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Showing CALCOCO2 — NDP52 is a alias.

CALCOCO2

Calcium-binding and coiled-coil domain-containing protein 2 · UniProt Q13137

Length
446 aa
Mass
52.3 kDa
Annotated
2026-06-09
73 papers in source corpus 45 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CALCOCO2/NDP52 is a multifunctional selective autophagy receptor that bridges ubiquitin-marked cargo — cytosolic bacteria, damaged mitochondria, and signaling proteins — to the autophagosome biogenesis machinery and autophagosomal membranes (PMID:19820708, PMID:20104023, PMID:26365381). It recognizes ubiquitinated cargo through its C2H2-type zinc finger, which binds mono- and poly-ubiquitin via a distinctive zinc-finger ubiquitin-binding mode (PMID:26506893), and engages galectin-8-coated damaged vacuoles through a selective interface that excludes other galectins (PMID:23511477, PMID:23386746). To nucleate autophagy, NDP52 forms a trimeric assembly with FIP200 (ULK complex) and SINTBAD/NAP1 (TBK1 complex) through distinct binding sites, recruiting and focally activating the ULK1 initiation machinery on cargo independently of AMPK and mTOR (PMID:30853402, PMID:30853401); structurally, NDP52 engages the FIP200 Claw domain via its SKICH domain and LIR motif and allosterically promotes ULK1-complex membrane binding (PMID:34389544, PMID:32773036). It selectively binds LC3C through a noncanonical aromatic-residue-lacking LIR essential for antibacterial autophagy (PMID:23022382), while a separate canonical LIR engaging LC3A/B and GABARAPL2 — together with myosin VI — drives autophagosome maturation and lysosomal fusion as a function distinct from cargo capture (PMID:25771791). In mitophagy, NDP52 is recruited to PINK1/PARKIN-ubiquitinated mitochondria where it and OPTN are required for TBK1 activation in a self-reinforcing feedback loop (PMID:26365381), is recruited by GTP-bound Rab35 (PMID:28848034), and acts as a redox sensor that oligomerizes via disulfide bonds upon cysteine oxidation to amplify mitochondrial clearance (PMID:36514953). NDP52 also functions as a selective autophagy receptor for innate-immune signaling molecules, mediating degradation of ubiquitinated MAVS, TRIF/TRAF6, NF-κB p65, and NOX4 to restrain inflammatory and antiviral signaling (PMID:21964925, PMID:28965816, PMID:39269442, PMID:41662915). Beyond autophagy, NDP52 acts in the nucleus, binding double-stranded DNA and partnering with myosin VI to activate RNA Polymerase II transcription (PMID:29187741, PMID:37202403). A common Val248Ala variant is associated with Crohn's disease and impairs NDP52's suppression of NF-κB-driven inflammatory gene expression (PMID:23624108).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1995 Medium

    Established NDP52 as a discrete cellular protein with defined domain architecture, before any function was known, by identifying it as a nuclear domain 10 component responsive to viral infection and interferon.

    Evidence cDNA cloning, immunofluorescence colocalization with PML, monoclonal antibody characterization

    PMID:7540613

    Open questions at the time
    • No molecular function assigned
    • Link between ND10 localization and later autophagy roles not established
    • Mechanism of interferon-induced redistribution unknown
  2. 2007 Medium

    Identified the first direct binding partner, myosin VI, and a role at the trans-Golgi as a negative regulator of secretory traffic, providing an early functional handle.

    Evidence Yeast two-hybrid, in vitro binding, co-IP, EM, RNAi with secretion readout

    PMID:17635994

    Open questions at the time
    • Relationship of Golgi traffic role to autophagy not established
    • Physiological context of secretory regulation unclear
  3. 2009 High

    Defined NDP52 as an autophagy receptor that links ubiquitin-coated cytosolic bacteria to the autophagosome by recognizing ubiquitin and recruiting TBK1 via NAP1/SINTBAD.

    Evidence siRNA knockdown, colocalization, co-IP, Salmonella proliferation assay

    PMID:19820708 PMID:20104023

    Open questions at the time
    • Structural basis of ubiquitin recognition not yet defined
    • How NDP52 connects to autophagosomal membranes molecularly not resolved
  4. 2011 Medium

    Showed NDP52 directs cargo to context-dependent autophagy pathways and acts in concert with p62 at distinct cargo microdomains, while also degrading innate-immune adaptors TRIF/TRAF6.

    Evidence siRNA knockdown, colocalization, bacterial survival assays, co-IP with signaling readout

    PMID:21079414 PMID:21646350 PMID:21964925

    Open questions at the time
    • Determinants selecting septin/actin-dependent vs -independent routes unknown
    • Mechanism of TRAF6-mediated NDP52 ubiquitination and A20 suppression not fully resolved
  5. 2012 High

    Resolved how NDP52 selects a specific ATG8 ortholog, defining the noncanonical LIR that binds LC3C and is essential for antibacterial autophagy.

    Evidence Structural analysis, mutagenesis, siRNA knockdown, bacterial survival assay

    PMID:23022382

    Open questions at the time
    • Roles of other ATG8 family members not yet defined
    • Whether LC3C binding suffices for membrane recruitment unresolved
  6. 2013 High

    Established the galectin-8 'danger receptor' connection and disease relevance, showing NDP52 exclusively binds galectin-8 to sense damaged vacuoles and that a Crohn's-associated variant impairs NF-κB regulation.

    Evidence Crystal structures of NDP52-galectin-8, binding assays, bacterial growth assays; exome sequencing with in vitro NF-κB functional studies

    PMID:23386746 PMID:23511477 PMID:23624108 PMID:23869922

    Open questions at the time
    • How galectin-8 sensing integrates with ubiquitin recognition not mechanistically unified
    • Disease variant effect in vivo not established
  7. 2014 High

    Placed NDP52 within an oxidative-stress transcriptional program and neurodegeneration, showing Nrf2 induces NDP52 to drive autophagic clearance of phosphorylated tau.

