{"gene":"PARP16","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2012,"finding":"PARP16 is a tail-anchored endoplasmic reticulum transmembrane protein with its catalytic domain facing the cytosol. It ADP-ribosylates itself, PERK, and IRE1α during ER stress, and this ADP-ribosylation is sufficient to activate PERK and IRE1α in the absence of ER stress, increasing their kinase activities and the endonuclease activity of IRE1α. The C-terminal luminal tail of PARP16 is required for its function during ER stress, suggesting it transduces stress signals to the cytoplasmic PARP catalytic domain. ATF6 is not regulated by PARP16.","method":"Immunofluorescence, protease protection assay (topology), in vitro ADP-ribosylation assays, overexpression/knockdown with kinase/endonuclease activity readouts, domain deletion mutagenesis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (localization, enzymatic assay, mutagenesis, gain/loss-of-function) in a single rigorous study, replicated in subsequent papers","pmids":["23103912"],"is_preprint":false},{"year":2012,"finding":"PARP16/ARTD15 localizes to membranes of the nuclear envelope and endoplasmic reticulum as a tail-anchored protein with a cytosolic catalytic domain. It functions as a mono-ADP-ribosyltransferase. Karyopherin-β1, a component of the nuclear trafficking machinery, was identified as a binding partner and substrate of PARP16, which mono-ADP-ribosylates it.","method":"Immunofluorescence, electron microscopy, protease protection assay, immunoprecipitation coupled with mass spectrometry, in vitro mono-ADP-ribosylation assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal Co-IP/MS identification of substrate, direct enzymatic assay, orthogonal localization methods, single lab","pmids":["22701565"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of human PARP16/ARTD15 was determined, revealing a novel α-helical domain that packs against the transferase domain without contacting the NAD+-binding crevice or the donor loop. PARP16 displays auto-mono(ADP-ribosylation) activity and is inhibited by canonical poly(ADP-ribose) polymerase inhibitors.","method":"X-ray crystallography, in vitro auto-ADP-ribosylation assay, inhibitor enzyme assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biochemical validation of enzymatic activity, published in peer-reviewed journal","pmids":["22661712"],"is_preprint":false},{"year":2017,"finding":"Epigallocatechin-3-gallate (EGCG) directly binds PARP16 and inhibits its mono-ADP-ribosyltransferase activity in vitro. This inhibition suppresses ER stress-induced phosphorylation of PERK in a PARP16-dependent manner, enhancing cancer cell apoptosis under ER stress conditions.","method":"In vitro PARP16 activity assay, binding assay, PERK phosphorylation measurement, siRNA knockdown with rescue experiments","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro enzyme inhibition plus cellular epistasis (PARP16-dependent effect), single lab with two orthogonal approaches","pmids":["28698806"],"is_preprint":false},{"year":2020,"finding":"PARP16 ADP-ribosylates PERK and IRE1α and promotes proliferation and migration of smooth muscle cells during PDGF-BB stimulation. The histone H3 lysine 4 methyltransferase SMYD3 epigenetically upregulates PARP16 transcription by binding to the Parp16 promoter and increasing H3K4me3 levels, constituting a SMYD3-PARP16 signaling axis that drives UPR activation and neointimal hyperplasia.","method":"ChIP-seq, ChIP, siRNA knockdown, overexpression, in vivo mouse vascular injury model, ADP-ribosylation assays","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq for epigenetic regulation plus functional knockdown/overexpression with defined cellular phenotype, single lab","pmids":["34094832"],"is_preprint":false},{"year":2021,"finding":"Chemical proteomics identified PARP16 as a unique target of the PARP inhibitor talazoparib (in addition to PARP1) in small cell lung cancer cells. Silencing PARP16 significantly reduces cell survival, particularly in combination with PARP1 inhibition, contributing to talazoparib's overall mechanism of action.","method":"Chemical proteomics (activity-based protein profiling), siRNA silencing, cell viability assays, drug combination screening, global phosphoproteomics","journal":"Cell chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical proteomics target identification plus functional validation by silencing, single lab, multiple orthogonal methods","pmids":["34329582"],"is_preprint":false},{"year":2022,"finding":"A structure-guided covalent inhibitor (DB008) was designed to react with a non-conserved cysteine (Cys169) in the NAD+-binding pocket of PARP16. Covalent labeling in cells is dependent on Cys169. PARP16 is sequestered into a detergent-insoluble fraction under prolonged amino acid starvation, and catalytic inhibition by DB008 prevented this sequestration, indicating that PARP16's catalytic activity regulates its solubility in response to nutrient stress.","method":"Structure-guided inhibitor design, copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry, site-directed mutagenesis (Cys169), cell fractionation, in-cell competition labeling","journal":"Chemical science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-guided design with mutagenesis validation of binding site plus functional cellular consequence, single lab