{"gene":"PARP9","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2015,"finding":"PARP9 forms a complex with DTX3L (BBAP) that functions as an E3 ubiquitin ligase; this complex acts on host histone H2BJ to promote interferon-stimulated gene expression and on viral 3C proteases to degrade them via the immunoproteasome, providing a double layer of antiviral immunity.","method":"Co-immunoprecipitation, transgenic mouse model, transduced human cells, functional rescue assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus in vivo genetic model with defined phenotypic readout, replicated across multiple cell/organism systems","pmids":["26479788"],"is_preprint":false},{"year":2016,"finding":"PARP9 and PARP14 have opposing roles in macrophage activation: PARP14 induces ADP-ribosylation of STAT1, which suppresses its phosphorylation, while PARP9 suppresses this PARP14-dependent ADP-ribosylation, thereby promoting STAT1 phosphorylation and pro-inflammatory gene expression in IFNγ-stimulated macrophages. Mutations at the PARP14 ADP-ribosylation sites on STAT1 lead to increased phosphorylation.","method":"siRNA silencing in primary macrophages, global proteomic analysis, ADP-ribosylation assays, phosphorylation assays, site-directed mutagenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — enzymatic activity demonstrated, mutagenesis of modification sites validates mechanism, multiple orthogonal methods","pmids":["27796300"],"is_preprint":false},{"year":2017,"finding":"The DTX3L/PARP9 heterodimer mediates NAD+-dependent mono-ADP-ribosylation of ubiquitin at its C-terminal Gly76 residue exclusively in the context of ubiquitin processing by E1 and E2 enzymes; this ADP-ribosylation of Gly76 precludes ubiquitylation of substrates. Poly(ADP-ribose) binding to PARP9 macrodomains increases the E3 ligase activity of DTX3L, while PARP9 ADP-ribosylation activity restrains DTX3L E3 function.","method":"In vitro ADP-ribosylation assay, site-directed mutagenesis of NAD+-binding site, reconstituted ubiquitination assay, PAR-binding assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro biochemistry with mutagenesis, clearly defining substrate (Gly76 of ubiquitin) and regulatory mechanism","pmids":["28525742"],"is_preprint":false},{"year":2012,"finding":"PARP9 (BAL1) is recruited to DNA damage sites in a PARP1-dependent and PAR-dependent manner; once recruited, its partner E3 ligase BBAP (DTX3L) mediates local ubiquitylation, promoting subsequent recruitment of 53BP1 and BRCA1. This pathway limits DNA damage and enhances cellular viability independently of ATM, MDC1, and RNF8.","method":"Laser micro-irradiation with live imaging, co-immunoprecipitation, siRNA knockdown with DNA damage assays (γH2AX foci), epistasis with ATM/MDC1/RNF8 inhibitors","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment linked to functional consequence, genetic epistasis, multiple orthogonal methods","pmids":["23230272"],"is_preprint":false},{"year":2013,"finding":"PARP9 (BAL1/ARTD9) physically interacts with both STAT1α and STAT1β through its macrodomains in an ADP-ribosylation-dependent manner, stimulates phosphorylation of both STAT1 isoforms at Y701, promotes nuclear accumulation of the transcriptionally repressive isoform STAT1β, and together with STAT1β directly represses IRF1 expression while enhancing IRF2 and BCL6 expression in DLBCL.","method":"Co-immunoprecipitation, immunofluorescence, Western blotting, siRNA knockdown, overexpression experiments in DLBCL cell lines","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP demonstrates physical interaction, functional assays show downstream effects, but single lab","pmids":["23487038"],"is_preprint":false},{"year":2013,"finding":"DTX3L (BBAP) forms a complex with PARP9 (ARTD9) and PARP14 (ARTD8); these three proteins physically interact and together mediate proliferation, chemoresistance, and survival of metastatic prostate cancer cells. DTX3L and PARP9 act together as repressors of tumor suppressor IRF1.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown with cell viability and migration assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP confirms complex, functional KD phenotype, but single lab and limited mechanistic depth for PARP9-specific activity","pmids":["24886089"],"is_preprint":false},{"year":2021,"finding":"PARP9 serves as a non-canonical RNA sensor in dendritic cells; it directly binds viral double-stranded RNA and recruits and activates the PI3K/AKT3 pathway independently of MAVS. PI3K/AKT3 then activates IRF3 (at Ser385) and IRF7 (at Ser437/438) to drive type I IFN production. PARP9-deficient mice show enhanced susceptibility to RNA virus infection due to impaired type I IFN production.","method":"RNA pulldown/binding assay, KO mouse model with viral infection, siRNA knockdown, phosphorylation site mapping, PI3K/AKT3 inhibitor epistasis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — direct RNA binding demonstrated, KO mouse phenotype with defined signaling pathway, phosphorylation site identification","pmids":["33976210"],"is_preprint":false},{"year":2021,"finding":"IFN-induced ADP-ribosylation of host proteins is dependent on PARP9 and its binding partner DTX3L; the SARS-CoV-2 Nsp3 macrodomain reverses this PARP9/DTX3L-dependent ADP-ribosylation. Deletion of PARP9 or DTX3L does not impair IFN signaling or induction of IFN-responsive genes, indicating PARP9/DTX3L-dependent ADP-ribosylation acts as a downstream effector rather than a regulator of IFN signaling.","method":"Immunofluorescence-based ADP-ribosylation assay, CRISPR KO cell lines, ectopic expression of Nsp3 macrodomain, IFN signaling reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO, overexpression, functional assay), clearly defines pathway position of PARP9/DTX3L ADP-ribosylation","pmids":["34358560"],"is_preprint":false},{"year":2022,"finding":"The DTX3L D3 domain (residues 230–510) mediates interaction with PARP9 with nanomolar affinity and apparent 1:1 stoichiometry; the DTX3L N-terminal region (residues 1–200) mediates higher-order