    Evidence Promoter ARE analysis, overexpression, Nrf2-KO mouse, co-IP with AD brain tissue, autophagy flux assay

    PMID:24667209

    Open questions at the time
    • Direct receptor-substrate recognition mode for tau not defined
    • Causal role in human tauopathy not established
  8. 2015 High

    Separated NDP52's two membrane-related functions and defined its ubiquitin-binding domain, establishing distinct cargo-targeting (LC3C) versus maturation (LC3A/B, GABARAPL2, myosin VI) roles and the C2H2 zinc finger as the ubiquitin sensor.

    Evidence Domain mutagenesis, co-IP, fusion assays; crystal structure of C2H2 ZF-ubiquitin complex with mutagenesis

    PMID:25771791 PMID:26506893

    Open questions at the time
    • How the two LIR functions are temporally coordinated unclear
    • Role of the second unconventional zinc finger not defined
  9. 2015 High

    Extended NDP52 to mitochondrial quality control, showing it acts with OPTN to drive TBK1 activation in a feedback loop required for PINK1/PARKIN mitophagy.

    Evidence Quantitative/phospho-proteomics, co-IP, in vitro kinase assay, siRNA knockdown, live imaging

    PMID:26365381

    Open questions at the time
    • Division of labor between NDP52 and OPTN not yet parsed
    • How TBK1 activation feeds back to receptor recruitment not fully mapped
  10. 2017 High

    Identified upstream recruitment regulators (Rab35 GTPase) and established NDP52 as a receptor for autophagic degradation of MAVS, integrating it into antiviral signaling control.

    Evidence Co-IP, GTPase binding assays, GTPase-cycle mutants, mitophagy assay; ubiquitination mapping, IFN reporter assays

    PMID:28848034 PMID:28965816

    Open questions at the time
    • How Rab35 recruitment is coordinated with ubiquitin/galectin sensing unclear
    • Generality of K27-ubiquitin-driven NDP52 recognition not established
  11. 2018 High

    Provided structural and mechanistic detail of the TBK1-adaptor interface (SKICH-NAP1) and revealed phosphoregulation and a ubiquitin-independent mitochondrial substrate (MTPAP).

    Evidence Crystal structures of SKICH-NAP1 complexes with mutagenesis; co-IP, proteasome/ubiquitin inhibitor dissection, LC3 recruitment assay

    PMID:30154446 PMID:30309841 PMID:30459273

    Open questions at the time
    • In vivo relevance of SKICH phosphorylation sites not established
    • Mechanism of ubiquitin-independent cargo engagement incompletely defined
  12. 2019 High

    Defined the autophagy initiation module, showing NDP52 forms a trimeric complex with FIP200 and SINTBAD/NAP1 and that focal NDP52 placement is sufficient to activate the ULK1 complex independently of AMPK/mTOR.

    Evidence Co-IP, point mutagenesis, CRISPR KO, xenophagy assay; chemically inducible dimerization with epistasis

    PMID:30853401 PMID:30853402

    Open questions at the time
    • How signals are integrated to time ULK1 activation in vivo unclear
    • Quantitative thresholds for receptor clustering not defined
  13. 2019 High

    Revealed ubiquitin-independent membrane recruitment of NDP52 by ATG8/GABARAPs for feedback amplification, plus non-autophagy roles in spindle orientation and RNAPII-dependent transcription.

    Evidence LIR mutagenesis with CRISPR KO mitophagy assays; TIRFM and in vitro actin assays; FLIM-FRET, FRAP, in vitro DNA binding, mRNA quantification

    PMID:29187741 PMID:30679426 PMID:31201383

    Open questions at the time
    • Whether nuclear and autophagic functions are mechanistically linked unknown
    • Physiological significance of spindle and transcription roles not established
  14. 2020 High

    Mapped the structural and biophysical basis of ULK1-complex recruitment, showing NDP52 engages the FIP200 Claw and allosterically promotes membrane binding via a parallel-axis division with OPTN-ATG9A.

    Evidence Crystal structures and competitive binding; HDX-MS, EM, GUV reconstitution; CRISPR epistasis

    PMID:32773036 PMID:32892694 PMID:34389544

    Open questions at the time
    • How NAP1/Claw/ATG8 competition is resolved in vivo unclear
    • Coordination of NDP52 and OPTN parallel axes not fully defined
  15. 2022 High

    Identified NDP52 as a redox sensor that oligomerizes via disulfide bonds to amplify mitophagy, and demonstrated a cellular requirement in beta-cell mitochondrial quality.

    Evidence Cysteine mutagenesis, redox/crosslinking assays, CRISPR KO mitophagy quantification; genome-wide CRISPR screen with EM and flux assays

    PMID:36514953 PMID:36543916

    Open questions at the time
    • How oxidation-driven oligomerization couples to receptor function structurally incomplete
    • Physiological redox thresholds in vivo not defined
  16. 2023 Medium

    Expanded the substrate and regulatory landscape, defining post-translational modifications (SUMOylation, crotonylated cofactor BEX2) and additional cargo (HBV envelopes via Rab9, processing-body scaffold Pat1b) and direct dsDNA binding in transcription.

    Evidence SUMOylation/IP-MS proteomics, point mutants, co-IP, mitophagy and viral replication assays, super-resolution imaging, transcriptome analysis

    PMID:36634147 PMID:37202403 PMID:37777549 PMID:37942585 PMID:38114531

    Open questions at the time
    • Hierarchy and crosstalk among PTMs unclear
    • Which functions of the diverse cargo repertoire are physiologically dominant unknown
  17. 2024 Medium

    Refined adaptor specificity and signaling-control roles, showing AZI2 (not TBKBP1) is required for NDP52-driven mitophagy and that NDP52 degrades K63-ubiquitinated p65 to suppress NF-κB; defined a Rab9-dependent antiviral route distinct from canonical autophagy.