but multiple orthogonal methods","pmids":["36544740"],"is_preprint":false},{"year":2020,"finding":"PARP16 catalyzes the priming mono-ADP-ribosylation of VEGF in the endoplasmic reticulum, which is a prerequisite for subsequent poly-ADP-ribosylation of VEGF by Tankyrase-2 (TNKS-2) in the Golgi, thereby modulating VEGF biological activity in the secretory pathway.","method":"ADP-ribosylation assays, co-immunoprecipitation, knockdown experiments","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited methodological detail in abstract, single publication","pmids":["32472322"],"is_preprint":false},{"year":2023,"finding":"PARP16 functions as an RNA-binding protein that binds APP mRNA and protects it from degradation, thereby increasing APP protein levels and contributing to Alzheimer's disease pathology. Knockdown of PARP16 in APP/PS1 mice decreased amyloid deposition and ER stress.","method":"Adeno-associated virus-mediated knockdown in mice, RNA-binding protein assays, APP mRNA stability assay, in vitro knockdown in HT22 cells","journal":"Aging and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro loss-of-function with defined molecular mechanism (mRNA stabilization), single lab, orthogonal in vivo and in vitro approaches","pmids":["37163422"],"is_preprint":false},{"year":2023,"finding":"PARP16 ADP-ribosylates PERK and IRE1α to modulate their activation in ischemic neurons. Knockdown of PARP16 decreases ADP-ribosylation of PERK and IRE1α, reduces ER stress and neuronal death after oxygen-glucose deprivation/reoxygenation, while PARP16 overexpression promotes ER stress-mediated cell damage.","method":"Adeno-associated virus-mediated knockdown in mice, overexpression in primary cortical neurons, ADP-ribosylation assays, pharmacological UPR rescue with Brefeldin A","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro gain/loss-of-function with mechanistic rescue experiment, single lab","pmids":["36692424"],"is_preprint":false},{"year":2020,"finding":"SMYD3 epigenetically upregulates PARP16 expression by binding the Parp16 promoter and increasing H3K4me3, driving PARP16-dependent UPR and endothelial cell senescence in the context of Ang II-induced vascular aging.","method":"ChIP assay, siRNA knockdown, overexpression, cell senescence assays, mouse vascular aging model","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding plus functional cellular consequence, single lab, replicates findings from companion paper","pmids":["33144524"],"is_preprint":false},{"year":2024,"finding":"KDM6B (a histone H3K27 demethylase) epigenetically upregulates PARP16 expression by reducing H3K27me3 levels at the Parp16 locus. KDM6B knockdown reduced PARP16 expression and protected neurons from Aβ-induced cytotoxicity; PARP16 overexpression negated the neuroprotective effect of KDM6B knockdown.","method":"Chromatin immunoprecipitation (ChIP), siRNA knockdown, adeno-associated virus-mediated knockdown, overexpression rescue experiments in primary neurons and APP/PS1 mice","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP validation of epigenetic mechanism plus functional epistasis rescue experiment, single lab","pmids":["39603516"],"is_preprint":false},{"year":2020,"finding":"Latonduine A and its synthetic analogue MCG315 correct F508del-CFTR trafficking through simultaneous inhibition of both PARP3 and PARP16. Neither selective PARP3 nor selective PARP16 inhibitors alone showed corrector activity, but their combination recapitulated the activity of latonduine A, confirming a dual-target mechanism.","method":"Pull-down experiments, enzyme inhibition assays, siRNA knockdown, F508del-CFTR trafficking cell-based assay, structure-activity relationship study with selective inhibitors","journal":"ACS omega","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzyme inhibition assays plus siRNA knockdown and pharmacological epistasis with defined cellular phenotype (CFTR trafficking), single lab, multiple orthogonal methods","pmids":["33073085"],"is_preprint":false},{"year":2026,"finding":"PARP16 undergoes NAD+-dependent auto-MARylation, with NAD+ supplied by NMNAT-2. PARP16 MARylates ribosomal proteins, thereby fine-tuning translation and maintaining protein homeostasis. Inhibition of PARP16 (by DB008) or genetic depletion reduces ribosome-associated MARylation, enhances global protein synthesis, increases protein aggregation, and impairs tumor cell growth. CRISPR deletion of PARP16 abolished these effects, confirming on-target activity.","method":"In vitro auto-MARylation assay, CRISPR knockout, drug-resistant PARP16 mutant, ribosome MARylation mass spectrometry, polysome profiling, protein aggregation assay, xenograft tumor model","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in vitro, genetic CRISPR deletion, drug-resistant mutant rescue, in vivo xenograft, multiple orthogonal mechanistic methods","pmids":["41959139"],"is_preprint":true}],"current_model":"PARP16 is a tail-anchored, ER-resident mono-ADP-ribosyltransferase (MARylating enzyme) whose cytosolic catalytic domain, supplied with NAD+ by NMNAT-2, auto-MARylates and modifies substrates including PERK and IRE1α (activating their kinase/endonuclease activities to drive the UPR), karyopherin-β1 (regulating nuclear trafficking), ribosomal proteins (fine-tuning translation and protein homeostasis), and VEGF (priming it for subsequent poly-ADP-ribosylation by Tankyrase-2); its transcription is epigenetically regulated by SMYD3 (via H3K4me3) and KDM6B (via H3K27me3), and its catalytic activity controls its own solubility under nutrient stress."