oligomeric assembly of the DTX3L-PARP9 complex. ADP-ribosylation of ubiquitin at Gly76 by DTX3L-PARP9 is reversible in vitro by macrodomain-type hydrolases.","method":"Recombinant protein reconstitution, binding affinity measurements, size-exclusion chromatography, in vitro ADP-ribosylation and de-ADP-ribosylation assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — reconstituted biochemistry with defined domain mapping and stoichiometry","pmids":["35037691"],"is_preprint":false},{"year":2024,"finding":"PARP14 is the major enzyme responsible for IFN-induced ADP-ribosylation; the PARP9/DTX3L complex regulates PARP14 protein levels via post-translational mechanisms and through the hydrolytic activity of PARP9 macrodomain 1. Both PARP9/DTX3L and PARP14 localize to IFNγ-induced cytoplasmic inclusions containing ADP-ribosylated proteins. PARP14 itself and DTX3L are likely targets of PARP14 ADP-ribosylation, and these modifications are reversed by the SARS-CoV-2 Nsp3 macrodomain.","method":"Immunofluorescence, CRISPR KO, ADP-ribosylation proteomics, Western blotting, macrodomain hydrolysis assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, two independent companion papers, defines PARP9 macrodomain 1 hydrolytic regulatory role","pmids":["38834853","38834852"],"is_preprint":false},{"year":2024,"finding":"KH-like domains present in PARP9 and DTX3L mediate protein-protein interactions between PARP9-DTX3L and between PARP14-DTX3L; homodimerization of DTX3L is also coordinated by a KH-like domain and disrupted by site-specific mutation. Interaction of DTX3L with PARP14 in vitro suppresses PARP14 auto-ADP-ribosylation and promotes trans-ADP-ribosylation of PARP9 and DTX3L.","method":"Site-directed mutagenesis, in vitro binding assays, ADP-ribosylation assays, siRNA knockdown with cell survival assays","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1–2 — in vitro biochemistry with mutagenesis, but single lab","pmids":["38182103"],"is_preprint":false},{"year":2006,"finding":"PARP9 (BAL1) and BBAP (DTX3L) are regulated by a bidirectional, IFNγ-responsive promoter on chromosome 3q21; BBAP regulates the subcellular localization of PARP9 through a dynamic shuttling mechanism, demonstrating functional requirement for coordinated BBAP-PARP9 expression. Doxycycline-induced PARP9 overexpression increases expression of multiple IFN-stimulated genes, directly implicating PARP9 in the IFN signaling pathway.","method":"Promoter reporter assays, subcellular fractionation, immunofluorescence, doxycycline-inducible overexpression system with gene expression profiling","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct localization experiment with functional link, promoter characterization, single lab","pmids":["16809771"],"is_preprint":false},{"year":2008,"finding":"PARP9 (Parp-9) gene lies head-to-head and shares its promoter with the gene encoding its partner Bbap on chromosome 16B3 in mice; Parp-9 is developmentally regulated and prominently expressed in the thymus and specific regions of the brain and gut, with highest adult expression in thymus and intestine.","method":"In situ hybridization, quantitative RT-PCR during mouse development, Northern blotting","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 3 — direct expression/localization analysis across tissues and developmental stages, single lab","pmids":["18069692"],"is_preprint":false},{"year":2019,"finding":"In IFNγ-stimulated macrophages, both PARP9 (ARTD9) and PARP14 (ARTD8) themselves undergo ADP-ribosylation, as detected by mass spectrometry; IFNγ treatment increases the ADP-ribosylation status of PARP9.","method":"Mass spectrometry-based ADP-ribosylome analysis using Af1521 enrichment and 10H antibody enrichment with EThcD/HCD activation","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 1 — first characterization of ADP-ribosylation on PARP9 itself by rigorous MS workflow, single lab","pmids":["30848916"],"is_preprint":false},{"year":2018,"finding":"PARP9 knockdown inhibits breast cancer cell migration, indicating PARP9 promotes cellular migration.","method":"siRNA knockdown with transwell migration assay","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 — single method (KD + migration assay), no pathway placement, single lab","pmids":["30128030"],"is_preprint":false}],"current_model":"PARP9 is a macrodomain-containing mono-ADP-ribosyltransferase that functions primarily as a heterodimer with the E3 ubiquitin ligase DTX3L: together they ADP-ribosylate ubiquitin at Gly76 to restrain DTX3L's E3 activity, regulate PARP14 protein levels and activity during interferon signaling (where PARP9 macrodomain 1 hydrolyzes PARP14-deposited ADP-ribosylation), promote interferon-stimulated gene expression by acting on histone H2BJ and degrading viral proteases, suppress STAT1 phosphorylation by opposing PARP14-mediated STAT1 ADP-ribosylation in macrophages, recruit to PARP1-activated DNA damage sites to facilitate BRCA1/53BP1-dependent repair, and sense viral RNA to activate the PI3K/AKT3-IRF3/IRF7 axis for type I interferon production."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing that PARP9 and DTX3L are co-regulated from a shared bidirectional IFN-γ-responsive promoter and that DTX3L controls PARP9 subcellular localization answered how these two functionally linked genes achieve coordinated expression and spatial coupling.","evidence":"Promoter reporter assays, subcellular fractionation, and inducible overexpression with gene expression profiling in human cells","pmids":["16809771"],"confidence":"Medium","gaps":["Mechanism by which DTX3L relocates PARP9 not defined","No direct enzymatic activity of PARP9 characterized at this stage"]},{"year":2012,"claim":"Demonstrating PARP1/PAR-dependent recruitment of PARP9 to DNA damage sites, where DTX3L-mediated ubiquitylation promotes 53BP1 and BRCA1 recruitment independently of ATM/MDC1/RNF8, established PARP9 as a reader-effector bridging PARylation to ubiquitin-dependent DNA repair.","evidence":"Laser micro-irradiation with live imaging, co-IP, siRNA