{"gene":"CALCOCO2","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1995,"finding":"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.","method":"Immunofluorescence, cDNA cloning/sequencing, monoclonal antibody generation","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiments and protein characterization by immunofluorescence and cDNA sequencing, single study but multiple orthogonal methods","pmids":["7540613"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, immunofluorescence, electron microscopy, RNAi knockdown with phenotypic readout","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding confirmed in vitro and in vivo, multiple orthogonal methods, single lab","pmids":["17635994"],"is_preprint":false},{"year":2009,"finding":"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.","method":"siRNA knockdown, immunofluorescence colocalization, co-immunoprecipitation, bacterial proliferation assay","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across multiple labs, reciprocal binding assays, loss-of-function with defined bacterial phenotype, multiple orthogonal methods","pmids":["19820708"],"is_preprint":false},{"year":2010,"finding":"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.","method":"siRNA knockdown, immunofluorescence, bacterial proliferation assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated finding, loss-of-function with defined phenotype, consistent with companion paper PMID:19820708","pmids":["20104023"],"is_preprint":false},{"year":2011,"finding":"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.","method":"siRNA knockdown, immunofluorescence colocalization, bacterial survival assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by double knockdown, direct colocalization, defined phenotypic readout, single lab","pmids":["21079414"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Gene silencing, co-immunoprecipitation, autophagy inhibitor assays, proinflammatory gene expression analysis","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, gene silencing with defined signaling phenotype, single lab, multiple substrates tested","pmids":["21964925"],"is_preprint":false},{"year":2011,"finding":"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.","method":"siRNA knockdown, immunofluorescence, bacterial survival assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined pathway distinction, single lab, two bacterial model systems","pmids":["21646350"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Structural analysis (NMR/crystallography), mutagenesis, siRNA knockdown, bacterial survival assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination with mutagenesis validation and functional loss-of-function phenotype, multiple orthogonal methods","pmids":["23022382"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Autophagy inhibition, TBK1 inhibition, NF-κB reporter assay, co-immunoprecipitation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological and genetic perturbation with signaling readout, single lab, single study","pmids":["23209807"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Crystal structure determination, biochemical binding assays, bacterial growth assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, multiple binding partners characterized, replicated by companion study PMID:23386746","pmids":["23511477"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Crystal structure determination, in vitro binding assay, bacterial growth assay","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, consistent with PMID:23511477","pmids":["23386746"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Exome sequencing, genotyping, in vitro functional studies of NF-κB signaling","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional studies in cell-based systems, genetic association plus in vitro mechanistic follow-up, single lab","pmids":["23624108"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation, domain mapping, immunofluorescence, deubiquitinase activity assay in vitro","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro enzymatic assay plus binding and localization studies, single lab","pmids":["23869922"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Promoter analysis (ARE identification), overexpression, Nrf2-KO mouse model, co-immunoprecipitation with brain tissue, autophagy flux assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mouse, promoter analysis, co-IP with disease tissue), in vivo and in vitro validation","pmids":["24667209"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Quantitative proteomics (TMT), co-immunoprecipitation, phosphoproteomics, in vitro kinase assay, siRNA knockdown, live-cell imaging","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay plus quantitative proteomics plus functional KD with defined mitophagy phenotype, multiple orthogonal methods","pmids":["26365381"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Domain mutagenesis, co-immunoprecipitation, siRNA knockdown, immunofluorescence, autophagosome-lysosome fusion assay","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis separating two binding domains with distinct functional consequences, multiple interaction partners confirmed, replicated in companion paper PMID:25998689","pmids":["25771791"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Biochemical assays (binding), crystal structure of C2H2 ZF/ubiquitin complex, mutagenesis","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis, domain-specific functional dissection, single lab but rigorous structural study","pmids":["26506893"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, IFN reporter assay, mutagenesis of MAVS lysine residues","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific ubiquitination mapped, receptor identified by knockdown, mechanistic chain from E3 ligase to autophagy receptor to substrate degradation established with multiple orthogonal methods","pmids":["28965816"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, GTPase binding assay, dominant-negative/constitutively active Rab35, immunofluorescence, mitophagy assay","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated, GTPase cycle manipulation, functional mitophagy readout, single lab","pmids":["28848034"],"is_preprint":false},{"year":2017,"finding":"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.","method":"FLIM-FRET, co-immunoprecipitation, FRAP, siRNA