},"narrative":{"mechanistic_narrative":"PARP16 (ARTD15) is a tail-anchored, ER- and nuclear-envelope-resident mono-ADP-ribosyltransferase whose catalytic domain faces the cytosol and acts as a node linking the secretory pathway to the unfolded protein response [PMID:23103912, PMID:22701565]. Its crystal structure reveals a transferase domain capped by a novel α-helical domain, and it carries out auto-mono-ADP-ribosylation that is blocked by canonical PARP inhibitors [PMID:22661712]. Mechanistically, PARP16 ADP-ribosylates the UPR transducers PERK and IRE1α, and this modification is sufficient to activate their kinase and endonuclease activities even without ER stress, with the C-terminal luminal tail required to relay the stress signal to the cytosolic catalytic domain while ATF6 is left unaffected [PMID:23103912]. PARP16 additionally MARylates karyopherin-β1, a nuclear-trafficking component identified as a direct binding partner and substrate [PMID:22701565], and MARylates ribosomal proteins in an NAD+-dependent manner (NAD+ supplied by NMNAT-2) to restrain global protein synthesis and maintain proteostasis, with loss of activity increasing translation and protein aggregation and impairing tumor growth [PMID:41959139]. PARP16 catalytic activity also governs its own behavior, sequestering the enzyme into a detergent-insoluble fraction under amino-acid starvation [PMID:36544740]. Across vascular and neuronal disease models, PARP16 transcription is epigenetically controlled — upregulated by SMYD3 via H3K4me3 and by KDM6B via removal of H3K27me3 — driving UPR-dependent phenotypes such as neointimal hyperplasia, endothelial senescence, and Aβ-associated neurotoxicity [PMID:34094832, PMID:33144524, PMID:39603516]. PARP16 is pharmacologically tractable through both natural-product inhibitors and a structure-guided covalent inhibitor (DB008) targeting Cys169 in the NAD+ pocket [PMID:28698806, PMID:36544740].","teleology":[{"year":2012,"claim":"Established PARP16's identity as a membrane-anchored MARylating enzyme and its core mechanism: that it ADP-ribosylates PERK and IRE1α to activate the UPR independently of ER stress.","evidence":"Topology/protease protection, in vitro ADP-ribosylation, gain/loss-of-function with kinase/endonuclease readouts, and domain deletion in cells","pmids":["23103912","22701565"],"confidence":"High","gaps":["How the luminal tail senses ER stress and signals across the membrane is not defined","ATF6 arm is excluded but the basis for selectivity is unknown"]},{"year":2012,"claim":"Provided the structural and biochemical framework, revealing a novel α-helical domain abutting the transferase fold and confirming auto-MARylation sensitive to canonical PARP inhibitors.","evidence":"X-ray crystallography with in vitro auto-ADP-ribosylation and inhibitor assays","pmids":["22661712"],"confidence":"High","gaps":["No substrate-bound or membrane-context structure","Function of the α-helical domain not assigned"]},{"year":2017,"claim":"Demonstrated that pharmacological inhibition of PARP16 catalytic activity suppresses PERK phosphorylation and sensitizes cancer cells to ER-stress apoptosis, validating PARP16 as a druggable UPR regulator.","evidence":"In vitro enzyme/binding assays with EGCG plus siRNA knockdown and rescue in cells","pmids":["28698806"],"confidence":"Medium","gaps":["EGCG is non-selective; off-target contributions not excluded","Whether direct PERK MARylation is the inhibited event was not shown"]},{"year":2020,"claim":"Connected PARP16 expression to upstream epigenetic control, showing SMYD3 directly binds the Parp16 promoter and deposits H3K4me3 to drive UPR-dependent vascular pathologies.","evidence":"ChIP/ChIP-seq, knockdown/overexpression, and mouse vascular injury and aging models","pmids":["34094832","33144524"],"confidence":"Medium","gaps":["Whether SMYD3 acts directly versus via additional factors not fully resolved","Tissue specificity of the SMYD3-PARP16 axis unknown"]},{"year":2020,"claim":"Extended PARP16's substrate range into the secretory pathway by positioning it as the priming MARylase for VEGF that licenses subsequent Tankyrase-2 poly-ADP-ribosylation.","evidence":"ADP-ribosylation assays, co-IP, and knockdown","pmids":["32472322"],"confidence":"Low","gaps":["Single low-detail report; awaits independent confirmation","MARylation site on VEGF and functional consequence not mapped"]},{"year":2020,"claim":"Showed PARP16 is a co-target in disease-relevant pharmacology, with dual PARP3/PARP16 inhibition required to correct F508del-CFTR trafficking.","evidence":"Pull-down, enzyme inhibition, siRNA, and CFTR trafficking assays with selective inhibitor combinations","pmids":["33073085"],"confidence":"Medium","gaps":["Direct PARP16 substrate in the CFTR pathway not identified","Mechanistic link between PARP16 activity and CFTR folding unresolved"]},{"year":2021,"claim":"Identified PARP16 as an unexpected target of the clinical PARP inhibitor talazoparib whose silencing reduces cancer cell survival, broadening its therapeutic relevance.","evidence":"Chemical proteomics, siRNA silencing, viability and combination assays in small cell lung cancer