CALCOCO2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005776 autophagosome	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference to autophagosome localization is consistent with direct experimental work placing CALCOCO2/NDP52 on pathogen-containing autophagosomes during selective autophagy. Reason: Autophagosome localization is part of the core receptor/adaptor role of CALCOCO2 in selective autophagy. Supporting Evidence: PMID:25771791 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.
GO:0016605 PML body	IBA GO_REF:0000033	REMOVE	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. Reason: Later direct evidence argues that CALCOCO2 is not a PML-body protein; the earlier assignment is likely an overinterpretation of early antibody staining. Supporting Evidence: PMID:9230084 Our NDP52-specific sera revealed mainly cytoplasmic staining but no ND pattern, neither in untreated nor in IFN-treated cells.
GO:0098792 xenophagy	IBA GO_REF:0000033	ACCEPT	Summary: Xenophagy is a well-supported core CALCOCO2 function, and the IBA is reinforced by direct human-cell studies on antibacterial autophagy. Reason: CALCOCO2/NDP52 is a canonical selective-autophagy receptor for cytosol-exposed intracellular bacteria. Supporting Evidence: PMID:22246324 By recruiting NDP52 (also known as CALCOCO2), galectin 8 activates antibacterial autophagy. PMID:25771791 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. file:human/CALCOCO2/CALCOCO2-deep-research-falcon.md CALCOCO2/NDP52 recognizes ubiquitin-coated bacteria and can also bind galectin-8
GO:1901098 positive regulation of autophagosome maturation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: CALCOCO2 promotes maturation of pathogen-containing autophagosomes after initial cargo capture. Reason: This is a supported downstream role within xenophagy, but it is more contextual than the core cargo-adaptor activity itself. Supporting Evidence: PMID:25771791 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.
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: This is an early large-scale human interactome entry rather than a mechanistically informative CALCOCO2 function annotation. Reason: Generic protein binding from a proteome-scale interaction map is too nonspecific to retain once CALCOCO2's receptor-level autophagy function is known.
GO:0005515 protein binding	IPI PMID:18330356 Construction and characterization of a normalized yeast two-...	MARK AS OVER ANNOTATED	Summary: This annotation derives from normalized yeast two-hybrid resource development rather than a focused CALCOCO2 functional study. Reason: Generic protein binding from broad interaction-library screening is not an informative CALCOCO2 molecular function term.
GO:0005515 protein binding	IPI PMID:18985028 Hepatitis C virus infection protein network.	MARK AS OVER ANNOTATED	Summary: The paper is a host-virus interaction network study and does not establish a specific CALCOCO2 molecular function beyond generic binding. Reason: The selective-autophagy receptor role is the biologically meaningful function to retain; generic host-virus network binding is too broad.
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	MARK AS OVER ANNOTATED	Summary: This is a high-throughput interactome methodology paper rather than a focused functional analysis of CALCOCO2. Reason: Generic protein binding from large-scale interactome generation is too nonspecific for curated GO retention.
GO:0005515 protein binding	IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ...	MARK AS OVER ANNOTATED	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. Reason: The network context is interesting, but a protein binding annotation does not capture the receptor/adaptor function that matters for GO. Supporting Evidence: PMID:21903422 At least four proteins (CALCOCO2, ATG7, ATG9A, and RB1CC1) appear to connect the HI5 to autophagy.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MARK AS OVER ANNOTATED	Summary: This annotation comes from a proteome-scale liver interaction map, not a mechanistic CALCOCO2 study. Reason: Generic protein binding from large network studies is too broad to keep as a meaningful CALCOCO2 annotation.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: This is another broad human interactome resource entry. Reason: The annotation adds little biological meaning compared with the receptor/adaptor function supported by targeted selective-autophagy papers.
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	MARK AS OVER ANNOTATED	Summary: The study focuses on interaction perturbations in human genetic disorders, not on a specific CALCOCO2 molecular activity. Reason: Generic protein binding is too uninformative here for GO curation.
GO:0005515 protein binding	IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ...	MARK AS OVER ANNOTATED	Summary: This annotation comes from a large-scale alternative-splicing interactome analysis. Reason: It does not resolve a CALCOCO2-specific molecular function beyond broad interaction capacity.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: BioPlex-scale interaction data identified CALCOCO2-associated partners, but not a specific curated function. Reason: A generic protein binding term from co-complex mapping is too broad relative to the selective-autophagy receptor function.