    Evidence CRISPR KO with phospho-site mutagenesis; ubiquitination mapping, NF-κB reporter, myeloid-specific KO mouse; ternary complex mapping and ATG5-KO epistasis

    PMID:38752371 PMID:38965634 PMID:39269442 PMID:39276928

    Open questions at the time
    • Basis for selective AZI2 vs TBKBP1 usage unclear
    • How Rab9-dependent and canonical autophagy routes are partitioned not defined
  18. 2026 Medium

    Extended the receptor's reach to redox and cell-fate control, showing NDP52 recruits E3 ligases to degrade NOX4 (suppressing ferroptosis) and CAPZA1 via its ZF2 domain (preventing senescence-associated signaling).

    Evidence Co-IP, ubiquitination assays, ferroptosis/degeneration models, ZF2 deletion, CRISPR KO mouse

    PMID:41662915 PMID:42061478

    Open questions at the time
    • Generality of E3-ligase recruitment by NDP52 unclear
    • Mechanism by which ZF2 selects CAPZA1 not structurally defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NDP52's diverse modalities — ubiquitin, galectin, redox, and PTM sensing; autophagic versus nuclear/transcriptional roles — are integrated and prioritized within a single cell remains unresolved.
  • No unified model of cargo selection across competing inputs
  • Nuclear transcriptional function not mechanistically connected to autophagy role
  • In vivo physiological priorities among the many documented substrates unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0003677 DNA binding 2 GO:0140110 transcription regulator activity 2 GO:0008092 cytoskeletal protein binding 1 GO:0140097 catalytic activity, acting on DNA 1 GO:0140299 molecular sensor activity 1
Localization
GO:0005739 mitochondrion 4 GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-9612973 Autophagy 7 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
AZI2GABARAPL2LC3CMYO6OPTNRB1CC1TBK1TBKBP1
Complex memberships
NDP52-FIP200-SINTBAD/NAP1 autophagy initiation complexNDP52-galectin-8-LC3C ternary complexNDP52-myosin VI-RNAPII transcription complex