knockdown with mRNA level measurement, in vitro DNA-binding assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biophysical methods, loss-of-function with defined transcriptional phenotype, single lab","pmids":["29187741"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Crystal structure determination, biochemical binding assays, mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with mutagenesis and functional binding characterization, multiple complexes solved","pmids":["30459273"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, proteasome/ubiquitin inhibitor treatment, mitophagy assay, LC3 recruitment quantification","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping, pharmacological dissection, single lab","pmids":["30309841"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, viral titer assay, IFN signaling assay, mutagenesis of cleavage site","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding, cleavage site mapping, functional signaling assay, single lab","pmids":["30154446"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation, point mutagenesis of binding sites, CRISPR KO, xenophagy assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — trimeric complex defined by selective mutagenesis with functional consequences, multiple orthogonal methods, replicated in companion paper PMID:30853401","pmids":["30853402"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Chemically inducible dimerization (CID), CRISPR KO, mitophagy/pexophagy assay, epistasis analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — CID gain-of-function with systematic CRISPR KO epistasis, multiple orthogonal methods, replicated in companion paper PMID:30853402","pmids":["30853401"],"is_preprint":false},{"year":2019,"finding":"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.","method":"siRNA knockdown, TIRFM, live-cell imaging, in vitro actin assembly assay, phospholipid vesicle binding","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined spindle phenotype, in vitro reconstitution of actin regulation, single lab","pmids":["31201383"],"is_preprint":false},{"year":2019,"finding":"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.","method":"LIR motif mutagenesis, CRISPR KO, mitophagy quantification, live-cell imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — LIR mutagenesis combined with CRISPR KO epistasis, quantitative mitophagy assay, redefines existing model","pmids":["30679426"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Crystal structure determination, biochemical binding assays, competitive binding assay","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of multiple complexes with competitive binding characterization, rigorous structural study","pmids":["34389544"],"is_preprint":false},{"year":2020,"finding":"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.","method":"CRISPR KO, epistasis analysis, mitophagy assay, co-immunoprecipitation","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR epistasis with defined pathway placement, single lab, consistent with PMID:30853402","pmids":["32892694"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Hydrogen-deuterium exchange mass spectrometry (HDX-MS), electron microscopy, GUV reconstitution","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — HDX-MS structural mapping plus in vitro reconstitution on GUVs, multiple orthogonal methods, allosteric mechanism established","pmids":["32773036"],"is_preprint":false},{"year":2021,"finding":"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.","method":"NMR structural modeling, co-immunoprecipitation, mitophagy assay, cytokine measurement in B cells from MS patients and controls","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural modeling with functional binding and mitophagy assays, single lab","pmids":["33723372"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Cysteine mutagenesis, redox assay, crosslinking, CRISPR KO, mitophagy quantification","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-directed mutagenesis of cysteines with in vitro redox assay plus functional mitophagy phenotype, multiple methods in single study","pmids":["36514953"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Genome-wide CRISPR pooled screen, loss-of-function validation, electron microscopy, autophagy flux assay","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with defined cellular phenotypes, single study, functional mechanistic follow-up","pmids":["36543916"],"is_preprint":false},{"year":2023,"finding":"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.","method":"In vitro DNA binding assay, super-resolution microscopy (PALM/STORM), siRNA knockdown with transcriptome analysis, FRAP","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus live-cell imaging plus transcriptomic readout, multiple orthogonal methods, single lab","pmids":["37202403"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, viral replication assay, lysosomal targeting assay, ATG5 KO epistasis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of ternary complex, KO epistasis distinguishing pathway, single lab","pmids":["38114531"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, site-directed mutagenesis (K59R), mitophagy assay, in vivo tumor model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis demonstrating modification-dependent interaction, in vitro and in vivo validation, single lab","pmids":["37777549"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, MAVS degradation assay, IFN signaling assay","journal":"Veterinary research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus epistasis via NDP52 KD, defined degradation pathway, single lab","pmids":["38965634"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, autophagic flux assay, PB quantification","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct co-IP of NDP52 with PB scaffold, autophagy gene KD epistasis, single lab","pmids":["36634147"],"is_preprint":false},{"year":2024,"finding":"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.","method":"CRISPR KO (AZI2, TBKBP1, OPTN), mitophagy assay, phosphorylation site mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO epistasis distinguishing two TBK1 adaptors, phospho-site mutagenesis, single lab","pmids":["39276928"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay with site-specific mapping, siRNA