GO:0005515 protein binding	IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m...	MARK AS OVER ANNOTATED	Summary: This is an interaction-perturbation framework paper rather than a primary CALCOCO2 functional study. Reason: Generic protein binding does not capture CALCOCO2 biology in a GO-useful way.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: The paper surveys how genetic variation disrupts protein interactions across the population scale. Reason: This is too indirect and nonspecific to retain as a curated CALCOCO2 molecular function annotation.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: This entry comes from a reference human binary interactome map. Reason: A broad protein binding term from a large binary-interaction resource is not the right level of function for CALCOCO2.
GO:0005515 protein binding	IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro...	MARK AS OVER ANNOTATED	Summary: This annotation reflects kinase-network association rather than a focused mechanistic CALCOCO2 activity. Reason: Generic protein binding from interaction-network expansion is too nonspecific for retained GO curation.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Cell-line-specific interactome remodeling identifies CALCOCO2 partners but not a specific molecular function. Reason: The receptor/adaptor function should be curated directly instead of keeping a generic protein binding term from proteome-scale maps.
GO:0005515 protein binding	IPI PMID:34524948 Global Proximity Interactome of the Human Macroautophagy Pat...	MARK AS OVER ANNOTATED	Summary: The macroautophagy proximity interactome places CALCOCO2 in pathway neighborhoods, but the GO term retained here is only generic protein binding. Reason: This dataset is pathway-relevant, but the specific function to retain is selective-autophagy cargo adaptor activity rather than generic binding.
GO:0000421 autophagosome membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt-based subcellular mapping is consistent with CALCOCO2 acting at autophagosomal membranes through LC3/GABARAP-family interactions. Reason: This is a plausible mechanistic localization, but the strongest direct cellular-component evidence is the broader autophagosome term. Supporting Evidence: PMID:25771791 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.
GO:0005856 cytoskeleton	IEA GO_REF:0000044	UNDECIDED	Summary: UniProt lists cytoskeleton association, but I did not review the underlying primary publication supporting that specific localization. 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. Supporting Evidence: file:human/CALCOCO2/CALCOCO2-uniprot.txt Cytoplasm, cytoskeleton
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Perinuclear cytoplasmic localization is consistent with the reviewed UniProt entry and with older direct microscopy. Reason: This is a supported but contextual localization that should not be confused with the core autophagy-adaptor role. Supporting Evidence: file:human/CALCOCO2/CALCOCO2-uniprot.txt Cytoplasm, perinuclear region
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Cytosolic localization is consistent with CALCOCO2 acting as a cytosolic receptor for damaged vesicles, bacteria, and mitochondria. Reason: Cytosolic localization is a core prerequisite for CALCOCO2's selective-autophagy receptor function.
GO:0005515 protein binding	IPI PMID:23022382 LC3C, bound selectively by a noncanonical LIR motif in NDP52...	MODIFY	Summary: This paper defines the functionally important CALCOCO2-LC3C interaction required for antibacterial autophagy. Reason: Generic protein binding is too vague; the biology is better captured as autophagy cargo adaptor activity. Proposed replacements: autophagy cargo adaptor activity Supporting Evidence: PMID:23022382 the selectivity of the autophagy receptor NDP52 for LC3C is crucial for innate immunity
GO:0098792 xenophagy	IMP PMID:23022382 LC3C, bound selectively by a noncanonical LIR motif in NDP52...	ACCEPT	Summary: Direct perturbation experiments support CALCOCO2/NDP52 as required for antibacterial autophagy. Reason: This is a core selective-autophagy process for CALCOCO2. Supporting Evidence: PMID:23022382 LC3C is required for antibacterial autophagy
GO:0005515 protein binding	IPI PMID:34389544 Structural and biochemical advances on the recruitment of th...	MODIFY	Summary: Structural and biochemical work dissects CALCOCO2 interactions with RB1CC1, NAP1, TBK1, and ATG8-family machinery during selective autophagy initiation. Reason: The underlying biology is receptor/adaptor function in selective autophagy, not generic protein binding. Proposed replacements: autophagy cargo adaptor activity Supporting Evidence: PMID:34389544 NDP52 (also known as CALCOCO2) is a crucial multifunctional autophagy receptor in mammals
GO:0016605 PML body	IDA PMID:7540613 Molecular characterization of NDP52, a novel protein of the ...	REMOVE	Summary: The original NDP52/PML-body assignment does not hold up against the later direct re-evaluation of localization. Reason: Better evidence indicates CALCOCO2 is mainly cytoplasmic and not a bona fide PML-body component. Supporting Evidence: PMID:9230084 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.