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 NDP52 is a novel protein of nuclear domain 10 (ND10) that colocalizes with the ND10 protein PML, contains an extended central coiled-coil domain with a leucine zipper motif and a C-terminal LIM domain homology region, and is redistributed upon viral infection and interferon treatment, suggesting a role in viral life cycle regulation. Immunofluorescence, cDNA cloning/sequencing, monoclonal antibody generation The Journal of cell biology Medium 7540613
2007 NDP52 directly binds myosin VI (MVI) via a mapped binding site; both proteins localize at the trans-Golgi complex and perinuclear vesicles. Knockdown of NDP52 reduces membrane ruffling, increases stress fibres and focal adhesions, and upregulates constitutive alkaline phosphatase secretion, indicating NDP52 acts as a negative regulator of secretory traffic at the Golgi complex. Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, immunofluorescence, electron microscopy, RNAi knockdown with phenotypic readout Journal of cell science Medium 17635994
2009 NDP52 directly recognizes ubiquitin-coated Salmonella enterica in human cells and, by binding adaptor proteins Nap1 and Sintbad, recruits TBK1. Knockdown of NDP52 impaired autophagy of Salmonella and facilitated bacterial proliferation. NDP52 also recruited LC3 to bacteria, establishing it as an autophagy receptor linking ubiquitinated bacteria to autophagosomal membranes. siRNA knockdown, immunofluorescence colocalization, co-immunoprecipitation, bacterial proliferation assay Nature immunology High 19820708
2010 NDP52 binds the ubiquitin coat on cytosolic bacteria (Salmonella, Streptococcus pyogenes) and simultaneously binds ATG8/LC3, delivering bacteria into autophagosomes. Cells lacking NDP52 accumulate ubiquitin-coated bacteria outside LC3+ autophagosomes and fail to restrict bacterial proliferation. siRNA knockdown, immunofluorescence, bacterial proliferation assay Autophagy High 20104023
2011 NDP52 and p62 are recruited independently to distinct non-overlapping microdomains on intracytosolic Shigella and Listeria ActA mutants, and both are required for efficient antibacterial autophagy; depletion of either impairs autophagy, but combined depletion is not synergistic, indicating they act in the same pathway. siRNA knockdown, immunofluorescence colocalization, bacterial survival assay Autophagy Medium 21079414
2011 NDP52 mediates selective autophagic degradation of the TLR adaptor TRIF and signaling molecule TRAF6 (but not TRAF3) downstream of poly(I:C) stimulation; NDP52 is polyubiquitinated by TRAF6 and is involved in TRAF6 aggregation. This autophagic regulation is normally suppressed by the ubiquitin-editing enzyme A20. Gene silencing, co-immunoprecipitation, autophagy inhibitor assays, proinflammatory gene expression analysis Cellular and molecular life sciences : CMLS Medium 21964925
2011 NDP52 targets Shigella to an autophagy pathway dependent on septin and actin, while targeting Listeria ActA mutant to a septin/actin-independent pathway, demonstrating that NDP52 can direct cargo to distinct selective autophagy pathways depending on context. siRNA knockdown, immunofluorescence, bacterial survival assay The Journal of biological chemistry Medium 21646350
2012 NDP52 selectively binds LC3C (not other ATG8 orthologs) through a noncanonical LIR motif lacking an aromatic residue, which is compensated by LC3C-specific interactions. This NDP52-LC3C interaction is essential for antibacterial autophagy; cells lacking either protein fail to protect the cytoplasm against Salmonella. Structural analysis (NMR/crystallography), mutagenesis, siRNA knockdown, bacterial survival assay Molecular cell High 23022382
2012 In K-Ras-dependent NSCLC cells, NDP52 and its paralogue Tax1bp1 are sequestered by basal autophagy driven by TBK1, and this autophagic clearance of NDP52/Tax1bp1 promotes non-canonical NF-κB signaling. Autophagy inhibition, TBK1 inhibition, NF-κB reporter assay, co-immunoprecipitation PloS one Medium 23209807
2013 Crystal structure of galectin-8 complexed with an NDP52 peptide reveals how NDP52 exclusively binds galectin-8 (not other galectins). Dimeric NDP52 forms a ternary complex with two monomeric galectin-8 molecules and two LC3C molecules. The structural basis explains NDP52 selectivity for galectin-8 in antibacterial autophagy. Crystal structure determination, biochemical binding assays, bacterial growth assays Nature communications High 23511477
2013 Crystal structure of the NDP52-galectin-8 complex shows that NDP52 exclusively binds galectin-8 due to steric hindrance preventing interactions with other galectins. This selectivity is required for Salmonella growth restriction in human cells. Crystal structure determination, in vitro binding assay, bacterial growth assay Science signaling High 23386746
2013 A common missense variant Val248Ala in NDP52 is associated with Crohn's disease and functionally impairs NDP52's ability to inhibit NF-κB activation of inflammatory genes and affects stability of proteins in Toll-like receptor pathways. Exome sequencing, genotyping, in vitro functional studies of NF-κB signaling Gastroenterology Medium 23624108
2013 The chlamydial deubiquitinase ChlaOTU binds both ubiquitin and NDP52 via distinct domains. NDP52 is recruited to Chlamydia entry sites and is dispensable for infection and bacterial growth, demonstrating that ChlaOTU counteracts NDP52-mediated clearance by removing ubiquitin signals. Co-immunoprecipitation, domain mapping, immunofluorescence, deubiquitinase activity assay in vitro Cellular microbiology Medium 23869922
2014 Nrf2 transcriptionally induces NDP52 via three antioxidant response elements (AREs) in its promoter. NDP52 overexpression facilitates clearance of phosphorylated tau via autophagy, and in Nrf2-knockout mice, phosphorylated and sarkosyl-insoluble tau accumulates concurrent with decreased NDP52 levels. NDP52 associates with phosphorylated tau from Alzheimer's disease brain samples. Promoter analysis (ARE identification), overexpression, Nrf2-KO mouse model, co-immunoprecipitation with brain tissue, autophagy flux assay Nature communications High 24667209
2015 Assembly of ubiquitin chains on damaged mitochondria (via PINK1-PARKIN pathway) triggers recruitment of NDP52 and OPTN concomitantly with TBK1 activation. TBK1 physically associates with NDP52 and phosphorylates OPTN; TBK1 activation requires both OPTN and NDP52. This constitutes a self-reinforcing positive feedback loop promoting efficient mitophagy. Quantitative proteomics (TMT), co-immunoprecipitation, phosphoproteomics, in vitro kinase assay, siRNA knockdown, live-cell imaging Molecular cell High 26365381