knockdown, NF-κB reporter assay, myeloid-specific KO mouse","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination mapping with receptor identification by KD, in vivo KO model, single lab","pmids":["39269442"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, CALCOCO2 mutant analysis, ATG5 KO epistasis, viral replication assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ternary complex mapping, mutant epistasis analysis, single lab, companion to PMID:38114531","pmids":["38752371"],"is_preprint":false},{"year":2023,"finding":"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.","method":"SUMOylation proteomics, co-IP/LC-MS/MS, point mutation (K262R), confocal microscopy, mitophagy assay","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific SUMOylation identified by proteomics, mutagenesis with defined mitophagy phenotype, single lab","pmids":["37942585"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation, in vitro phosphatase assay, Drosophila tauopathy model, tau quantification","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro biochemical assay for PP2A interaction, variant functional characterization in cell and animal models, single lab","pmids":["40234443"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Co-immunoprecipitation, molecular docking, ubiquitination assay, ferroptosis assay, in vivo cardiac model","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay with defined cellular phenotype, single lab","pmids":["41662915"],"is_preprint":false},{"year":2026,"finding":"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.","method":"IP-MS proteomics, co-immunoprecipitation, ZF2 domain deletion, CRISPR KO mouse, in vitro and in vivo degeneration models","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identified by IP-MS and validated by co-IP, domain deletion with defined phenotype, in vivo KO model, single lab","pmids":["42061478"],"is_preprint":false}],"current_model":"NDP52/CALCOCO2 is a multifunctional selective autophagy receptor that recognizes ubiquitin-coated cytosolic bacteria and damaged mitochondria via its C2H2-type zinc finger ubiquitin-binding domain, and simultaneously recruits autophagosome biogenesis machinery (ULK1/FIP200 complex via SKICH domain and LIR, TBK1 via NAP1/SINTBAD adaptors) and autophagosomal membranes (via LC3C through a noncanonical LIR motif, and LC3A/B/GABARAPL2 via a canonical LIR for maturation) to initiate and complete selective autophagy; NDP52 also acts as a redox sensor (forming disulfide-linked oligomers upon oxidative stress) to amplify mitophagy, recruits myosin VI to promote autophagosome-lysosome fusion, links galectin-8-coated damaged vacuoles to autophagy, mediates degradation of signaling molecules (MAVS, TRIF, TRAF6, p65, NOX4) to regulate innate immune signaling, and has nuclear functions including activating RNA Polymerase II transcription via myosin VI and altering DNA conformation by direct dsDNA binding."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1995,"claim":"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","pmids":["7540613"],"confidence":"Medium","gaps":["No molecular function assigned","Link between ND10 localization and later autophagy roles not established","Mechanism of interferon-induced redistribution unknown"]},{"year":2007,"claim":"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","pmids":["17635994"],"confidence":"Medium","gaps":["Relationship of Golgi traffic role to autophagy not established","Physiological context of secretory regulation unclear"]},{"year":2009,"claim":"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","pmids":["19820708","20104023"],"confidence":"High","gaps":["Structural basis of ubiquitin recognition not yet defined","How NDP52 connects to autophagosomal membranes molecularly not resolved"]},{"year":2011,"claim":"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","pmids":["21079414","21646350","21964925"],"confidence":"Medium","gaps":["Determinants selecting septin/actin-dependent vs -independent routes unknown","Mechanism of TRAF6-mediated NDP52 ubiquitination and A20 suppression not fully resolved"]},{"year":2012,"claim":"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","pmids":["23022382"],"confidence":"High","gaps":["Roles of other ATG8 family members not yet defined","Whether LC3C binding suffices for membrane recruitment unresolved"]},{"year":2013,"claim":"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","pmids":["23511477","23386746","23624108","23869922"],"confidence":"High","gaps":["How galectin-8 sensing integrates with ubiquitin recognition not mechanistically unified","Disease variant effect in vivo not established"]},{"year":2014,"claim":"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","pmids":["24667209"],"confidence":"High","gaps":["Direct receptor-substrate recognition mode for tau not defined","Causal role in human tauopathy not established"]},{"year":2015,"claim":"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","pmids":["25771791","26506893"],"confidence":"High","gaps":["How the two LIR functions are temporally coordinated unclear","Role of the second unconventional zinc finger not defined"]},{"year":2015,"claim":"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","pmids":["26365381"],"confidence":"High","gaps":["Division of labor between NDP52 and OPTN not yet parsed","How TBK1 activation feeds back to receptor recruitment not fully mapped"]},{"year":2017,"claim":"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","pmids":["28848034","28965816"],"confidence":"High","gaps":["How Rab35 recruitment is coordinated with ubiquitin/galectin sensing unclear","Generality of K27-ubiquitin-driven NDP52 recognition not established"]},{"year":2018,"claim":"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","pmids":["30459273","30309841","30154446"],"confidence":"High","gaps":["In vivo relevance of SKICH phosphorylation sites not established","Mechanism of ubiquitin-independent cargo engagement incompletely defined"]},{"year":2019,"claim":"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","pmids":["30853402","30853401"],"confidence":"High","gaps":["How signals are integrated to time ULK1 activation in vivo unclear","Quantitative thresholds for receptor clustering not defined"]},{"year":2019,"claim":"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","pmids":["30679426","31201383","29187741"],"confidence":"High","gaps":["Whether