knockdown, epistasis with ATM/MDC1/RNF8 pathway inhibitors","pmids":["23230272"],"confidence":"High","gaps":["Direct ubiquitin substrate at damage sites not identified","Contribution of PARP9 catalytic activity versus scaffolding at damage sites unclear"]},{"year":2013,"claim":"Identifying physical interactions between PARP9 macrodomains and STAT1 isoforms, and showing that PARP9 promotes STAT1 phosphorylation while repressing IRF1 and enhancing BCL6, placed PARP9 within JAK-STAT signaling in lymphoma cells.","evidence":"Co-IP, immunofluorescence, siRNA knockdown, overexpression in DLBCL cell lines","pmids":["23487038","24886089"],"confidence":"Medium","gaps":["Whether PARP9–STAT1 interaction is direct or ADP-ribose-bridged was not fully resolved","PARP9-specific enzymatic contribution versus DTX3L/PARP14 contribution not separated"]},{"year":2016,"claim":"Showing that PARP9 and PARP14 have opposing roles on STAT1—PARP14 ADP-ribosylates STAT1 to suppress its phosphorylation while PARP9 counteracts this modification—resolved the mechanism by which PARP9 promotes pro-inflammatory macrophage activation.","evidence":"siRNA silencing in primary macrophages, ADP-ribosylation and phosphorylation assays, site-directed mutagenesis of STAT1 modification sites","pmids":["27796300"],"confidence":"High","gaps":["Whether PARP9 removes ADP-ribose enzymatically or blocks PARP14 access was not distinguished","In vivo validation in animal models not performed"]},{"year":2017,"claim":"Reconstituting the DTX3L–PARP9 complex in vitro and demonstrating NAD+-dependent mono-ADP-ribosylation of ubiquitin Gly76—which blocks substrate ubiquitylation—defined the first catalytic product of the heterodimer and revealed a novel cross-talk between ADP-ribosylation and ubiquitin signaling.","evidence":"Reconstituted in vitro ubiquitination and ADP-ribosylation assays with site-directed mutagenesis and PAR-binding assays","pmids":["28525742"],"confidence":"High","gaps":["Physiological substrates whose ubiquitylation is regulated by Gly76 ADP-ribosylation not identified","Structural basis for dual catalytic activity not resolved"]},{"year":2021,"claim":"Discovering that PARP9 directly binds viral dsRNA and activates a PI3K/AKT3–IRF3/IRF7 axis for type I IFN production independently of MAVS revealed an unexpected innate immune sensor function for PARP9 beyond its ADP-ribosyltransferase role.","evidence":"RNA pulldown, PARP9-KO mouse model with RNA virus challenge, siRNA knockdown, phosphorylation site mapping, PI3K/AKT3 inhibitor epistasis","pmids":["33976210"],"confidence":"High","gaps":["RNA-binding domain within PARP9 not mapped","Whether RNA sensing requires DTX3L partnership not tested","Structural basis for dsRNA recognition unknown"]},{"year":2021,"claim":"Establishing that IFN-induced ADP-ribosylation of host proteins depends on PARP9/DTX3L and is reversed by the SARS-CoV-2 Nsp3 macrodomain, while being dispensable for IFN signaling itself, positioned PARP9/DTX3L-dependent ADP-ribosylation as an antiviral effector mechanism rather than a signal transduction component.","evidence":"CRISPR KO cell lines, immunofluorescence-based ADP-ribosylation assay, ectopic Nsp3 macrodomain expression, IFN signaling reporters","pmids":["34358560"],"confidence":"High","gaps":["Identity of host protein targets of PARP9/DTX3L-dependent ADP-ribosylation not comprehensively defined","Whether antiviral effect operates through ADP-ribosylation of viral proteins in addition to host proteins not tested"]},{"year":2022,"claim":"Mapping the DTX3L D3 domain as the nanomolar-affinity interface for PARP9 and showing reversibility of Gly76 ADP-ribosylation by macrodomain hydrolases provided the biochemical architecture and regulatory logic of the heterodimer.","evidence":"Recombinant protein reconstitution, binding affinity measurements, size-exclusion chromatography, de-ADP-ribosylation assays","pmids":["35037691"],"confidence":"High","gaps":["High-resolution structure of the full DTX3L–PARP9 complex not determined","Physiological hydrolase responsible for reversing Gly76 modification in cells not identified"]},{"year":2024,"claim":"Demonstrating that PARP14 is the major IFN-induced ADP-ribosyltransferase and that PARP9 macrodomain 1 hydrolyzes PARP14-deposited ADP-ribose to regulate PARP14 levels clarified that PARP9 functions as both a reader and eraser of ADP-ribosylation, providing a unified model for PARP9–PARP14 antagonism.","evidence":"CRISPR KO, ADP-ribosylation proteomics, macrodomain hydrolysis assays, immunofluorescence of cytoplasmic inclusions","pmids":["38834853","38834852","38182103"],"confidence":"High","gaps":["Structural basis for macrodomain 1 hydrolase specificity versus macrodomain 2 not resolved","Whether PARP9 hydrolase activity is regulated by post-translational modifications unknown"]},{"year":null,"claim":"A comprehensive structural model of the full-length DTX3L–PARP9 heterodimer, the physiological substrates whose ubiquitylation is governed by Gly76 ADP-ribosylation, and the RNA-binding determinants underlying PARP9's innate immune sensor function remain to be established.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of full DTX3L–PARP9 complex","Comprehensive identification of in vivo substrates of Gly76 ADP-ribosylation lacking","RNA-binding domain/motif in PARP9 not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,9]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[9]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,4,11]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,6,7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,6]}],"complexes":["DTX3L–PARP9 heterodimer"],"partners":["DTX3L","PARP14","STAT1","PARP1","AKT3","IRF3","IRF7"],"other_free_text":[]},"mechanistic_narrative":"PARP9 is a macrodomain-containing mono-ADP-ribosyltransferase that functions as an obligate heterodimer with the E3 ubiquitin ligase DTX3L to coordinate ADP-ribosylation and ubiquitin signaling in interferon responses and DNA damage repair. The DTX3L–PARP9 complex ADP-ribosylates ubiquitin at Gly76, which precludes substrate ubiquitylation and restrains DTX3L E3 ligase activity, while poly(ADP-ribose) binding by PARP9 macrodomains reciprocally enhances DTX3L E3 function [PMID:28525742, PMID:35037691]. PARP9 opposes PARP14-mediated ADP-ribosylation of STAT1 to promote STAT1 phosphorylation and pro-inflammatory gene expression in IFN-γ-stimulated macrophages, and its macrodomain 1 hydrolyzes PARP14-deposited ADP-ribose to regulate PARP14 protein levels and activity during interferon signaling [PMID:27796300, PMID:38834853]. PARP9 is recruited to DNA damage sites in a PARP1/PAR-dependent manner where it facilitates DTX3L-mediated ubiquitylation and subsequent 53BP1/BRCA1 recruitment [PMID:23230272], and independently acts as a non-canonical viral dsRNA sensor that activates PI3K/AKT3–IRF3/IRF7-dependent type I interferon production [PMID:33976210]."