2015 NDP52 promotes autophagosome maturation (fusion with lysosomes) during xenophagy via interaction with LC3A, LC3B, and/or GABARAPL2 through a distinct LIR motif, and by interacting with MYOSIN VI. This maturation function is independent of its cargo-targeting function (which relies on LC3C interaction), demonstrating a dual role for NDP52 in xenophagy. Domain mutagenesis, co-immunoprecipitation, siRNA knockdown, immunofluorescence, autophagosome-lysosome fusion assay Cell host & microbe High 25771791
2015 The C2H2-type zinc finger of NDP52/CALCOCO2 specifically recognizes mono-ubiquitin and poly-ubiquitin chains via a unique zinc finger-ubiquitin binding mode. The cargo-binding region also contains a dynamic unconventional zinc finger but only the C2H2-type ZF mediates ubiquitin recognition. Biochemical assays (binding), crystal structure of C2H2 ZF/ubiquitin complex, mutagenesis Autophagy High 26506893
2017 Tetherin recruits E3 ubiquitin ligase MARCH8 to catalyze K27-linked ubiquitin chains on MAVS at lysine 7, generating a recognition signal for NDP52-dependent selective autophagic degradation of MAVS, thereby negatively regulating RLR-mediated type I IFN signaling. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, IFN reporter assay, mutagenesis of MAVS lysine residues Molecular cell High 28965816
2017 Rab35 GTPase in its active GTP-bound form directly binds and recruits NDP52 to bacteria-containing endosomes and damaged mitochondria, and promotes NDP52-ubiquitin interaction. This is inhibited by TBC1D10A (a Rab35 GAP) and stimulated by TBK1. Co-immunoprecipitation, GTPase binding assay, dominant-negative/constitutively active Rab35, immunofluorescence, mitophagy assay The EMBO journal Medium 28848034
2017 NDP52 interacts with myosin VI (MVI) in the nucleus and relieves MVI auto-inhibition, enabling MVI DNA binding. The NDP52-MVI complex binds RNA Polymerase II, and depletion of NDP52 or MVI reduces steady-state mRNA levels, establishing NDP52 as an activator of RNAPII-dependent transcription. FLIM-FRET, co-immunoprecipitation, FRAP, siRNA knockdown with mRNA level measurement, in vitro DNA-binding assay Nature communications Medium 29187741
2018 Crystal structures of NDP52 SKICH domain and TAX1BP1 SKICH domain in complex with NAP1 reveal the molecular basis of TBK1 adaptor binding to these autophagy receptors. TBK1-mediated phosphorylation sites in the SKICH domains of NDP52 and TAX1BP1 affect their interactions with NAP1. Crystal structure determination, biochemical binding assays, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 30459273
2018 NDP52 interacts with mitochondrial RNA poly(A) polymerase (MTPAP) via its SKICH domain. During mitophagy, NDP52 invades depolarized mitochondria and engages MTPAP in a proteasome-dependent but ubiquitin-independent manner. The NDP52-MTPAP complex recruits more LC3 than NDP52 alone, enhancing mitophagy. Co-immunoprecipitation, proteasome/ubiquitin inhibitor treatment, mitophagy assay, LC3 recruitment quantification EMBO reports Medium 30309841
2018 CALCOCO2/NDP52 directly interacts with CVB3 capsid protein VP1 that is ubiquitinated during infection. NDP52 (but not SQSTM1) suppresses antiviral type I IFN signaling by promoting autophagic degradation of MAVS. Viral proteinase 3C cleaves NDP52 at glutamine 139, generating a stable C-terminal fragment that retains the proviral MAVS-degradation function. Co-immunoprecipitation, siRNA knockdown, viral titer assay, IFN signaling assay, mutagenesis of cleavage site Cell death and differentiation Medium 30154446
2019 NDP52 forms a trimeric complex with FIP200 (subunit of the ULK complex) and SINTBAD/NAP1 (subunits of the TBK1 complex) to recruit upstream autophagy machinery to bacteria. FIP200 and SINTBAD/NAP1 are each recruited independently via NDP52 via distinct binding sites identified by selective point mutations, and both must be present for xenophagy to proceed. Co-immunoprecipitation, point mutagenesis of binding sites, CRISPR KO, xenophagy assay Molecular cell High 30853402
2019 Ectopic placement of NDP52 on mitochondria or peroxisomes is sufficient to initiate selective autophagy by focally localizing and activating the ULK1 complex. NDP52-induced mitophagy requires its interaction with FIP200/ULK1 complex, facilitated by TBK1. Focal ULK1 activation occurs independently of AMPK and mTOR. Ectopic tethering of ULK1 to cargo bypasses the requirement for autophagy receptors and TBK1. Chemically inducible dimerization (CID), CRISPR KO, mitophagy/pexophagy assay, epistasis analysis Molecular cell High 30853401
2019 NDP52 regulates spindle orientation by binding phosphatidic acid-containing vesicles, which absorb cytoplasmic N-WASP to regulate cortical actin dynamics at the polar cortex. siRNA-mediated NDP52 suppression causes ring-like compact subcortical F-actin surrounding the spindle, defects in astral microtubule growth, and aberrant spindle orientation. NDP52 shortens actin filaments via N-WASP in vitro. siRNA knockdown, TIRFM, live-cell imaging, in vitro actin assembly assay, phospholipid vesicle binding Cell research Medium 31201383
2019 LC3/GABARAPs drive ubiquitin-independent recruitment of OPTN and NDP52 to growing phagophore membranes via the LIR motif during PINK1/Parkin mitophagy. The LIR motif of NDP52 is dispensable for Atg8 recruitment and cargo selectivity but is required for Atg8-mediated amplification of mitophagy via a positive feedback loop. LIR motif mutagenesis, CRISPR KO, mitophagy quantification, live-cell imaging Nature communications High 30679426
2020 NDP52 (CALCOCO2) interacts with RB1CC1/FIP200 (ULK complex) through both its SKICH domain and its LIR motif binding to the FIP200 Claw domain. Crystal structures reveal that RB1CC1 Claw and ATG8 family proteins compete for binding to NAP1 and NDP52, providing mechanistic insight into autophagy initiation complex assembly. Crystal structure determination, biochemical binding assays, competitive binding assay Science advances High 34389544
2020 NDP52 (CALCOCO2) recruits RB1CC1/FIP200 to initiate de novo biogenesis of autophagic membranes on ubiquitin-coated damaged mitochondria, while OPTN recruits ATG9A via a different axis (OPTN-ATG9A). These two distinct axes work in parallel to initiate PRKN-mediated mitophagy. CRISPR KO, epistasis analysis, mitophagy assay, co-immunoprecipitation Autophagy Medium 32892694
2020 NDP52 allosterically stimulates membrane-binding by the FIP200 coiled-coil subunit of the ULK1 complex by promoting a more dynamic conformation of the FIP200 membrane-binding region. HDX-MS mapped the NDP52 and membrane binding sites to unique regions of the FIP200 coiled coil, and GUV reconstitution confirmed that ULK1 complex membrane recruitment is triggered by NDP52 engagement. Hydrogen-deuterium exchange mass spectrometry (HDX-MS), electron microscopy, GUV reconstitution eLife High 32773036