nuclear and autophagic functions are mechanistically linked unknown","Physiological significance of spindle and transcription roles not established"]},{"year":2020,"claim":"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","pmids":["34389544","32773036","32892694"],"confidence":"High","gaps":["How NAP1/Claw/ATG8 competition is resolved in vivo unclear","Coordination of NDP52 and OPTN parallel axes not fully defined"]},{"year":2022,"claim":"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","pmids":["36514953","36543916"],"confidence":"High","gaps":["How oxidation-driven oligomerization couples to receptor function structurally incomplete","Physiological redox thresholds in vivo not defined"]},{"year":2023,"claim":"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","pmids":["37942585","37777549","38114531","36634147","37202403"],"confidence":"Medium","gaps":["Hierarchy and crosstalk among PTMs unclear","Which functions of the diverse cargo repertoire are physiologically dominant unknown"]},{"year":2024,"claim":"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","pmids":["39276928","39269442","38752371","38965634"],"confidence":"Medium","gaps":["Basis for selective AZI2 vs TBKBP1 usage unclear","How Rab9-dependent and canonical autophagy routes are partitioned not defined"]},{"year":2026,"claim":"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","pmids":["41662915","42061478"],"confidence":"Medium","gaps":["Generality of E3-ligase recruitment by NDP52 unclear","Mechanism by which ZF2 selects CAPZA1 not structurally defined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,23,24]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[19,33]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[31]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[19,33]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[25]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,19,33]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,3,16]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[14,18,21,31]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,3,7,14,15,23,24]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,17,39,36]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,13,22,34]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[19,33]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[14,26,31]}],"complexes":["NDP52-FIP200-SINTBAD/NAP1 autophagy initiation complex","NDP52-galectin-8-LC3C ternary complex","NDP52-myosin VI-RNAPII transcription complex"],"partners":["MYO6","TBK1","RB1CC1","AZI2","TBKBP1","LC3C","GABARAPL2","OPTN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13137","full_name":"Calcium-binding and coiled-coil domain-containing protein 2","aliases":["Antigen nuclear dot 52 kDa protein","Nuclear domain 10 protein NDP52","Nuclear domain 10 protein 52","Nuclear dot protein 52"],"length_aa":446,"mass_kda":52.3,"function":"Xenophagy-specific receptor required for autophagy-mediated intracellular bacteria degradation. Acts as an effector protein of galectin-sensed membrane damage that restricts the proliferation of infecting pathogens such as Salmonella typhimurium upon entry into the cytosol by targeting LGALS8-associated bacteria for autophagy (PubMed:22246324). Initially orchestrates bacteria targeting to autophagosomes and subsequently ensures pathogen degradation by regulating pathogen-containing autophagosome maturation (PubMed:23022382, PubMed:25771791). Bacteria targeting to autophagosomes relies on its interaction with MAP1LC3A, MAP1LC3B and/or GABARAPL2, whereas regulation of pathogen-containing autophagosome maturation requires the interaction with MAP3LC3C (PubMed:23022382, PubMed:25771791). May play a role in ruffle formation and actin cytoskeleton organization and seems to negatively regulate constitutive secretion (PubMed:17635994)","subcellular_location":"Cytoplasm, perinuclear region; Cytoplasm, cytoskeleton; Cytoplasmic vesicle, autophagosome membrane","url":"https://www.uniprot.org/uniprotkb/Q13137/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CALCOCO2","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CALCOCO2","total_profiled":1310},"omim":[{"mim_id":"606099","title":"LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 8; LGALS8","url":"https://www.omim.org/entry/606099"},{"mim_id":"604587","title":"CALCIUM BINDING AND COILED-COIL DOMAIN PROTEIN 2; CALCOCO2","url":"https://www.omim.org/entry/604587"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CALCOCO2"},"hgnc":{"alias_symbol":["MGC17318","NDP52"],"prev_symbol":[]},"alphafold":{"accession":"Q13137","domains":[{"cath_id":"2.60.40.2840","chopping":"20-126","consensus_level":"high","plddt":87.4762,"start":20,"end":126}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13137","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13137-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13137-F1-predicted_aligned_error_v6.png","plddt_mean":80.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CALCOCO2","jax_strain_url":"https://www.jax.org/strain/search?query=CALCOCO2"},"sequence":{"accession":"Q13137","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13137.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13137/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13137"}},"corpus_meta":[{"pmid":"26365381","id":"PMC_26365381","title":"The 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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.