},"prefetch_data":{"uniprot":{"accession":"Q8IXQ6","full_name":"Protein mono-ADP-ribosyltransferase PARP9","aliases":["ADP-ribosyltransferase diphtheria toxin-like 9","ARTD9","B aggressive lymphoma protein","Poly [ADP-ribose] polymerase 9","PARP-9"],"length_aa":854,"mass_kda":96.3,"function":"ADP-ribosyltransferase which, in association with E3 ligase DTX3L, plays a role in DNA damage repair and in immune responses including interferon-mediated antiviral defenses (PubMed:16809771, PubMed:23230272, PubMed:26479788, PubMed:27796300). Within the complex, enhances DTX3L E3 ligase activity which is further enhanced by PARP9 binding to poly(ADP-ribose) (PubMed:28525742). In association with DTX3L and in presence of E1 and E2 enzymes, mediates NAD(+)-dependent mono-ADP-ribosylation of ubiquitin which prevents ubiquitin conjugation to substrates such as histones (PubMed:28525742). During DNA repair, PARP1 recruits PARP9/BAL1-DTX3L complex to DNA damage sites via PARP9 binding to ribosylated PARP1 (PubMed:23230272). Subsequent PARP1-dependent PARP9/BAL1-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites (PubMed:23230272, PubMed:28525742). In response to DNA damage, PARP9-DTX3L complex is required for efficient non-homologous end joining (NHEJ); the complex function is negatively modulated by PARP9 activity (PubMed:28525742). Dispensable for B-cell receptor (BCR) assembly through V(D)J recombination and class switch recombination (CSR) (By similarity). In macrophages, positively regulates pro-inflammatory cytokines production in response to IFNG stimulation by suppressing PARP14-mediated STAT1 ADP-ribosylation and thus promoting STAT1 phosphorylation (PubMed:27796300). Also suppresses PARP14-mediated STAT6 ADP-ribosylation (PubMed:27796300)","subcellular_location":"Cytoplasm, cytosol; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8IXQ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PARP9","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":[],"url":"https://opencell.sf.czbiohub.org/search/PARP9","total_profiled":1310},"omim":[{"mim_id":"613143","title":"DELTEX E3 UBIQUITIN LIGASE 3L; DTX3L","url":"https://www.omim.org/entry/613143"},{"mim_id":"612066","title":"POLY(ADP-RIBOSE) POLYMERASE FAMILY, MEMBER 15; PARP15","url":"https://www.omim.org/entry/612066"},{"mim_id":"612065","title":"POLY(ADP-RIBOSE) POLYMERASE FAMILY, MEMBER 9; PARP9","url":"https://www.omim.org/entry/612065"},{"mim_id":"610028","title":"POLY(ADP-RIBOSE) POLYMERASE FAMILY, MEMBER 14; PARP14","url":"https://www.omim.org/entry/610028"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PARP9"},"hgnc":{"alias_symbol":["BAL","BAL1","ARTD9"],"prev_symbol":[]},"alphafold":{"accession":"Q8IXQ6","domains":[{"cath_id":"3.90.1150","chopping":"61-97_540-625","consensus_level":"medium","plddt":85.2742,"start":61,"end":625},{"cath_id":"3.40.220.10","chopping":"108-297","consensus_level":"high","plddt":92.3591,"start":108,"end":297},{"cath_id":"3.40.220.10","chopping":"312-491","consensus_level":"high","plddt":89.7057,"start":312,"end":491},{"cath_id":"3.90.228.10","chopping":"644-824","consensus_level":"high","plddt":84.7335,"start":644,"end":824}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXQ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXQ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXQ6-F1-predicted_aligned_error_v6.png","plddt_mean":78.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PARP9","jax_strain_url":"https://www.jax.org/strain/search?query=PARP9"},"sequence":{"accession":"Q8IXQ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IXQ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IXQ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXQ6"}},"corpus_meta":[{"pmid":"18413445","id":"PMC_18413445","title":"Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells.","date":"2008","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/18413445","citation_count":413,"is_preprint":false},{"pmid":"14582906","id":"PMC_14582906","title":"Exosomes with major histocompatibility complex class II and co-stimulatory molecules are present in human BAL fluid.","date":"2003","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/14582906","citation_count":292,"is_preprint":false},{"pmid":"27796300","id":"PMC_27796300","title":"PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27796300","citation_count":233,"is_preprint":false},{"pmid":"26479788","id":"PMC_26479788","title":"PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection.","date":"2015","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26479788","citation_count":185,"is_preprint":false},{"pmid":"28525742","id":"PMC_28525742","title":"Ubiquitin Modification by the E3 Ligase/ADP-Ribosyltransferase Dtx3L/Parp9.