2021 The natural NDP52 variant G140E (NDP52GE) is located near the LIR motif and enhances binding to LC3C (and LC3B) while maintaining comparable phospho-tau binding to wild-type NDP52. The G140E variant promotes more efficient autophagosome formation and mitophagy, and NDP52 expression in B cells limits pro-inflammatory TNF-α production via efficient mitophagy. NMR structural modeling, co-immunoprecipitation, mitophagy assay, cytokine measurement in B cells from MS patients and controls Cell death and differentiation Medium 33723372
2022 NDP52 acts as a redox sensor during PINK1/Parkin-mediated mitophagy: oxidation of NDP52 at redox-sensitive cysteine residues promotes disulfide bond formation and oligomerization of NDP52 on damaged mitochondria. NDP52 oligomerization facilitates recruitment of autophagy machinery for rapid mitochondrial degradation. Cysteine mutagenesis, redox assay, crosslinking, CRISPR KO, mitophagy quantification The EMBO journal High 36514953
2022 Loss of CALCOCO2 in a pancreatic beta cell line is associated with distorted mitochondria, fewer proinsulin-containing immature granules, and accumulation of autophagosomes upon autophagy inhibition, indicating CALCOCO2 regulates mitochondrial quality and autophagy flux in beta cells. Genome-wide CRISPR pooled screen, loss-of-function validation, electron microscopy, autophagy flux assay Nature genetics Medium 36543916
2023 NDP52 directly binds to double-stranded DNA with high affinity in vitro, inducing changes in DNA structure. In cells, NDP52 clusters with RNAPII at transcription initiation sites and its overexpression promotes formation of additional transcriptional clusters. NDP52 depletion reduces overall gene expression levels, and transcription inhibition alters NDP52 nuclear dynamics. In vitro DNA binding assay, super-resolution microscopy (PALM/STORM), siRNA knockdown with transcriptome analysis, FRAP Nature communications Medium 37202403
2023 NDP52 forms a complex with Rab9 and HBV envelope proteins and links HBV to a Rab9-dependent lysosomal degradation pathway that is independent of galectin-8 and ATG5, distinct from antibacterial autophagy. Inactivating NDP52 in hepatocytes results in decreased targeting of viral envelopes to lysosomes and increased viral replication. Co-immunoprecipitation, siRNA knockdown, viral replication assay, lysosomal targeting assay, ATG5 KO epistasis Nature communications Medium 38114531
2023 Crotonylated BEX2 promotes mitophagy by facilitating the interaction between NDP52 and LC3B. BEX2 crotonylation at K59 is critical for this function; K59R mutation inhibits BEX2-mediated enhancement of NDP52-LC3B interaction and mitophagy. Co-immunoprecipitation, site-directed mutagenesis (K59R), mitophagy assay, in vivo tumor model Cell death & disease Medium 37777549
2023 TRIM26 physically associates with MAVS and promotes its selective autophagic degradation through NDP52; TRIM26-induced MAVS degradation is almost entirely blocked in NDP52-knockdown cells, establishing NDP52 as the essential autophagy receptor for TRIM26-mediated MAVS clearance. Co-immunoprecipitation, siRNA knockdown, MAVS degradation assay, IFN signaling assay Veterinary research Medium 38965634
2023 KSHV Kaposin B promotes processing body (PB) disassembly via NDP52-mediated selective autophagy; the PB scaffolding protein Pat1b co-immunoprecipitates with NDP52, establishing PB components as NDP52 cargo. Co-immunoprecipitation, siRNA knockdown, autophagic flux assay, PB quantification PLoS pathogens Medium 36634147
2024 AZI2/NAP1 (TBK1 adaptor), but not TBKBP1/SINTBAD, is specifically required for NDP52-driven mitophagy. AZI2 is recruited to damaged mitochondria and phosphorylated at S318 during mitophagy, and impairment of this phosphorylation partially inhibits mitochondrial degradation. CRISPR KO (AZI2, TBKBP1, OPTN), mitophagy assay, phosphorylation site mutagenesis The Journal of biological chemistry Medium 39276928
2024 Vangl2 recruits E3 ubiquitin ligase PDLIM2 to catalyze K63-linked ubiquitination on NF-κB p65, generating a recognition signal for NDP52-mediated selective autophagic degradation of p65, thereby suppressing NF-κB inflammatory signaling. Co-immunoprecipitation, ubiquitination assay with site-specific mapping, siRNA knockdown, NF-κB reporter assay, myeloid-specific KO mouse eLife Medium 39269442
2024 CALCOCO2/NDP52 mediates antiviral response to HBV via RAB9-dependent lysosomal degradation that is independent of galectin-8, ATG5, and the RB1CC1-CALCOCO2-TBKBP1-AZI2 complex. CALCOCO2 forms a ternary complex with RAB9 and viral envelope proteins specifically in the presence of HBV envelope proteins. Co-immunoprecipitation, CALCOCO2 mutant analysis, ATG5 KO epistasis, viral replication assay Autophagy Medium 38752371
2023 MUL1 E3 ligase mediates SUMO2-dependent SUMOylation of NDP52 at lysine 262. This SUMOylation promotes NDP52's role in mitophagy: NDP52-K262R mutation inhibits LC3 interaction with NDP52 and impairs NDP52 recruitment of mitochondria to the autophagic pathway via EEA1/RAB11, but does not affect mitochondrial delivery to lysosomes via LAMP2A. SUMOylation proteomics, co-IP/LC-MS/MS, point mutation (K262R), confocal microscopy, mitophagy assay Journal of cellular physiology Medium 37942585
2025 NDP52 GE variant (G140E) binds LC3C and LC3B more efficiently than wild-type NDP52 while maintaining comparable phospho-tau binding. NDP52 is shown to be a direct target of protein phosphatase 2A (PP2A) in vitro. NDP52GE more effectively reduces pathological tau accumulation in cell and Drosophila models of AD. Co-immunoprecipitation, in vitro phosphatase assay, Drosophila tauopathy model, tau quantification Cell death & disease Medium 40234443
2026 NDP52 recruits the E3 ligase ASB2 to NOX4, mediating K48-linked ubiquitination and autophagic degradation of NOX4 upon autophagy activation. This NDP52-ASB2-NOX4 axis suppresses ferroptosis in cardiomyocytes. Co-immunoprecipitation, molecular docking, ubiquitination assay, ferroptosis assay, in vivo cardiac model Free radical biology & medicine Medium 41662915
2026 NDP52 promotes autophagic degradation of CAPZA1 (F-actin capping protein) through its ZF2 (C2H2 zinc finger) domain, identified by IP-MS proteomics as a substrate. Loss of NDP52 causes CAPZA1 accumulation, ROS accumulation, and p53/Rb-dependent cell cycle arrest and NF-κB SASP signaling in nucleus pulposus cells. Deletion of the ZF2 domain abolishes NDP52's protective function. IP-MS proteomics, co-immunoprecipitation, ZF2 domain deletion, CRISPR KO mouse, in vitro and in vivo degeneration models Free radical biology & medicine Medium 42061478