cells","pmids":["34329582"],"confidence":"Medium","gaps":["Substrate mediating the survival effect not defined","Selectivity of talazoparib for PARP16 versus other PARPs incompletely quantified"]},{"year":2022,"claim":"Delivered a selective covalent chemical tool (DB008) targeting non-conserved Cys169 and uncovered that PARP16 catalytic activity controls its own solubility under nutrient stress.","evidence":"Structure-guided design, Cys169 mutagenesis, click-chemistry in-cell labeling, and cell fractionation under amino-acid starvation","pmids":["36544740"],"confidence":"High","gaps":["Auto-MARylation target sites driving sequestration not mapped","Functional purpose of insoluble sequestration unclear"]},{"year":2023,"claim":"Implicated PARP16 in neurodegeneration through two routes: as an RNA-binding protein that stabilizes APP mRNA, and as a UPR driver in ischemic neuronal death.","evidence":"AAV-mediated knockdown and overexpression in mice and primary neurons, RNA-binding/mRNA stability assays, ADP-ribosylation assays, and UPR rescue with Brefeldin A","pmids":["37163422","36692424"],"confidence":"Medium","gaps":["RNA-binding activity not reconciled with catalytic MARylation function","Whether APP mRNA binding is direct and which domain mediates it not established"]},{"year":2024,"claim":"Identified a second epigenetic activator, KDM6B, which derepresses Parp16 by erasing H3K27me3, with PARP16 acting downstream to mediate Aβ neurotoxicity.","evidence":"ChIP, siRNA and AAV knockdown, and overexpression epistasis rescue in neurons and APP/PS1 mice","pmids":["39603516"],"confidence":"Medium","gaps":["Interplay between KDM6B and SMYD3 control of the same locus unresolved","Direct versus indirect KDM6B recruitment not addressed"]},{"year":2026,"claim":"Defined a proteostatic role in which NMNAT-2-supplied NAD+ fuels PARP16 auto-MARylation and ribosomal-protein MARylation to restrain translation, with loss promoting aggregation and impairing tumor growth.","evidence":"In vitro reconstitution, CRISPR knockout, drug-resistant mutant rescue, ribosome MARylation MS, polysome profiling, and xenograft (preprint)","pmids":["41959139"],"confidence":"High","gaps":["Preprint not yet peer-reviewed","Specific ribosomal protein MARylation sites and their translational consequence not pinpointed"]},{"year":null,"claim":"How PARP16's distinct activities — transmembrane UPR signaling, ribosomal/translational control, RNA binding, and self-solubility regulation — are integrated and selected among its diverse substrates remains unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model of substrate selection across UPR sensors, karyopherin-β1, ribosomal proteins, and VEGF","Physiological signals that switch PARP16 between functions undefined","No structure of PARP16 engaging any protein substrate"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,13]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[13]}],"complexes":[],"partners":["EIF2AK3","ERN1","KPNB1","NMNAT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N5Y8","full_name":"Protein mono-ADP-ribosyltransferase PARP16","aliases":["ADP-ribosyltransferase diphtheria toxin-like 15","Poly [ADP-ribose] polymerase 16","PARP-16"],"length_aa":322,"mass_kda":36.4,"function":"Intracellular mono-ADP-ribosyltransferase that plays a role in different processes, such as protein translation and unfolded protein response (UPR), through the mono-ADP-ribosylation of proteins involved in those processes (PubMed:22701565, PubMed:23103912, PubMed:25043379, PubMed:34314702). Acts as an inhibitor of protein translation by catalyzing mono-ADP-ribosylation of ribosomal subunits, such as RPL14 and RPS6, thereby inhibiting polysome assembly and mRNA loading (PubMed:34314702). Mono-ADP-ribosylation of ribosomal subunits is promoted by NMNAT2 (PubMed:34314702). Involved in the unfolded protein response (UPR) by ADP-ribosylating and activating EIF2AK3 and ERN1, two important UPR effectors (PubMed:23103912). May also mediate mono-ADP-ribosylation of karyopherin KPNB1 a nuclear import factor (PubMed:22701565). May not modify proteins on arginine or cysteine residues compared to other mono-ADP-ribosyltransferases (PubMed:22701565)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q8N5Y8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PARP16","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TMED10","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PARP16","total_profiled":1310},"omim":[{"mim_id":"620391","title":"POLY(ADP-RIBOSE) POLYMERASE FAMILY, MEMBER 16; PARP16","url":"https://www.omim.org/entry/620391"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PARP16"},"hgnc":{"alias_symbol":["FLJ20509","FLJ25281","pART15","ARTD15"],"prev_symbol":["C15orf30"]},"alphafold":{"accession":"Q8N5Y8","domains":[{"cath_id":"-","chopping":"3-89","consensus_level":"medium","plddt":93.7653,"start":3,"end":89},{"cath_id":"3.90.228.10","chopping":"94-271","consensus_level":"medium","plddt":88.6044,"start":94,"end":271}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N5Y8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N5Y8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N5Y8-F1-predicted_aligned_error_v6.png","plddt_mean":88.