\",\n      \"method\": \"Immunofluorescence, cDNA cloning/sequencing, monoclonal antibody generation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiments and protein characterization by immunofluorescence and cDNA sequencing, single study but multiple orthogonal methods\",\n      \"pmids\": [\"7540613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, immunofluorescence, electron microscopy, RNAi knockdown with phenotypic readout\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding confirmed in vitro and in vivo, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"17635994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, immunofluorescence colocalization, co-immunoprecipitation, bacterial proliferation assay\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across multiple labs, reciprocal binding assays, loss-of-function with defined bacterial phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"19820708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, bacterial proliferation assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated finding, loss-of-function with defined phenotype, consistent with companion paper PMID:19820708\",\n      \"pmids\": [\"20104023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, immunofluorescence colocalization, bacterial survival assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by double knockdown, direct colocalization, defined phenotypic readout, single lab\",\n      \"pmids\": [\"21079414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Gene silencing, co-immunoprecipitation, autophagy inhibitor assays, proinflammatory gene expression analysis\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, gene silencing with defined signaling phenotype, single lab, multiple substrates tested\",\n      \"pmids\": [\"21964925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, bacterial survival assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined pathway distinction, single lab, two bacterial model systems\",\n      \"pmids\": [\"21646350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Structural analysis (NMR/crystallography), mutagenesis, siRNA knockdown, bacterial survival assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination with mutagenesis validation and functional loss-of-function phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"23022382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Autophagy inhibition, TBK1 inhibition, NF-κB reporter assay, co-immunoprecipitation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological and genetic perturbation with signaling readout, single lab, single study\",\n      \"pmids\": [\"23209807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structure determination, biochemical binding assays, bacterial growth assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, multiple binding partners characterized, replicated by companion study PMID:23386746\",\n      \"pmids\": [\"23511477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structure determination, in vitro binding assay, bacterial growth assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, consistent with PMID:23511477\",\n      \"pmids\": [\"23386746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Exome sequencing, genotyping, in vitro functional studies of NF-κB signaling\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional studies in cell-based systems, genetic association plus in vitro mechanistic follow-up, single lab\",\n      \"pmids\": [\"23624108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, immunofluorescence, deubiquitinase activity assay in vitro\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro enzymatic assay plus binding and localization studies, single lab\",\n      \"pmids\": [\"23869922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Promoter analysis (ARE identification), overexpression, Nrf2-KO mouse model, co-immunoprecipitation with brain tissue, autophagy flux assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mouse, promoter analysis, co-IP with disease tissue), in vivo and in vitro validation\",\n      \"pmids\": [\"24667209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Quantitative proteomics (TMT), co-immunoprecipitation, phosphoproteomics, in vitro kinase assay, siRNA knockdown, live-cell imaging\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay plus quantitative proteomics plus functional KD with defined mitophagy phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"26365381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Domain mutagenesis, co-immunoprecipitation, siRNA knockdown, immunofluorescence, autophagosome-lysosome fusion assay\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis separating two binding domains with distinct functional consequences, multiple interaction partners confirmed, replicated in companion paper PMID:25998689\",\n      \"pmids\": [\"25771791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical assays (binding), crystal structure of C2H2 ZF/ubiquitin complex, mutagenesis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis, domain-specific functional dissection, single lab but rigorous structural study\",\n      \"pmids\": [\"26506893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, IFN reporter assay, mutagenesis of MAVS lysine residues\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific ubiquitination mapped, receptor identified by knockdown, mechanistic chain from E3 ligase to autophagy receptor to substrate degradation established with multiple orthogonal methods\",\n      \"pmids\": [\"28965816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, GTPase binding assay, dominant-negative/constitutively active Rab35, immunofluorescence, mitophagy assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated, GTPase cycle manipulation, functional mitophagy readout, single lab\",\n      \"pmids\": [\"28848034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"FLIM-FRET, co-immunoprecipitation, FRAP, siRNA knockdown with mRNA level measurement, in vitro DNA-binding assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biophysical methods, loss-of-function with defined transcriptional phenotype, single lab\",\n      \"pmids\": [\"29187741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structure determination, biochemical binding assays, mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with mutagenesis and functional binding characterization, multiple complexes solved\",\n      \"pmids\": [\"30459273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, proteasome/ubiquitin inhibitor treatment, mitophagy assay, LC3 recruitment quantification\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping, pharmacological dissection, single lab\",\n      \"pmids\": [\"30309841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, viral titer assay, IFN signaling assay, mutagenesis of cleavage site\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding, cleavage site mapping, functional signaling assay, single lab\",\n      \"pmids\": [\"30154446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, point mutagenesis of binding sites, CRISPR KO, xenophagy assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — trimeric complex defined by selective mutagenesis with functional consequences, multiple