GO:0005515 protein binding	IPI PMID:22246324 Galectin 8 targets damaged vesicles for autophagy to defend ...	MODIFY	Summary: The galectin-8 study shows a specific CALCOCO2 interaction that activates antibacterial autophagy. Reason: The mechanistically meaningful function is selective-autophagy cargo adaptor activity, not generic protein binding. Proposed replacements: autophagy cargo adaptor activity Supporting Evidence: PMID:22246324 We found in a LUMIER assay that galectin-8 and NDP52 interacted specifically PMID:22246324 By recruiting NDP52 (also known as CALCOCO2), galectin 8 activates antibacterial autophagy.
GO:0005515 protein binding	IPI PMID:23245322 The LRR and RING domain protein LRSAM1 is an E3 ligase cruci...	MODIFY	Summary: The LRSAM1 study places CALCOCO2/NDP52 in ubiquitin-dependent antibacterial autophagy and documents a direct CALCOCO2-LRSAM1 interaction. Reason: The biologically useful curation target is CALCOCO2's cargo-adaptor role in selective autophagy rather than generic protein binding. Proposed replacements: autophagy cargo adaptor activity Supporting Evidence: PMID:23245322 The ubiquitinated coat is bound by ubiquitin interacting autophagy adaptor proteins (e.g., NDP52 and p62), resulting in recruitment of autophagic machinery PMID:23245322 We observed an interaction between LRSAM1 and NDP52, but not GABARAPL2, LC3, or p62
GO:0005776 autophagosome	IDA PMID:25771791 Autophagy receptor NDP52 regulates pathogen-containing autop...	ACCEPT	Summary: CALCOCO2/NDP52 is directly implicated at pathogen-containing autophagosomes during antibacterial autophagy. Reason: This is core subcellular biology for CALCOCO2's validated selective-autophagy role. Supporting Evidence: PMID:25771791 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.
GO:0098792 xenophagy	IMP PMID:25771791 Autophagy receptor NDP52 regulates pathogen-containing autop...	ACCEPT	Summary: Perturbation evidence shows CALCOCO2 controls both targeting and maturation steps in pathogen-selective autophagy. Reason: Xenophagy is a primary, literature-supported CALCOCO2 process. Supporting Evidence: PMID:25771791 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.
GO:1901098 positive regulation of autophagosome maturation	IMP PMID:25771791 Autophagy receptor NDP52 regulates pathogen-containing autop...	KEEP AS NON CORE	Summary: This paper specifically supports CALCOCO2 as a regulator of late pathogen-containing autophagosome maturation. Reason: The term is valid, but it captures a later step downstream of the core receptor/adaptor function. Supporting Evidence: PMID:25771791 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.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: Membrane-proteome detection is compatible with transient association during autophagy, but the term itself is overly broad for CALCOCO2. Reason: More informative and biologically grounded locations are autophagosome, cytosol, and perinuclear cytoplasm; CALCOCO2 is not best described as a generic membrane component. Supporting Evidence: PMID:19946888 The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes.
GO:0005737 cytoplasm	IDA PMID:9230084 Cellular localization, expression, and structure of the nucl...	ACCEPT	Summary: Later localization work found CALCOCO2/NDP52 to be mainly cytoplasmic, not a nuclear-dot protein. Reason: Cytoplasmic localization is strongly supported and is fundamental to the selective-autophagy receptor role. Supporting Evidence: PMID:9230084 Our NDP52-specific sera revealed mainly cytoplasmic staining but no ND pattern, neither in untreated nor in IFN-treated cells.
GO:0034341 response to type II interferon	IDA PMID:9230084 Cellular localization, expression, and structure of the nucl...	REMOVE	Summary: The localization study explicitly reported only marginal induction by IFN-gamma and no clear interferon-driven relocalization phenotype. Reason: The evidence does not justify a robust biological-process annotation to response to type II interferon. Supporting Evidence: PMID:9230084 NDP52 mRNA and protein levels were only marginally enhanced by IFN gamma and not enhanced at all by IFN beta.
GO:0042803 protein homodimerization activity	IPI PMID:9230084 Cellular localization, expression, and structure of the nucl...	KEEP AS NON CORE	Summary: CALCOCO2/NDP52 homodimerization was directly demonstrated. Reason: This is a valid molecular feature but is not the main function to foreground relative to selective-autophagy adaptor biology. Supporting Evidence: PMID:9230084 NDP52 homodimerization but no heterodimerization with Sp100 or PML could be demonstrated.