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PARP16","jax_strain_url":"https://www.jax.org/strain/search?query=PARP16"},"sequence":{"accession":"Q8N5Y8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N5Y8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N5Y8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N5Y8"}},"corpus_meta":[{"pmid":"23103912","id":"PMC_23103912","title":"PARP16 is a tail-anchored endoplasmic reticulum protein required for the PERK- and IRE1α-mediated unfolded protein response.","date":"2012","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23103912","citation_count":162,"is_preprint":false},{"pmid":"22701565","id":"PMC_22701565","title":"PARP16/ARTD15 is a novel endoplasmic-reticulum-associated mono-ADP-ribosyltransferase that interacts with, and modifies karyopherin-ß1.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22701565","citation_count":76,"is_preprint":false},{"pmid":"28698806","id":"PMC_28698806","title":"Epigallocatechin-3-gallate enhances ER stress-induced cancer cell apoptosis by directly targeting PARP16 activity.","date":"2017","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/28698806","citation_count":35,"is_preprint":false},{"pmid":"34329582","id":"PMC_34329582","title":"The non-canonical target PARP16 contributes to polypharmacology of the PARP inhibitor talazoparib and its synergy with WEE1 inhibitors.","date":"2021","source":"Cell chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/34329582","citation_count":30,"is_preprint":false},{"pmid":"34094832","id":"PMC_34094832","title":"SMYD3-PARP16 axis accelerates unfolded protein response and mediates neointima formation.","date":"2020","source":"Acta pharmaceutica Sinica. 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It ADP-ribosylates itself, PERK, and IRE1α during ER stress, and this ADP-ribosylation is sufficient to activate PERK and IRE1α in the absence of ER stress, increasing their kinase activities and the endonuclease activity of IRE1α. The C-terminal luminal tail of PARP16 is required for its function during ER stress, suggesting it transduces stress signals to the cytoplasmic PARP catalytic domain. ATF6 is not regulated by PARP16.\",\n      \"method\": \"Immunofluorescence, protease protection assay (topology), in vitro ADP-ribosylation assays, overexpression/knockdown with kinase/endonuclease activity readouts, domain deletion mutagenesis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (localization, enzymatic assay, mutagenesis, gain/loss-of-function) in a single rigorous study, replicated in subsequent papers\",\n      \"pmids\": [\"23103912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PARP16/ARTD15 localizes to membranes of the nuclear envelope and endoplasmic reticulum as a tail-anchored protein with a cytosolic catalytic domain. It functions as a mono-ADP-ribosyltransferase. Karyopherin-β1, a component of the nuclear trafficking machinery, was identified as a binding partner and substrate of PARP16, which mono-ADP-ribosylates it.\",\n      \"method\": \"Immunofluorescence, electron microscopy, protease protection assay, immunoprecipitation coupled with mass spectrometry, in vitro mono-ADP-ribosylation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal Co-IP/MS identification of substrate, direct enzymatic assay, orthogonal localization methods, single lab\",\n      \"pmids\": [\"22701565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of human PARP16/ARTD15 was determined, revealing a novel α-helical domain that packs against the transferase domain without contacting the NAD+-binding crevice or the donor loop. PARP16 displays auto-mono(ADP-ribosylation) activity and is inhibited by canonical poly(ADP-ribose) polymerase inhibitors.\",\n      \"method\": \"X-ray crystallography, in vitro auto-ADP-ribosylation assay, inhibitor enzyme assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biochemical validation of enzymatic activity, published in peer-reviewed journal\",\n      \"pmids\": [\"22661712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Epigallocatechin-3-gallate (EGCG) directly binds PARP16 and inhibits its mono-ADP-ribosyltransferase activity in vitro. This inhibition suppresses ER stress-induced phosphorylation of PERK in a PARP16-dependent manner, enhancing cancer cell apoptosis under ER stress conditions.\",\n      \"method\": \"In vitro PARP16 activity assay, binding assay, PERK phosphorylation measurement, siRNA knockdown with rescue experiments\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro enzyme inhibition plus cellular epistasis (PARP16-dependent effect), single lab with two orthogonal approaches\",\n      \"pmids\": [\"28698806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PARP16 ADP-ribosylates PERK and IRE1α and promotes proliferation and migration of smooth muscle cells during PDGF-BB stimulation. The histone H3 lysine 4 methyltransferase SMYD3 epigenetically upregulates PARP16 transcription by binding to the Parp16 promoter and increasing H3K4me3 levels, constituting a SMYD3-PARP16 signaling axis that drives UPR activation and neointimal hyperplasia.\",\n      \"method\": \"ChIP-seq, ChIP, siRNA knockdown, overexpression, in vivo mouse vascular injury model, ADP-ribosylation assays\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq for epigenetic regulation plus functional knockdown/overexpression with defined cellular phenotype, single lab\",\n      \"pmids\": [\"34094832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Chemical proteomics identified PARP16 as a unique target of the PARP inhibitor talazoparib (in addition to PARP1) in small cell lung cancer cells. Silencing PARP16 significantly reduces cell survival, particularly in combination with PARP1 inhibition, contributing to talazoparib's overall mechanism of action.