orthogonal methods, replicated in companion paper PMID:30853401\",\n      \"pmids\": [\"30853402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Chemically inducible dimerization (CID), CRISPR KO, mitophagy/pexophagy assay, epistasis analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CID gain-of-function with systematic CRISPR KO epistasis, multiple orthogonal methods, replicated in companion paper PMID:30853402\",\n      \"pmids\": [\"30853401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, TIRFM, live-cell imaging, in vitro actin assembly assay, phospholipid vesicle binding\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined spindle phenotype, in vitro reconstitution of actin regulation, single lab\",\n      \"pmids\": [\"31201383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"LIR motif mutagenesis, CRISPR KO, mitophagy quantification, live-cell imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — LIR mutagenesis combined with CRISPR KO epistasis, quantitative mitophagy assay, redefines existing model\",\n      \"pmids\": [\"30679426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structure determination, biochemical binding assays, competitive binding assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of multiple complexes with competitive binding characterization, rigorous structural study\",\n      \"pmids\": [\"34389544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR KO, epistasis analysis, mitophagy assay, co-immunoprecipitation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR epistasis with defined pathway placement, single lab, consistent with PMID:30853402\",\n      \"pmids\": [\"32892694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Hydrogen-deuterium exchange mass spectrometry (HDX-MS), electron microscopy, GUV reconstitution\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — HDX-MS structural mapping plus in vitro reconstitution on GUVs, multiple orthogonal methods, allosteric mechanism established\",\n      \"pmids\": [\"32773036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"NMR structural modeling, co-immunoprecipitation, mitophagy assay, cytokine measurement in B cells from MS patients and controls\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural modeling with functional binding and mitophagy assays, single lab\",\n      \"pmids\": [\"33723372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Cysteine mutagenesis, redox assay, crosslinking, CRISPR KO, mitophagy quantification\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-directed mutagenesis of cysteines with in vitro redox assay plus functional mitophagy phenotype, multiple methods in single study\",\n      \"pmids\": [\"36514953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide CRISPR pooled screen, loss-of-function validation, electron microscopy, autophagy flux assay\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with defined cellular phenotypes, single study, functional mechanistic follow-up\",\n      \"pmids\": [\"36543916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro DNA binding assay, super-resolution microscopy (PALM/STORM), siRNA knockdown with transcriptome analysis, FRAP\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus live-cell imaging plus transcriptomic readout, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37202403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, viral replication assay, lysosomal targeting assay, ATG5 KO epistasis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of ternary complex, KO epistasis distinguishing pathway, single lab\",\n      \"pmids\": [\"38114531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (K59R), mitophagy assay, in vivo tumor model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis demonstrating modification-dependent interaction, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"37777549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, MAVS degradation assay, IFN signaling assay\",\n      \"journal\": \"Veterinary research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus epistasis via NDP52 KD, defined degradation pathway, single lab\",\n      \"pmids\": [\"38965634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, autophagic flux assay, PB quantification\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct co-IP of NDP52 with PB scaffold, autophagy gene KD epistasis, single lab\",\n      \"pmids\": [\"36634147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR KO (AZI2, TBKBP1, OPTN), mitophagy assay, phosphorylation site mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO epistasis distinguishing two TBK1 adaptors, phospho-site mutagenesis, single lab\",\n      \"pmids\": [\"39276928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with site-specific mapping, siRNA knockdown, NF-κB reporter assay, myeloid-specific KO mouse\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination mapping with receptor identification by KD, in vivo KO model, single lab\",\n      \"pmids\": [\"39269442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, CALCOCO2 mutant analysis, ATG5 KO epistasis, viral replication assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ternary complex mapping, mutant epistasis analysis, single lab, companion to PMID:38114531\",\n      \"pmids\": [\"38752371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"SUMOylation proteomics, co-IP/LC-MS/MS, point mutation (K262R), confocal microscopy, mitophagy assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific SUMOylation identified by proteomics, mutagenesis with defined mitophagy phenotype, single lab\",\n      \"pmids\": [\"37942585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphatase assay, Drosophila tauopathy model, tau quantification\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro biochemical assay for PP2A interaction, variant functional characterization in cell and animal models, single lab\",\n      \"pmids\": [\"40234443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, molecular docking, ubiquitination assay, ferroptosis assay, in vivo cardiac model\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay with defined cellular phenotype, single lab\",\n      \"pmids\": [\"41662915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"IP-MS proteomics, co-immunoprecipitation, ZF2 domain deletion, CRISPR KO mouse, in vitro and in vivo