invasion.
  findings:
  - statement: Galectin-8 recruits CALCOCO2/NDP52 to damaged pathogen-containing
      vacuoles to activate antibacterial autophagy
    supporting_text: By recruiting NDP52 (also known as CALCOCO2), galectin 8
      activates antibacterial autophagy.
- id: PMID:23022382
  title: LC3C, bound selectively by a noncanonical LIR motif in NDP52, is required
    for antibacterial autophagy.
  findings:
  - statement: NDP52-LC3C selectivity is functionally important for antibacterial
      autophagy
    supporting_text: the selectivity of the autophagy receptor NDP52 for LC3C is
      crucial for innate immunity
- id: PMID:23245322
  title: The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent
    autophagy of intracellular Salmonella Typhimurium.
  findings:
  - statement: NDP52 acts as a ubiquitin-dependent antibacterial autophagy adaptor
    supporting_text: The ubiquitinated coat is bound by ubiquitin interacting
      autophagy adaptor proteins (e.g., NDP52 and p62), resulting in recruitment
      of autophagic machinery
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:25771791
  title: Autophagy receptor NDP52 regulates pathogen-containing autophagosome maturation.
  findings:
  - statement: CALCOCO2/NDP52 promotes pathogen-containing autophagosome
      maturation in xenophagy
    supporting_text: NDP52 also promotes the maturation of autophagosomes via its
      interaction with LC3A, LC3B, and/or GABARAPL2 through a distinct
      LC3-interacting region, and with MYOSIN VI.
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
- id: PMID:26266977
  title: The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy.
  findings:
  - statement: CALCOCO2/NDP52 is a primary receptor for PINK1/Parkin-mediated
      mitophagy
    supporting_text: two receptors previously linked to xenophagy, NDP52 and
      optineurin, are the primary receptors for PINK1- and parkin-mediated
      mitophagy.
- id: PMID:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:29892012
  title: An interactome perturbation framework prioritizes damaging missense mutations
    for developmental disorders.
  findings: []
- id: PMID:30853401
  title: Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective
    Autophagy.
  findings:
  - statement: Targeted mitochondrial CALCOCO2/NDP52 is sufficient to initiate
      selective autophagy through ULK1 activation
    supporting_text: ectopic placement of NDP52 on mitochondria or peroxisomes is
      sufficient to initiate selective autophagy by focally localizing and
      activating the ULK1 complex.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32707033
  title: Kinase Interaction Network Expands Functional and Disease Roles of Human
    Kinases.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34382418
  title: NDP52 Protects Against Myocardial Infarction-Provoked Cardiac Anomalies
    Through Promoting Autophagosome-Lysosome Fusion via Recruiting TBK1 and RAB7.
  findings:
  - statement: CALCOCO2/NDP52 promotes late mitophagy flux through a fusion-linked
      TBK1-RAB7 pathway
    supporting_text: NDP52 promoted mitophagy flux through the recruitment of
      Ras-associated protein RAB7 (RAB7) and TANK-binding kinase 1 (TBK1).
- id: PMID:34389544
  title: Structural and biochemical advances on the recruitment of the autophagy-initiating
    ULK and TBK1 complexes by autophagy receptor NDP52.
  findings: []
- id: PMID:34524948
  title: Global Proximity Interactome of the Human Macroautophagy Pathway.
  findings: []
- id: PMID:7540613
  title: Molecular characterization of NDP52, a novel protein of the nuclear domain
    10, which is redistributed upon virus infection and interferon treatment.
  findings: []
- id: PMID:9230084
  title: Cellular localization, expression, and structure of the nuclear dot protein
    52.
  findings:
  - statement: CALCOCO2/NDP52 localizes mainly in the cytoplasm rather than in
      nuclear dots
    supporting_text: Our NDP52-specific sera revealed mainly cytoplasmic staining
      but no ND pattern, neither in untreated nor in IFN-treated cells.
  - statement: CALCOCO2/NDP52 forms homodimers
    supporting_text: NDP52 homodimerization but no heterodimerization with Sp100
      or PML could be demonstrated.
core_functions:
- description: CALCOCO2/NDP52 is a selective-autophagy cargo adaptor that
    recognizes cargo-associated damage or ubiquitin-linked signals and recruits
    autophagy machinery through LC3/GABARAP- and ULK-complex-linked interactions.
    This receptor function underlies its best-supported biology in xenophagy and
    mitophagy.
  molecular_function:
    id: GO:0160247
    label: autophagy cargo adaptor activity
  directly_involved_in:
  - id: GO:0098792
    label: xenophagy
  - id: GO:0000423
    label: mitophagy
  locations:
  - id: GO:0005776
    label: autophagosome
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:22246324
    supporting_text: By recruiting NDP52 (also known as CALCOCO2), galectin 8
      activates antibacterial autophagy.
  - reference_id: PMID:26266977
    supporting_text: Once recruited to mitochondria, NDP52 and optineurin recruit
      the autophagy factors ULK1, DFCP1 and WIPI1 to focal spots proximal to
      mitochondria
proposed_new_terms: []
suggested_questions:
- question: Which cargo-recognition routes are sufficiently general to annotate at
    the CALCOCO2 gene-product level, and which are cargo- or context-specific
    extensions of the same adaptor activity?
- question: When should CALCOCO2 late-stage autophagy roles be captured as
    separate process annotations versus downstream consequences of cargo-adaptor
    activity?
suggested_experiments:
- description: Separation-of-function mutagenesis to distinguish cargo recognition
    and recruitment activities from later autophagosome maturation or fusion roles
  hypothesis: CALCOCO2 uses partially separable interfaces for initial cargo
    capture versus late autophagic flux control.
- description: Side-by-side perturbation assays in bacterial damage,
    mitochondrial depolarization, and lysosomal damage models
  hypothesis: CALCOCO2 has a conserved core adaptor activity with cargo-context-
    specific downstream dependencies.
tags:
- selective-autophagy
- xenophagy
- mitophagy