GO:0048471 perinuclear region of cytoplasm	IDA PMID:9230084 Cellular localization, expression, and structure of the nucl...	KEEP AS NON CORE	Summary: Perinuclear cytoplasmic staining is compatible with the broader cytoplasmic localization described in the revised localization study. Reason: This is a supported but contextual sublocalization rather than a core statement about CALCOCO2 function. Supporting Evidence: file:human/CALCOCO2/CALCOCO2-uniprot.txt Cytoplasm, perinuclear region
GO:0005515 protein binding	IPI PMID:12869526 HCC-associated protein HCAP1, a variant of GEMIN4, interacts...	MARK AS OVER ANNOTATED	Summary: A direct HCAP1/GEMIN4 interaction was reported, but the annotation remains generic and peripheral to CALCOCO2's established biology. Reason: This isolated interaction does not define a useful GO molecular function for CALCOCO2 compared with the well-supported autophagy adaptor role. Supporting Evidence: PMID:12869526 Then, the interaction between HCAP1 and NDP52 was confirmed by GST pull-down assay and a coimmunoprecipitation experiment.
GO:0005634 nucleus	TAS PMID:7540613 Molecular characterization of NDP52, a novel protein of the ...	KEEP AS NON CORE	Summary: Later work supports nucleus association in fractions, but not PML-body localization or a nucleus-centered function. Reason: Nuclear association is not the main CALCOCO2 biology, but a minor or contextual localization cannot be excluded. Supporting Evidence: PMID:9230084 In subcellular fractionation experiments, NDP52 was found in cytoplasmic and nuclear fractions. file:human/CALCOCO2/CALCOCO2-deep-research-falcon.md CALCOCO2/NDP52 has a mechanistically supported nuclear role
GO:0016032 viral process	TAS PMID:7540613 Molecular characterization of NDP52, a novel protein of the ...	REMOVE	Summary: Virus-associated redistribution observations do not establish CALCOCO2 as directly involved in viral process in a GO-curatable way. Reason: The evidence is observational and predates the clearer selective autophagy receptor framework for CALCOCO2. Supporting Evidence: PMID:7540613 Molecular characterization of NDP52, a novel protein of the nuclear domain 10, which is redistributed upon virus infection and interferon treatment.
GO:0160247 autophagy cargo adaptor activity	IDA PMID:23022382 LC3C, bound selectively by a noncanonical LIR motif in NDP52...	NEW	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. Reason: This is the most specific molecular-function term capturing the core CALCOCO2 biology that is currently missing from GOA. Supporting Evidence: PMID:22246324 By recruiting NDP52 (also known as CALCOCO2), galectin 8 activates antibacterial autophagy. PMID:23022382 the selectivity of the autophagy receptor NDP52 for LC3C is crucial for innate immunity PMID:26266977 Once recruited to mitochondria, NDP52 and optineurin recruit the autophagy factors ULK1, DFCP1 and WIPI1 to focal spots proximal to mitochondria file:human/CALCOCO2/CALCOCO2-deep-research-falcon.md A selective autophagy receptor/adapter that recognizes ubiquitin chains
GO:0000423 mitophagy	IMP PMID:26266977 The ubiquitin kinase PINK1 recruits autophagy receptors to i...	NEW	Summary: CALCOCO2/NDP52 is directly required for PINK1/Parkin-linked mitophagy and recruits upstream autophagy-initiation factors to damaged mitochondria. Reason: This PN-aligned process assignment is strongly supported in the literature and is currently absent from the local GOA seed. Supporting Evidence: PMID:26266977 two receptors previously linked to xenophagy, NDP52 and optineurin, are the primary receptors for PINK1- and parkin-mediated mitophagy. PMID:30853401 ectopic placement of NDP52 on mitochondria or peroxisomes is sufficient to initiate selective autophagy by focally localizing and activating the ULK1 complex. file:human/CALCOCO2/CALCOCO2-deep-research-falcon.md CALCOCO2/NDP52 is not only a cargo tether but also an initiator/scaffold
GO:0061909 autophagosome-lysosome fusion	IMP PMID:34382418 NDP52 Protects Against Myocardial Infarction-Provoked Cardia...	NEW	Summary: CALCOCO2 also has a supported late-stage role in promoting autophagosome-lysosome fusion and mitophagy flux. Reason: The evidence supports a contextual late-autophagy function that is distinct from, and secondary to, the core cargo-adaptor role. Supporting Evidence: PMID:34382418 NDP52 promoted mitophagy flux through the recruitment of Ras-associated protein RAB7 (RAB7) and TANK-binding kinase 1 (TBK1). file:human/CALCOCO2/CALCOCO2-deep-research-falcon.md NDP52 and OPTN form sheet-like liquid condensates on ubiquitinated mitochondria during mitophagy

Gene Description

Existing Annotations Review

Core Functions

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.

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