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/28525742","citation_count":173,"is_preprint":false},{"pmid":"15572545","id":"PMC_15572545","title":"Predictive value of BAL cell differentials in the diagnosis of interstitial lung diseases.","date":"2004","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/15572545","citation_count":136,"is_preprint":false},{"pmid":"9628235","id":"PMC_9628235","title":"Inflammatory cytokines in BAL fluid and pulmonary hemodynamics in high-altitude pulmonary edema.","date":"1998","source":"Respiration physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9628235","citation_count":118,"is_preprint":false},{"pmid":"12952254","id":"PMC_12952254","title":"BAL findings in idiopathic nonspecific interstitial pneumonia and usual interstitial pneumonia.","date":"2003","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/12952254","citation_count":111,"is_preprint":false},{"pmid":"11978916","id":"PMC_11978916","title":"Increased levels of interleukin-8 in BAL fluid from smokers susceptible to pulmonary emphysema.","date":"2002","source":"Thorax","url":"https://pubmed.ncbi.nlm.nih.gov/11978916","citation_count":111,"is_preprint":false},{"pmid":"11110709","id":"PMC_11110709","title":"BAL is a novel risk-related gene in diffuse large B-cell lymphomas that enhances cellular migration.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11110709","citation_count":104,"is_preprint":false},{"pmid":"16809771","id":"PMC_16809771","title":"BAL1 and BBAP 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Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28213470","citation_count":17,"is_preprint":false},{"pmid":"32962817","id":"PMC_32962817","title":"Adiponectin and leptin levels in idiopathic pulmonary fibrosis: A new method for BAL and serum assessment.","date":"2020","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/32962817","citation_count":17,"is_preprint":false},{"pmid":"8726930","id":"PMC_8726930","title":"Integrin alpha E beta 7 expression on BAL CD4+, CD8+, and gamma delta T-cells in bleomycin-induced lung fibrosis in mouse.","date":"1996","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/8726930","citation_count":17,"is_preprint":false},{"pmid":"23686776","id":"PMC_23686776","title":"Incidence of pulmonary aspergillosis and correlation of conventional diagnostic methods with nested PCR and real-time PCR assay using BAL fluid in intensive care unit patients.","date":"2013","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/23686776","citation_count":17,"is_preprint":false},{"pmid":"17848747","id":"PMC_17848747","title":"CEA levels in serum and BAL in patients suffering from lung cancer: correlation with individuals presenting benign lung lesions and healthy volunteers.","date":"2007","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17848747","citation_count":17,"is_preprint":false},{"pmid":"21430262","id":"PMC_21430262","title":"HOPE-BAL: improved molecular diagnostics by application of a novel technique for fixation and paraffin embedding.","date":"2011","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/21430262","citation_count":17,"is_preprint":false},{"pmid":"19273541","id":"PMC_19273541","title":"Serum and BAL cytokine and antioxidant enzyme levels at different stages of pneumoconiosis in coal workers.","date":"2008","source":"Human & experimental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/19273541","citation_count":15,"is_preprint":false},{"pmid":"28479508","id":"PMC_28479508","title":"Integron types, gene cassettes and antimicrobial resistance profile of Acinetobacter baumannii isolated from BAL samples in Babol, north of Iran.","date":"2017","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/28479508","citation_count":15,"is_preprint":false},{"pmid":"20625676","id":"PMC_20625676","title":"Cell profile of BAL fluid in children and adolescents with and without lung disease.","date":"2010","source":"Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia","url":"https://pubmed.ncbi.nlm.nih.gov/20625676","citation_count":15,"is_preprint":false},{"pmid":"18947171","id":"PMC_18947171","title":"Modification of a common BAL technique to enhance sample diagnostic value.","date":"2008","source":"Journal of the American Association for Laboratory Animal Science : JAALAS","url":"https://pubmed.ncbi.nlm.nih.gov/18947171","citation_count":15,"is_preprint":false},{"pmid":"10460872","id":"PMC_10460872","title":"Eosinophilic alveolitis in BAL after lung transplantation.","date":"1999","source":"Transplant international : official journal of the European Society for Organ Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/10460872","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53437,"output_tokens":4071,"usd":0.110688},"stage2":{"model":"claude-opus-4-6","input_tokens":7527,"output_tokens":2992,"usd":0.168653},"total_usd":0.279341,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"PARP9 forms a complex with DTX3L (BBAP) that functions as an E3 ubiquitin ligase; this complex acts on host histone H2BJ to promote interferon-stimulated gene expression and on viral 3C proteases to degrade them via the immunoproteasome, providing a double layer of antiviral immunity.\",\n      \"method\": \"Co-immunoprecipitation, transgenic mouse model, transduced human cells, functional rescue assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus in vivo genetic model with defined phenotypic readout, replicated across multiple cell/organism systems\",\n      \"pmids\": [\"26479788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PARP9 and PARP14 have opposing roles in macrophage activation: PARP14 induces ADP-ribosylation of STAT1, which suppresses its phosphorylation, while PARP9 suppresses this PARP14-dependent ADP-ribosylation, thereby promoting STAT1 phosphorylation and pro-inflammatory gene expression in IFNγ-stimulated macrophages. Mutations at the PARP14 ADP-ribosylation sites on STAT1 lead to increased phosphorylation.\",\n      \"method\": \"siRNA silencing in primary macrophages, global proteomic analysis, ADP-ribosylation assays, phosphorylation assays, site-directed mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — enzymatic activity demonstrated, mutagenesis of modification sites validates mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"27796300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The DTX3L/PARP9 heterodimer mediates NAD+-dependent mono-ADP-ribosylation of ubiquitin at its C-terminal Gly76 residue exclusively in the context of ubiquitin processing by E1 and E2 enzymes; this ADP-ribosylation of Gly76 precludes ubiquitylation of substrates. Poly(ADP-ribose) binding to PARP9 macrodomains increases the E3 ligase activity of DTX3L, while PARP9 ADP-ribosylation activity restrains DTX3L E3 function.