degeneration models\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identified by IP-MS and validated by co-IP, domain deletion with defined phenotype, in vivo KO model, single lab\",\n      \"pmids\": [\"42061478\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NDP52/CALCOCO2 is a multifunctional selective autophagy receptor that recognizes ubiquitin-coated cytosolic bacteria and damaged mitochondria via its C2H2-type zinc finger ubiquitin-binding domain, and simultaneously recruits autophagosome biogenesis machinery (ULK1/FIP200 complex via SKICH domain and LIR, TBK1 via NAP1/SINTBAD adaptors) and autophagosomal membranes (via LC3C through a noncanonical LIR motif, and LC3A/B/GABARAPL2 via a canonical LIR for maturation) to initiate and complete selective autophagy; NDP52 also acts as a redox sensor (forming disulfide-linked oligomers upon oxidative stress) to amplify mitophagy, recruits myosin VI to promote autophagosome-lysosome fusion, links galectin-8-coated damaged vacuoles to autophagy, mediates degradation of signaling molecules (MAVS, TRIF, TRAF6, p65, NOX4) to regulate innate immune signaling, and has nuclear functions including activating RNA Polymerase II transcription via myosin VI and altering DNA conformation by direct dsDNA binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#2, #3, #14]. It recognizes ubiquitinated cargo through its C2H2-type zinc finger, which binds mono- and poly-ubiquitin via a distinctive zinc-finger ubiquitin-binding mode [#16], and engages galectin-8-coated damaged vacuoles through a selective interface that excludes other galectins [#9, #10]. 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 [#23, #24]; structurally, NDP52 engages the FIP200 Claw domain via its SKICH domain and LIR motif and allosterically promotes ULK1-complex membrane binding [#27, #29]. It selectively binds LC3C through a noncanonical aromatic-residue-lacking LIR essential for antibacterial autophagy [#7], 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 [#15]. 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 [#14], is recruited by GTP-bound Rab35 [#18], and acts as a redox sensor that oligomerizes via disulfide bonds upon cysteine oxidation to amplify mitochondrial clearance [#31]. NDP52 also functions as a selective autophagy receptor for innate-immune signaling molecules, mediating degradation of ubiquitinated MAVS, TRIF/TRAF6, NF-\\u03baB p65, and NOX4 to restrain inflammatory and antiviral signaling [#5, #17, #39, #43]. Beyond autophagy, NDP52 acts in the nucleus, binding double-stranded DNA and partnering with myosin VI to activate RNA Polymerase II transcription [#19, #33]. A common Val248Ala variant is associated with Crohn's disease and impairs NDP52's suppression of NF-\\u03baB-driven inflammatory gene expression [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"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.\",\n      \"evidence\": \"cDNA cloning, immunofluorescence colocalization with PML, monoclonal antibody characterization\",\n      \"pmids\": [\"7540613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function assigned\", \"Link between ND10 localization and later autophagy roles not established\", \"Mechanism of interferon-induced redistribution unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-IP, EM, RNAi with secretion readout\",\n      \"pmids\": [\"17635994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship of Golgi traffic role to autophagy not established\", \"Physiological context of secretory regulation unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined NDP52 as an autophagy receptor that links ubiquitin-coated cytosolic bacteria to the autophagosome by recognizing ubiquitin and recruiting TBK1 via NAP1/SINTBAD.\",\n      \"evidence\": \"siRNA knockdown, colocalization, co-IP, Salmonella proliferation assay\",\n      \"pmids\": [\"19820708\", \"20104023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ubiquitin recognition not yet defined\", \"How NDP52 connects to autophagosomal membranes molecularly not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA knockdown, colocalization, bacterial survival assays, co-IP with signaling readout\",\n      \"pmids\": [\"21079414\", \"21646350\", \"21964925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants selecting septin/actin-dependent vs -independent routes unknown\", \"Mechanism of TRAF6-mediated NDP52 ubiquitination and A20 suppression not fully resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how NDP52 selects a specific ATG8 ortholog, defining the noncanonical LIR that binds LC3C and is essential for antibacterial autophagy.\",\n      \"evidence\": \"Structural analysis, mutagenesis, siRNA knockdown, bacterial survival assay\",\n      \"pmids\": [\"23022382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Roles of other ATG8 family members not yet defined\", \"Whether LC3C binding suffices for membrane recruitment unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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-\\u03baB regulation.\",\n      \"evidence\": \"Crystal structures of NDP52-galectin-8, binding assays, bacterial growth assays; exome sequencing with in vitro NF-\\u03baB functional studies\",\n      \"pmids\": [\"23511477\", \"23386746\", \"23624108\", \"23869922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How galectin-8 sensing integrates with ubiquitin recognition not mechanistically unified\", \"Disease variant effect in vivo not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed NDP52 within an oxidative-stress transcriptional program and neurodegeneration, showing Nrf2 induces NDP52 to drive autophagic clearance of phosphorylated tau.\",\n      \"evidence\": \"Promoter ARE analysis, overexpression, Nrf2-KO mouse, co-IP with AD brain tissue, autophagy flux assay\",\n      \"pmids\": [\"24667209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct receptor-substrate recognition mode for tau not defined\", \"Causal role in human tauopathy not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Domain mutagenesis, co-IP, fusion assays; crystal structure of C2H2 ZF-ubiquitin complex with mutagenesis\",\n      \"pmids\": [\"25771791\", \"26506893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the two LIR functions are temporally coordinated unclear\", \"Role of the second unconventional zinc finger not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended NDP52 to mitochondrial quality control, showing it acts with OPTN to drive TBK1 activation in a feedback loop required for PINK1/PARKIN mitophagy.