Source papers

Stage 0 corpus · 73 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The PINK1-PARKIN Mitochondrial Ubiquitylation Pathway Drives a Program of OPTN/NDP52 Recruitment and TBK1 Activation to Promote Mitophagy. Molecular cell 738 26365381
2009 The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nature immunology 728 19820708
2019 Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy. Molecular cell 394 30853401
2014 Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nature communications 271 24667209
2012 LC3C, bound selectively by a noncanonical LIR motif in NDP52, is required for antibacterial autophagy. Molecular cell 271 23022382
2019 The Cargo Receptor NDP52 Initiates Selective Autophagy by Recruiting the ULK Complex to Cytosol-Invading Bacteria. Molecular cell 250 30853402
2011 p62 and NDP52 proteins target intracytosolic Shigella and Listeria to different autophagy pathways. The Journal of biological chemistry 238 21646350
2019 LC3/GABARAPs drive ubiquitin-independent recruitment of Optineurin and NDP52 to amplify mitophagy. Nature communications 196 30679426
2017 Tetherin Suppresses Type I Interferon Signaling by Targeting MAVS for NDP52-Mediated Selective Autophagic Degradation in Human Cells. Molecular cell 192 28965816
2011 The ubiquitin-binding adaptor proteins p62/SQSTM1 and NDP52 are recruited independently to bacteria-associated microdomains to target Salmonella to the autophagy pathway. Autophagy 163 21079414
2013 Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies. Gastroenterology 135 23624108
1995 Molecular characterization of NDP52, a novel protein of the nuclear domain 10, which is redistributed upon virus infection and interferon treatment. The Journal of cell biology 124 7540613
2015 Autophagy receptor NDP52 regulates pathogen-containing autophagosome maturation. Cell host & microbe 117 25771791
2012 TBK1 kinase addiction in lung cancer cells is mediated via autophagy of Tax1bp1/Ndp52 and non-canonical NF-κB signalling. PloS one 113 23209807
2013 Structural basis for recognition of autophagic receptor NDP52 by the sugar receptor galectin-8. Nature communications 94 23511477
2010 NDP52, a novel autophagy receptor for ubiquitin-decorated cytosolic bacteria. Autophagy 81 20104023
2007 T6BP and NDP52 are myosin VI binding partners with potential roles in cytokine signalling and cell adhesion. Journal of cell science 80 17635994
2011 Regulation of Toll-like receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20. Cellular and molecular life sciences : CMLS 77 21964925
2017 Rab35 GTPase recruits NDP52 to autophagy targets. The EMBO journal 75 28848034
2018 CALCOCO2/NDP52 and SQSTM1/p62 differentially regulate coxsackievirus B3 propagation. Cell death and differentiation 69 30154446
2013 Sterical hindrance promotes selectivity of the autophagy cargo receptor NDP52 for the danger receptor galectin-8 in antibacterial autophagy. Science signaling 68 23386746
2015 Molecular basis of ubiquitin recognition by the autophagy receptor CALCOCO2. Autophagy 64 26506893
2020 The autophagy adaptor NDP52 and the FIP200 coiled-coil allosterically activate ULK1 complex membrane recruitment. eLife 62 32773036
2022 NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy. The EMBO journal 58 36514953
2018 Mechanistic insights into the interactions of NAP1 with the SKICH domains of NDP52 and TAX1BP1. Proceedings of the National Academy of Sciences of the United States of America 53 30459273
2022 A genome-wide CRISPR screen identifies CALCOCO2 as a regulator of beta cell function influencing type 2 diabetes risk. Nature genetics 46 36543916
2017 NDP52 activates nuclear myosin VI to enhance RNA polymerase II transcription. Nature communications 45 29187741
2023 Crotonylated BEX2 interacts with NDP52 and enhances mitophagy to modulate chemotherapeutic agent-induced apoptosis in non-small-cell lung cancer cells. Cell death & disease 43 37777549
2021 Structural and biochemical advances on the recruitment of the autophagy-initiating ULK and TBK1 complexes by autophagy receptor NDP52. Science advances 41 34389544
2020 Two different axes CALCOCO2-RB1CC1 and OPTN-ATG9A initiate PRKN-mediated mitophagy. Autophagy 38 32892694
2014 NDP52 associates with phosphorylated tau in brains of an Alzheimer disease mouse model. Biochemical and biophysical research communications 37 25450380
2013 The chlamydial OTU domain-containing protein ChlaOTU is an early type III secretion effector targeting ubiquitin and NDP52. Cellular microbiology 34 23869922
2017 Influenza virus protein PB1-F2 interacts with CALCOCO2 (NDP52) to modulate innate immune response. The Journal of general virology 32 28613140
2018 NDP52 interacts with mitochondrial RNA poly(A) polymerase to promote mitophagy. EMBO reports 29 30309841
2018 Novel Insights into NDP52 Autophagy Receptor Functioning. Trends in cell biology 26 29395717
2021 Characterization of a natural variant of human NDP52 and its functional consequences on mitophagy. Cell death and differentiation 25 33723372
2009 NDP52: the missing link between ubiquitinated bacteria and autophagy. Nature immunology 25 19841643
2015 Dual function of CALCOCO2/NDP52 during xenophagy. Autophagy 24 25998689
2013 Autophagy receptor CALCOCO2/NDP52 takes center stage in Crohn disease. Autophagy 24 23820297