\",\n      \"method\": \"Chemical proteomics (activity-based protein profiling), siRNA silencing, cell viability assays, drug combination screening, global phosphoproteomics\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical proteomics target identification plus functional validation by silencing, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34329582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A structure-guided covalent inhibitor (DB008) was designed to react with a non-conserved cysteine (Cys169) in the NAD+-binding pocket of PARP16. Covalent labeling in cells is dependent on Cys169. PARP16 is sequestered into a detergent-insoluble fraction under prolonged amino acid starvation, and catalytic inhibition by DB008 prevented this sequestration, indicating that PARP16's catalytic activity regulates its solubility in response to nutrient stress.\",\n      \"method\": \"Structure-guided inhibitor design, copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry, site-directed mutagenesis (Cys169), cell fractionation, in-cell competition labeling\",\n      \"journal\": \"Chemical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-guided design with mutagenesis validation of binding site plus functional cellular consequence, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36544740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PARP16 catalyzes the priming mono-ADP-ribosylation of VEGF in the endoplasmic reticulum, which is a prerequisite for subsequent poly-ADP-ribosylation of VEGF by Tankyrase-2 (TNKS-2) in the Golgi, thereby modulating VEGF biological activity in the secretory pathway.\",\n      \"method\": \"ADP-ribosylation assays, co-immunoprecipitation, knockdown experiments\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited methodological detail in abstract, single publication\",\n      \"pmids\": [\"32472322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PARP16 functions as an RNA-binding protein that binds APP mRNA and protects it from degradation, thereby increasing APP protein levels and contributing to Alzheimer's disease pathology. Knockdown of PARP16 in APP/PS1 mice decreased amyloid deposition and ER stress.\",\n      \"method\": \"Adeno-associated virus-mediated knockdown in mice, RNA-binding protein assays, APP mRNA stability assay, in vitro knockdown in HT22 cells\",\n      \"journal\": \"Aging and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro loss-of-function with defined molecular mechanism (mRNA stabilization), single lab, orthogonal in vivo and in vitro approaches\",\n      \"pmids\": [\"37163422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PARP16 ADP-ribosylates PERK and IRE1α to modulate their activation in ischemic neurons. Knockdown of PARP16 decreases ADP-ribosylation of PERK and IRE1α, reduces ER stress and neuronal death after oxygen-glucose deprivation/reoxygenation, while PARP16 overexpression promotes ER stress-mediated cell damage.\",\n      \"method\": \"Adeno-associated virus-mediated knockdown in mice, overexpression in primary cortical neurons, ADP-ribosylation assays, pharmacological UPR rescue with Brefeldin A\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro gain/loss-of-function with mechanistic rescue experiment, single lab\",\n      \"pmids\": [\"36692424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SMYD3 epigenetically upregulates PARP16 expression by binding the Parp16 promoter and increasing H3K4me3, driving PARP16-dependent UPR and endothelial cell senescence in the context of Ang II-induced vascular aging.\",\n      \"method\": \"ChIP assay, siRNA knockdown, overexpression, cell senescence assays, mouse vascular aging model\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding plus functional cellular consequence, single lab, replicates findings from companion paper\",\n      \"pmids\": [\"33144524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM6B (a histone H3K27 demethylase) epigenetically upregulates PARP16 expression by reducing H3K27me3 levels at the Parp16 locus. KDM6B knockdown reduced PARP16 expression and protected neurons from Aβ-induced cytotoxicity; PARP16 overexpression negated the neuroprotective effect of KDM6B knockdown.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), siRNA knockdown, adeno-associated virus-mediated knockdown, overexpression rescue experiments in primary neurons and APP/PS1 mice\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validation of epigenetic mechanism plus functional epistasis rescue experiment, single lab\",\n      \"pmids\": [\"39603516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Latonduine A and its synthetic analogue MCG315 correct F508del-CFTR trafficking through simultaneous inhibition of both PARP3 and PARP16. Neither selective PARP3 nor selective PARP16 inhibitors alone showed corrector activity, but their combination recapitulated the activity of latonduine A, confirming a dual-target mechanism.