\",\n      \"evidence\": \"Quantitative/phospho-proteomics, co-IP, in vitro kinase assay, siRNA knockdown, live imaging\",\n      \"pmids\": [\"26365381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Division of labor between NDP52 and OPTN not yet parsed\", \"How TBK1 activation feeds back to receptor recruitment not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified upstream recruitment regulators (Rab35 GTPase) and established NDP52 as a receptor for autophagic degradation of MAVS, integrating it into antiviral signaling control.\",\n      \"evidence\": \"Co-IP, GTPase binding assays, GTPase-cycle mutants, mitophagy assay; ubiquitination mapping, IFN reporter assays\",\n      \"pmids\": [\"28848034\", \"28965816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Rab35 recruitment is coordinated with ubiquitin/galectin sensing unclear\", \"Generality of K27-ubiquitin-driven NDP52 recognition not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided structural and mechanistic detail of the TBK1-adaptor interface (SKICH-NAP1) and revealed phosphoregulation and a ubiquitin-independent mitochondrial substrate (MTPAP).\",\n      \"evidence\": \"Crystal structures of SKICH-NAP1 complexes with mutagenesis; co-IP, proteasome/ubiquitin inhibitor dissection, LC3 recruitment assay\",\n      \"pmids\": [\"30459273\", \"30309841\", \"30154446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of SKICH phosphorylation sites not established\", \"Mechanism of ubiquitin-independent cargo engagement incompletely defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, point mutagenesis, CRISPR KO, xenophagy assay; chemically inducible dimerization with epistasis\",\n      \"pmids\": [\"30853402\", \"30853401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How signals are integrated to time ULK1 activation in vivo unclear\", \"Quantitative thresholds for receptor clustering not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed ubiquitin-independent membrane recruitment of NDP52 by ATG8/GABARAPs for feedback amplification, plus non-autophagy roles in spindle orientation and RNAPII-dependent transcription.\",\n      \"evidence\": \"LIR mutagenesis with CRISPR KO mitophagy assays; TIRFM and in vitro actin assays; FLIM-FRET, FRAP, in vitro DNA binding, mRNA quantification\",\n      \"pmids\": [\"30679426\", \"31201383\", \"29187741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether nuclear and autophagic functions are mechanistically linked unknown\", \"Physiological significance of spindle and transcription roles not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Crystal structures and competitive binding; HDX-MS, EM, GUV reconstitution; CRISPR epistasis\",\n      \"pmids\": [\"34389544\", \"32773036\", \"32892694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NAP1/Claw/ATG8 competition is resolved in vivo unclear\", \"Coordination of NDP52 and OPTN parallel axes not fully defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified NDP52 as a redox sensor that oligomerizes via disulfide bonds to amplify mitophagy, and demonstrated a cellular requirement in beta-cell mitochondrial quality.\",\n      \"evidence\": \"Cysteine mutagenesis, redox/crosslinking assays, CRISPR KO mitophagy quantification; genome-wide CRISPR screen with EM and flux assays\",\n      \"pmids\": [\"36514953\", \"36543916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How oxidation-driven oligomerization couples to receptor function structurally incomplete\", \"Physiological redox thresholds in vivo not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"SUMOylation/IP-MS proteomics, point mutants, co-IP, mitophagy and viral replication assays, super-resolution imaging, transcriptome analysis\",\n      \"pmids\": [\"37942585\", \"37777549\", \"38114531\", \"36634147\", \"37202403\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy and crosstalk among PTMs unclear\", \"Which functions of the diverse cargo repertoire are physiologically dominant unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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-\\u03baB; defined a Rab9-dependent antiviral route distinct from canonical autophagy.\",\n      \"evidence\": \"CRISPR KO with phospho-site mutagenesis; ubiquitination mapping, NF-\\u03baB reporter, myeloid-specific KO mouse; ternary complex mapping and ATG5-KO epistasis\",\n      \"pmids\": [\"39276928\", \"39269442\", \"38752371\", \"38965634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis for selective AZI2 vs TBKBP1 usage unclear\", \"How Rab9-dependent and canonical autophagy routes are partitioned not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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).\",\n      \"evidence\": \"Co-IP, ubiquitination assays, ferroptosis/degeneration models, ZF2 deletion, CRISPR KO mouse\",\n      \"pmids\": [\"41662915\", \"42061478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of E3-ligase recruitment by NDP52 unclear\", \"Mechanism by which ZF2 selects CAPZA1 not structurally defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 23, 24]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [19, 33]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [31]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [19, 33]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 19, 33]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 3, 16]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [14, 18, 21, 31]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 3, 7, 14, 15, 23, 24]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 17, 39, 36]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 13, 22, 34]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [19, 33]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [14, 26, 31]}\n    ],\n    \"complexes\": [\n      \"NDP52-FIP200-SINTBAD/NAP1 autophagy initiation complex\",\n      \"NDP52-galectin-8-LC3C ternary complex\",\n      \"NDP52-myosin VI-RNAPII transcription complex\"\n    ],\n    \"partners\": [\n      \"MYO6\",\n      \"TBK1\",\n      \"RB1CC1\",\n      \"AZI2\",\n      \"TBKBP1\",\n      \"LC3C\",\n      \"GABARAPL2\",\n      \"OPTN\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}