\",\n      \"method\": \"In vitro ADP-ribosylation assay, site-directed mutagenesis of NAD+-binding site, reconstituted ubiquitination assay, PAR-binding assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro biochemistry with mutagenesis, clearly defining substrate (Gly76 of ubiquitin) and regulatory mechanism\",\n      \"pmids\": [\"28525742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PARP9 (BAL1) is recruited to DNA damage sites in a PARP1-dependent and PAR-dependent manner; once recruited, its partner E3 ligase BBAP (DTX3L) mediates local ubiquitylation, promoting subsequent recruitment of 53BP1 and BRCA1. This pathway limits DNA damage and enhances cellular viability independently of ATM, MDC1, and RNF8.\",\n      \"method\": \"Laser micro-irradiation with live imaging, co-immunoprecipitation, siRNA knockdown with DNA damage assays (γH2AX foci), epistasis with ATM/MDC1/RNF8 inhibitors\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment linked to functional consequence, genetic epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"23230272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PARP9 (BAL1/ARTD9) physically interacts with both STAT1α and STAT1β through its macrodomains in an ADP-ribosylation-dependent manner, stimulates phosphorylation of both STAT1 isoforms at Y701, promotes nuclear accumulation of the transcriptionally repressive isoform STAT1β, and together with STAT1β directly represses IRF1 expression while enhancing IRF2 and BCL6 expression in DLBCL.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, Western blotting, siRNA knockdown, overexpression experiments in DLBCL cell lines\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP demonstrates physical interaction, functional assays show downstream effects, but single lab\",\n      \"pmids\": [\"23487038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DTX3L (BBAP) forms a complex with PARP9 (ARTD9) and PARP14 (ARTD8); these three proteins physically interact and together mediate proliferation, chemoresistance, and survival of metastatic prostate cancer cells. DTX3L and PARP9 act together as repressors of tumor suppressor IRF1.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown with cell viability and migration assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP confirms complex, functional KD phenotype, but single lab and limited mechanistic depth for PARP9-specific activity\",\n      \"pmids\": [\"24886089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PARP9 serves as a non-canonical RNA sensor in dendritic cells; it directly binds viral double-stranded RNA and recruits and activates the PI3K/AKT3 pathway independently of MAVS. PI3K/AKT3 then activates IRF3 (at Ser385) and IRF7 (at Ser437/438) to drive type I IFN production. PARP9-deficient mice show enhanced susceptibility to RNA virus infection due to impaired type I IFN production.\",\n      \"method\": \"RNA pulldown/binding assay, KO mouse model with viral infection, siRNA knockdown, phosphorylation site mapping, PI3K/AKT3 inhibitor epistasis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct RNA binding demonstrated, KO mouse phenotype with defined signaling pathway, phosphorylation site identification\",\n      \"pmids\": [\"33976210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFN-induced ADP-ribosylation of host proteins is dependent on PARP9 and its binding partner DTX3L; the SARS-CoV-2 Nsp3 macrodomain reverses this PARP9/DTX3L-dependent ADP-ribosylation. Deletion of PARP9 or DTX3L does not impair IFN signaling or induction of IFN-responsive genes, indicating PARP9/DTX3L-dependent ADP-ribosylation acts as a downstream effector rather than a regulator of IFN signaling.\",\n      \"method\": \"Immunofluorescence-based ADP-ribosylation assay, CRISPR KO cell lines, ectopic expression of Nsp3 macrodomain, IFN signaling reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO, overexpression, functional assay), clearly defines pathway position of PARP9/DTX3L ADP-ribosylation\",\n      \"pmids\": [\"34358560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The DTX3L D3 domain (residues 230–510) mediates interaction with PARP9 with nanomolar affinity and apparent 1:1 stoichiometry; the DTX3L N-terminal region (residues 1–200) mediates higher-order oligomeric assembly of the DTX3L-PARP9 complex. ADP-ribosylation of ubiquitin at Gly76 by DTX3L-PARP9 is reversible in vitro by macrodomain-type hydrolases.\",\n      \"method\": \"Recombinant protein reconstitution, binding affinity measurements, size-exclusion chromatography, in vitro ADP-ribosylation and de-ADP-ribosylation assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted biochemistry with defined domain mapping and stoichiometry\",\n      \"pmids\": [\"35037691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PARP14 is the major enzyme responsible for IFN-induced ADP-ribosylation; the PARP9/DTX3L complex regulates PARP14 protein levels via post-translational mechanisms and through the hydrolytic activity of PARP9 macrodomain 1. Both PARP9/DTX3L and PARP14 localize to IFNγ-induced cytoplasmic inclusions containing ADP-ribosylated proteins. PARP14 itself and DTX3L are likely targets of PARP14 ADP-ribosylation, and these modifications are reversed by the SARS-CoV-2 Nsp3 macrodomain.\",\n      \"method\": \"Immunofluorescence, CRISPR KO, ADP-ribosylation proteomics, Western blotting, macrodomain hydrolysis assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, two independent companion papers, defines PARP9 macrodomain 1 hydrolytic regulatory role\",\n      \"pmids\": [\"38834853\", \"38834852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KH-like domains present in PARP9 and DTX3L mediate protein-protein interactions between PARP9-DTX3L and between PARP14-DTX3L; homodimerization of DTX3L is also coordinated by a KH-like domain and disrupted by site-specific mutation. Interaction of DTX3L with PARP14 in vitro suppresses PARP14 auto-ADP-ribosylation and promotes trans-ADP-ribosylation of PARP9 and DTX3L.