\",\n      \"method\": \"Pull-down experiments, enzyme inhibition assays, siRNA knockdown, F508del-CFTR trafficking cell-based assay, structure-activity relationship study with selective inhibitors\",\n      \"journal\": \"ACS omega\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzyme inhibition assays plus siRNA knockdown and pharmacological epistasis with defined cellular phenotype (CFTR trafficking), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33073085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PARP16 undergoes NAD+-dependent auto-MARylation, with NAD+ supplied by NMNAT-2. PARP16 MARylates ribosomal proteins, thereby fine-tuning translation and maintaining protein homeostasis. Inhibition of PARP16 (by DB008) or genetic depletion reduces ribosome-associated MARylation, enhances global protein synthesis, increases protein aggregation, and impairs tumor cell growth. CRISPR deletion of PARP16 abolished these effects, confirming on-target activity.\",\n      \"method\": \"In vitro auto-MARylation assay, CRISPR knockout, drug-resistant PARP16 mutant, ribosome MARylation mass spectrometry, polysome profiling, protein aggregation assay, xenograft tumor model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in vitro, genetic CRISPR deletion, drug-resistant mutant rescue, in vivo xenograft, multiple orthogonal mechanistic methods\",\n      \"pmids\": [\"41959139\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PARP16 is a tail-anchored, ER-resident mono-ADP-ribosyltransferase (MARylating enzyme) whose cytosolic catalytic domain, supplied with NAD+ by NMNAT-2, auto-MARylates and modifies substrates including PERK and IRE1α (activating their kinase/endonuclease activities to drive the UPR), karyopherin-β1 (regulating nuclear trafficking), ribosomal proteins (fine-tuning translation and protein homeostasis), and VEGF (priming it for subsequent poly-ADP-ribosylation by Tankyrase-2); its transcription is epigenetically regulated by SMYD3 (via H3K4me3) and KDM6B (via H3K27me3), and its catalytic activity controls its own solubility under nutrient stress.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PARP16 (ARTD15) is a tail-anchored, ER- and nuclear-envelope-resident mono-ADP-ribosyltransferase whose catalytic domain faces the cytosol and acts as a node linking the secretory pathway to the unfolded protein response [#0, #1]. Its crystal structure reveals a transferase domain capped by a novel α-helical domain, and it carries out auto-mono-ADP-ribosylation that is blocked by canonical PARP inhibitors [#2]. Mechanistically, PARP16 ADP-ribosylates the UPR transducers PERK and IRE1α, and this modification is sufficient to activate their kinase and endonuclease activities even without ER stress, with the C-terminal luminal tail required to relay the stress signal to the cytosolic catalytic domain while ATF6 is left unaffected [#0]. PARP16 additionally MARylates karyopherin-β1, a nuclear-trafficking component identified as a direct binding partner and substrate [#1], and MARylates ribosomal proteins in an NAD+-dependent manner (NAD+ supplied by NMNAT-2) to restrain global protein synthesis and maintain proteostasis, with loss of activity increasing translation and protein aggregation and impairing tumor growth [#13]. PARP16 catalytic activity also governs its own behavior, sequestering the enzyme into a detergent-insoluble fraction under amino-acid starvation [#6]. Across vascular and neuronal disease models, PARP16 transcription is epigenetically controlled — upregulated by SMYD3 via H3K4me3 and by KDM6B via removal of H3K27me3 — driving UPR-dependent phenotypes such as neointimal hyperplasia, endothelial senescence, and Aβ-associated neurotoxicity [#4, #10, #11]. PARP16 is pharmacologically tractable through both natural-product inhibitors and a structure-guided covalent inhibitor (DB008) targeting Cys169 in the NAD+ pocket [#3, #6].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established PARP16's identity as a membrane-anchored MARylating enzyme and its core mechanism: that it ADP-ribosylates PERK and IRE1α to activate the UPR independently of ER stress.\",\n      \"evidence\": \"Topology/protease protection, in vitro ADP-ribosylation, gain/loss-of-function with kinase/endonuclease readouts, and domain deletion in cells\",\n      \"pmids\": [\"23103912\", \"22701565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the luminal tail senses ER stress and signals across the membrane is not defined\", \"ATF6 arm is excluded but the basis for selectivity is unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided the structural and biochemical framework, revealing a novel α-helical domain abutting the transferase fold and confirming auto-MARylation sensitive to canonical PARP inhibitors.\",\n      \"evidence\": \"X-ray crystallography with in vitro auto-ADP-ribosylation and inhibitor assays\",\n      \"pmids\": [\"22661712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No substrate-bound or membrane-context structure\", \"Function of the α-helical domain not assigned\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that pharmacological inhibition of PARP16 catalytic activity suppresses PERK phosphorylation and sensitizes cancer cells to ER-stress apoptosis, validating PARP16 as a druggable UPR regulator.