2019 CALCOCO2/NDP52 initiates selective autophagy through recruitment of ULK and TBK1 kinase complexes. Autophagy 21 31258038
2021 NDP52 Protects Against Myocardial Infarction-Provoked Cardiac Anomalies Through Promoting Autophagosome-Lysosome Fusion via Recruiting TBK1 and RAB7. Antioxidants & redox signaling 19 34382418
2023 NDP52 mediates an antiviral response to hepatitis B virus infection through Rab9-dependent lysosomal degradation pathway. Nature communications 18 38114531
2020 Dual NDP52 Function in Persistent CSFV Infection. Frontiers in microbiology 18 31969869
2020 The Role of Autophagy and Autophagy Receptor NDP52 in Microbial Infections. International journal of molecular sciences 18 32187990
2019 The altered expression of autophagy-related genes participates in heart failure: NRBP2 and CALCOCO2 are associated with left ventricular dysfunction parameters in human dilated cardiomyopathy. PloS one 18 31009519
2023 Kaposi's sarcoma-associated herpesvirus (KSHV) utilizes the NDP52/CALCOCO2 selective autophagy receptor to disassemble processing bodies. PLoS pathogens 14 36634147
2019 NDP52 tunes cortical actin interaction with astral microtubules for accurate spindle orientation. Cell research 14 31201383
2022 Baicalein Activates Parkin-Dependent Mitophagy through NDP52 and OPTN. Cells 13 35406696
2021 A protective variant of the autophagy receptor CALCOCO2/NDP52 in Multiple Sclerosis (MS). Autophagy 13 33970776
2023 NDP52 SUMOylation contributes to low-dose X-rays-induced cardiac hypertrophy through PINK1/Parkin-mediated mitophagy via MUL1/SUMO2 signalling. Journal of cellular physiology 12 37942585
2023 Autophagy receptor NDP52 alters DNA conformation to modulate RNA polymerase II transcription. Nature communications 11 37202403
2021 Fasudil prevents neomycin-induced hair cell damage by inhibiting autophagy through the miR-489/NDP52 signaling pathway in HEI-OC1 cells. Experimental and therapeutic medicine 11 34849158
2024 TRIM26 facilitates PRV infection through NDP52-mediated autophagic degradation of MAVS. Veterinary research 10 38965634
2025 A variant of the autophagic receptor NDP52 counteracts phospho-TAU accumulation and emerges as a protective factor for Alzheimer's disease. Cell death & disease 9 40234443
2024 Vangl2 suppresses NF-κB signaling and ameliorates sepsis by targeting p65 for NDP52-mediated autophagic degradation. eLife 9 39269442
2021 Crosstalk Between NDP52 and LUBAC in Innate Immune Responses, Cell Death, and Xenophagy. Frontiers in immunology 8 33815386
2025 NDP52 and its emerging role in pathogenesis. Cell death & disease 7 40319017
2024 CALCOCO2 prevents AngII-induced atrial remodeling by regulating the interaction between mitophagy and mitochondrial stress. International immunopharmacology 7 39094358
2024 TBK1 adaptor AZI2/NAP1 regulates NDP52-driven mitochondrial autophagy. The Journal of biological chemistry 7 39276928
2023 The host protein CALCOCO2 interacts with bovine viral diarrhoea virus Npro, inhibiting type I interferon production and thereby promoting viral replication. Virulence 6 38047736
2025 Cuproptosis induced by curcumin interfering with proliferation and energy metabolism in colorectal cancer: 3D tumor model and computational simulations reveal curcumin inhibition of HSPD1 and CALCOCO2. European journal of pharmacology 5 40680982
2025 NDP52 deficiency accelerates chondrocyte degeneration through promoting pathogenic mitochondrial ROS via reverse electron transport. Redox biology 4 40618705
2025 Sec6 suppresses BoHV-1-triggered innate immunity through NDP52-mediated autophagic degradation of STING. Veterinary microbiology 2 41406560
2025 Encephalomyocarditis virus non-structural protein 2C induces the degradation of NDP52 autophagy protein to promote its own survival. Veterinary microbiology 1 40373618
2020 CALCOCO2 silencing represents a potential molecular therapeutic target for glioma. Archives of medical science : AMS 1 41684577
2026 UBE4B Mediates Mitophagy via NIPSNAP1 Ubiquitination and NDP52 Recruitment. International journal of molecular sciences 0 41596759
2026 The autophagy receptor NDP52 recruits the E3 ligase ASB2 to mediate NOX4 degradation, suppressing cardiomyocyte ferroptosis and ameliorating heart failure. Free radical biology & medicine 0 41662915
2026 XIST Improves Mitophagy and Exerts Perioperative Myocardial Protection Through miR-212-3p/CALCOCO2/OPTN. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 0 41674039
2026 ULK1 drives NDP52-mediated selective autophagic degradation of MHC-I to promote immune evasion in HPV-positive head and neck cancer. bioRxiv : the preprint server for biology 0 41889855
2026 The Role of CD44, CALCOCO2, ALDH4A1, and CLEC16A in the Cross-Talk Model of Epilepsy and Thyroid Cancer Progression. Molecular carcinogenesis 0 41950359
2026 NDP52-mediated autophagic degradation of CAPZA1 ameliorates intervertebral disc degeneration by suppressing cellular senescence. Free radical biology & medicine 0 42061478
2025 BST-2 Promotes N Protein Degradation and Inhibits Viral Replication Through the MARCHF8/NDP52 Autophagy Pathway. Microorganisms 0 40871369
2024 CALCOCO2/NDP52 associates with RAB9 to initiate an antiviral response to hepatitis B virus infection through a lysosomal degradation pathway. Autophagy 0 38752371

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