\",\n      \"method\": \"Site-directed mutagenesis, in vitro binding assays, ADP-ribosylation assays, siRNA knockdown with cell survival assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro biochemistry with mutagenesis, but single lab\",\n      \"pmids\": [\"38182103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PARP9 (BAL1) and BBAP (DTX3L) are regulated by a bidirectional, IFNγ-responsive promoter on chromosome 3q21; BBAP regulates the subcellular localization of PARP9 through a dynamic shuttling mechanism, demonstrating functional requirement for coordinated BBAP-PARP9 expression. Doxycycline-induced PARP9 overexpression increases expression of multiple IFN-stimulated genes, directly implicating PARP9 in the IFN signaling pathway.\",\n      \"method\": \"Promoter reporter assays, subcellular fractionation, immunofluorescence, doxycycline-inducible overexpression system with gene expression profiling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct localization experiment with functional link, promoter characterization, single lab\",\n      \"pmids\": [\"16809771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PARP9 (Parp-9) gene lies head-to-head and shares its promoter with the gene encoding its partner Bbap on chromosome 16B3 in mice; Parp-9 is developmentally regulated and prominently expressed in the thymus and specific regions of the brain and gut, with highest adult expression in thymus and intestine.\",\n      \"method\": \"In situ hybridization, quantitative RT-PCR during mouse development, Northern blotting\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct expression/localization analysis across tissues and developmental stages, single lab\",\n      \"pmids\": [\"18069692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In IFNγ-stimulated macrophages, both PARP9 (ARTD9) and PARP14 (ARTD8) themselves undergo ADP-ribosylation, as detected by mass spectrometry; IFNγ treatment increases the ADP-ribosylation status of PARP9.\",\n      \"method\": \"Mass spectrometry-based ADP-ribosylome analysis using Af1521 enrichment and 10H antibody enrichment with EThcD/HCD activation\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — first characterization of ADP-ribosylation on PARP9 itself by rigorous MS workflow, single lab\",\n      \"pmids\": [\"30848916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PARP9 knockdown inhibits breast cancer cell migration, indicating PARP9 promotes cellular migration.\",\n      \"method\": \"siRNA knockdown with transwell migration assay\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method (KD + migration assay), no pathway placement, single lab\",\n      \"pmids\": [\"30128030\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PARP9 is a macrodomain-containing mono-ADP-ribosyltransferase that functions primarily as a heterodimer with the E3 ubiquitin ligase DTX3L: together they ADP-ribosylate ubiquitin at Gly76 to restrain DTX3L's E3 activity, regulate PARP14 protein levels and activity during interferon signaling (where PARP9 macrodomain 1 hydrolyzes PARP14-deposited ADP-ribosylation), promote interferon-stimulated gene expression by acting on histone H2BJ and degrading viral proteases, suppress STAT1 phosphorylation by opposing PARP14-mediated STAT1 ADP-ribosylation in macrophages, recruit to PARP1-activated DNA damage sites to facilitate BRCA1/53BP1-dependent repair, and sense viral RNA to activate the PI3K/AKT3-IRF3/IRF7 axis for type I interferon production.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PARP9 is a macrodomain-containing mono-ADP-ribosyltransferase that functions as an obligate heterodimer with the E3 ubiquitin ligase DTX3L to coordinate ADP-ribosylation and ubiquitin signaling in interferon responses and DNA damage repair. The DTX3L–PARP9 complex ADP-ribosylates ubiquitin at Gly76, which precludes substrate ubiquitylation and restrains DTX3L E3 ligase activity, while poly(ADP-ribose) binding by PARP9 macrodomains reciprocally enhances DTX3L E3 function [PMID:28525742, PMID:35037691]. PARP9 opposes PARP14-mediated ADP-ribosylation of STAT1 to promote STAT1 phosphorylation and pro-inflammatory gene expression in IFN-γ-stimulated macrophages, and its macrodomain 1 hydrolyzes PARP14-deposited ADP-ribose to regulate PARP14 protein levels and activity during interferon signaling [PMID:27796300, PMID:38834853]. PARP9 is recruited to DNA damage sites in a PARP1/PAR-dependent manner where it facilitates DTX3L-mediated ubiquitylation and subsequent 53BP1/BRCA1 recruitment [PMID:23230272], and independently acts as a non-canonical viral dsRNA sensor that activates PI3K/AKT3–IRF3/IRF7-dependent type I interferon production [PMID:33976210].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that PARP9 and DTX3L are co-regulated from a shared bidirectional IFN-γ-responsive promoter and that DTX3L controls PARP9 subcellular localization answered how these two functionally linked genes achieve coordinated expression and spatial coupling.\",\n      \"evidence\": \"Promoter reporter assays, subcellular fractionation, and inducible overexpression with gene expression profiling in human cells\",\n      \"pmids\": [\"16809771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which DTX3L relocates PARP9 not defined\", \"No direct enzymatic activity of PARP9 characterized at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating PARP1/PAR-dependent recruitment of PARP9 to DNA damage sites, where DTX3L-mediated ubiquitylation promotes 53BP1 and BRCA1 recruitment independently of ATM/MDC1/RNF8, established PARP9 as a reader-effector bridging PARylation to ubiquitin-dependent DNA repair.