\",\n      \"evidence\": \"In vitro enzyme/binding assays with EGCG plus siRNA knockdown and rescue in cells\",\n      \"pmids\": [\"28698806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EGCG is non-selective; off-target contributions not excluded\", \"Whether direct PERK MARylation is the inhibited event was not shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected PARP16 expression to upstream epigenetic control, showing SMYD3 directly binds the Parp16 promoter and deposits H3K4me3 to drive UPR-dependent vascular pathologies.\",\n      \"evidence\": \"ChIP/ChIP-seq, knockdown/overexpression, and mouse vascular injury and aging models\",\n      \"pmids\": [\"34094832\", \"33144524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SMYD3 acts directly versus via additional factors not fully resolved\", \"Tissue specificity of the SMYD3-PARP16 axis unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended PARP16's substrate range into the secretory pathway by positioning it as the priming MARylase for VEGF that licenses subsequent Tankyrase-2 poly-ADP-ribosylation.\",\n      \"evidence\": \"ADP-ribosylation assays, co-IP, and knockdown\",\n      \"pmids\": [\"32472322\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single low-detail report; awaits independent confirmation\", \"MARylation site on VEGF and functional consequence not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed PARP16 is a co-target in disease-relevant pharmacology, with dual PARP3/PARP16 inhibition required to correct F508del-CFTR trafficking.\",\n      \"evidence\": \"Pull-down, enzyme inhibition, siRNA, and CFTR trafficking assays with selective inhibitor combinations\",\n      \"pmids\": [\"33073085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PARP16 substrate in the CFTR pathway not identified\", \"Mechanistic link between PARP16 activity and CFTR folding unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified PARP16 as an unexpected target of the clinical PARP inhibitor talazoparib whose silencing reduces cancer cell survival, broadening its therapeutic relevance.\",\n      \"evidence\": \"Chemical proteomics, siRNA silencing, viability and combination assays in small cell lung cancer cells\",\n      \"pmids\": [\"34329582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate mediating the survival effect not defined\", \"Selectivity of talazoparib for PARP16 versus other PARPs incompletely quantified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Delivered a selective covalent chemical tool (DB008) targeting non-conserved Cys169 and uncovered that PARP16 catalytic activity controls its own solubility under nutrient stress.\",\n      \"evidence\": \"Structure-guided design, Cys169 mutagenesis, click-chemistry in-cell labeling, and cell fractionation under amino-acid starvation\",\n      \"pmids\": [\"36544740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Auto-MARylation target sites driving sequestration not mapped\", \"Functional purpose of insoluble sequestration unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated PARP16 in neurodegeneration through two routes: as an RNA-binding protein that stabilizes APP mRNA, and as a UPR driver in ischemic neuronal death.\",\n      \"evidence\": \"AAV-mediated knockdown and overexpression in mice and primary neurons, RNA-binding/mRNA stability assays, ADP-ribosylation assays, and UPR rescue with Brefeldin A\",\n      \"pmids\": [\"37163422\", \"36692424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding activity not reconciled with catalytic MARylation function\", \"Whether APP mRNA binding is direct and which domain mediates it not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a second epigenetic activator, KDM6B, which derepresses Parp16 by erasing H3K27me3, with PARP16 acting downstream to mediate Aβ neurotoxicity.\",\n      \"evidence\": \"ChIP, siRNA and AAV knockdown, and overexpression epistasis rescue in neurons and APP/PS1 mice\",\n      \"pmids\": [\"39603516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between KDM6B and SMYD3 control of the same locus unresolved\", \"Direct versus indirect KDM6B recruitment not addressed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a proteostatic role in which NMNAT-2-supplied NAD+ fuels PARP16 auto-MARylation and ribosomal-protein MARylation to restrain translation, with loss promoting aggregation and impairing tumor growth.\",\n      \"evidence\": \"In vitro reconstitution, CRISPR knockout, drug-resistant mutant rescue, ribosome MARylation MS, polysome profiling, and xenograft (preprint)\",\n      \"pmids\": [\"41959139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Specific ribosomal protein MARylation sites and their translational consequence not pinpointed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PARP16's distinct activities — transmembrane UPR signaling, ribosomal/translational control, RNA binding, and self-solubility regulation — are integrated and selected among its diverse substrates remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model of substrate selection across UPR sensors, karyopherin-β1, ribosomal proteins, and VEGF\", \"Physiological signals that switch PARP16 between functions undefined\", \"No structure of PARP16 engaging any protein substrate\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 13]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EIF2AK3\", \"ERN1\", \"KPNB1\", \"NMNAT2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}