\",\n      \"evidence\": \"Laser micro-irradiation with live imaging, co-IP, siRNA knockdown, epistasis with ATM/MDC1/RNF8 pathway inhibitors\",\n      \"pmids\": [\"23230272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitin substrate at damage sites not identified\", \"Contribution of PARP9 catalytic activity versus scaffolding at damage sites unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying physical interactions between PARP9 macrodomains and STAT1 isoforms, and showing that PARP9 promotes STAT1 phosphorylation while repressing IRF1 and enhancing BCL6, placed PARP9 within JAK-STAT signaling in lymphoma cells.\",\n      \"evidence\": \"Co-IP, immunofluorescence, siRNA knockdown, overexpression in DLBCL cell lines\",\n      \"pmids\": [\"23487038\", \"24886089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PARP9–STAT1 interaction is direct or ADP-ribose-bridged was not fully resolved\", \"PARP9-specific enzymatic contribution versus DTX3L/PARP14 contribution not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that PARP9 and PARP14 have opposing roles on STAT1—PARP14 ADP-ribosylates STAT1 to suppress its phosphorylation while PARP9 counteracts this modification—resolved the mechanism by which PARP9 promotes pro-inflammatory macrophage activation.\",\n      \"evidence\": \"siRNA silencing in primary macrophages, ADP-ribosylation and phosphorylation assays, site-directed mutagenesis of STAT1 modification sites\",\n      \"pmids\": [\"27796300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PARP9 removes ADP-ribose enzymatically or blocks PARP14 access was not distinguished\", \"In vivo validation in animal models not performed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Reconstituting the DTX3L–PARP9 complex in vitro and demonstrating NAD+-dependent mono-ADP-ribosylation of ubiquitin Gly76—which blocks substrate ubiquitylation—defined the first catalytic product of the heterodimer and revealed a novel cross-talk between ADP-ribosylation and ubiquitin signaling.\",\n      \"evidence\": \"Reconstituted in vitro ubiquitination and ADP-ribosylation assays with site-directed mutagenesis and PAR-binding assays\",\n      \"pmids\": [\"28525742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates whose ubiquitylation is regulated by Gly76 ADP-ribosylation not identified\", \"Structural basis for dual catalytic activity not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovering that PARP9 directly binds viral dsRNA and activates a PI3K/AKT3–IRF3/IRF7 axis for type I IFN production independently of MAVS revealed an unexpected innate immune sensor function for PARP9 beyond its ADP-ribosyltransferase role.\",\n      \"evidence\": \"RNA pulldown, PARP9-KO mouse model with RNA virus challenge, siRNA knockdown, phosphorylation site mapping, PI3K/AKT3 inhibitor epistasis\",\n      \"pmids\": [\"33976210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding domain within PARP9 not mapped\", \"Whether RNA sensing requires DTX3L partnership not tested\", \"Structural basis for dsRNA recognition unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Establishing that IFN-induced ADP-ribosylation of host proteins depends on PARP9/DTX3L and is reversed by the SARS-CoV-2 Nsp3 macrodomain, while being dispensable for IFN signaling itself, positioned PARP9/DTX3L-dependent ADP-ribosylation as an antiviral effector mechanism rather than a signal transduction component.\",\n      \"evidence\": \"CRISPR KO cell lines, immunofluorescence-based ADP-ribosylation assay, ectopic Nsp3 macrodomain expression, IFN signaling reporters\",\n      \"pmids\": [\"34358560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of host protein targets of PARP9/DTX3L-dependent ADP-ribosylation not comprehensively defined\", \"Whether antiviral effect operates through ADP-ribosylation of viral proteins in addition to host proteins not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapping the DTX3L D3 domain as the nanomolar-affinity interface for PARP9 and showing reversibility of Gly76 ADP-ribosylation by macrodomain hydrolases provided the biochemical architecture and regulatory logic of the heterodimer.\",\n      \"evidence\": \"Recombinant protein reconstitution, binding affinity measurements, size-exclusion chromatography, de-ADP-ribosylation assays\",\n      \"pmids\": [\"35037691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the full DTX3L–PARP9 complex not determined\", \"Physiological hydrolase responsible for reversing Gly76 modification in cells not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that PARP14 is the major IFN-induced ADP-ribosyltransferase and that PARP9 macrodomain 1 hydrolyzes PARP14-deposited ADP-ribose to regulate PARP14 levels clarified that PARP9 functions as both a reader and eraser of ADP-ribosylation, providing a unified model for PARP9–PARP14 antagonism.\",\n      \"evidence\": \"CRISPR KO, ADP-ribosylation proteomics, macrodomain hydrolysis assays, immunofluorescence of cytoplasmic inclusions\",\n      \"pmids\": [\"38834853\", \"38834852\", \"38182103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for macrodomain 1 hydrolase specificity versus macrodomain 2 not resolved\", \"Whether PARP9 hydrolase activity is regulated by post-translational modifications unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A comprehensive structural model of the full-length DTX3L–PARP9 heterodimer, the physiological substrates whose ubiquitylation is governed by Gly76 ADP-ribosylation, and the RNA-binding determinants underlying PARP9's innate immune sensor function remain to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of full DTX3L–PARP9 complex\", \"Comprehensive identification of in vivo substrates of Gly76 ADP-ribosylation lacking\", \"RNA-binding domain/motif in PARP9 not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 4, 11]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 6, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"complexes\": [\n      \"DTX3L–PARP9 heterodimer\"\n    ],\n    \"partners\": [\n      \"DTX3L\",\n      \"PARP14\",\n      \"STAT1\",\n      \"PARP1\",\n      \"AKT3\",\n      \"IRF3\",\n      \"IRF7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}