{"gene":"PARP11","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2019,"finding":"PARP11 (ARTD11) mono-ADP-ribosylates the ubiquitin E3 ligase β-TrCP, which promotes IFNAR1 ubiquitination and degradation, thereby inhibiting IFN-I-activated signalling and facilitating viral immune evasion.","method":"Biochemical ADP-ribosylation assays, Co-IP, loss-of-function and overexpression in cell lines, in vivo mouse viral infection model","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, enzymatic assay identifying substrate, defined cellular phenotype (IFNAR1 degradation), in vivo validation, multiple orthogonal methods in single study","pmids":["30988430"],"is_preprint":false},{"year":2016,"finding":"Chemical genetic profiling using an engineered NAD+ analog identified ARTD11 (PARP11) MARylome targets in vitro, revealing nuclear pore complex proteins as isoform-specific targets; targeting was dependent on both the regulatory and catalytic domains of ARTD11.","method":"Chemical genetics (orthogonal NAD+ analog), in vitro MARylation assay, mass spectrometry","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution with engineered enzyme and domain mutagenesis, single lab, novel chemical genetic strategy","pmids":["26774478"],"is_preprint":false},{"year":2015,"finding":"PARP11 localizes to the nuclear envelope in spermatids and somatic cells by co-localizing with NUP153; its N-terminal WWE domain residues Y77, Q86, R95 and the presence of the catalytic domain are required for nuclear envelope colocalization, but catalytic activity itself is not required for colocalization with NUP153. Loss of PARP11 in mice causes teratozoospermia with nuclear envelope structural defects and chromatin detachment in elongating spermatids, resulting in male infertility.","method":"Knockout mouse model, immunofluorescence colocalization, site-directed mutagenesis of WWE domain, in vitro mono-ADP-ribosylation assay (auto-ribosylation), transfection of somatic cells","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined cellular phenotype, mutagenesis-based domain mapping, direct localization experiments, multiple orthogonal methods","pmids":["25673562"],"is_preprint":false},{"year":2018,"finding":"Structure-guided design of ITK7, a selective inhibitor (>200-fold selective over other PARPs) of PARP11 MARylation activity; live-cell imaging showed that ITK7 causes PARP11 to dissociate from the nuclear envelope, indicating that PARP11's catalytic activity regulates its nuclear envelope localization.","method":"Structure-guided inhibitor design, in vitro MARylation inhibition assay, live-cell imaging","journal":"Cell chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — structure-guided inhibitor with crystal structure data, enzymatic assay, live-cell imaging showing functional consequence of catalytic inhibition, single lab multiple methods","pmids":["30344052"],"is_preprint":false},{"year":2019,"finding":"PARP10, PARP11, and PARP15 (as well as TRPT1) ADP-ribosylate phosphorylated ends of RNA in vitro, identifying RNA as a novel substrate for mono-ADP-ribosylation; this modification can be reversed by cellular ADP-ribosylhydrolases (PARG, TARG1, MACROD1, MACROD2, ARH3).","method":"Biochemical in vitro ADP-ribosylation assays using purified proteins and RNA substrates, hydrolase reversal assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified components, replicated across multiple enzymes and hydrolases, orthogonal biochemical methods","pmids":["31216043"],"is_preprint":false},{"year":2022,"finding":"PARP11 mediates ADP-ribosylation of RNA in human cells (not only in vitro), counteracted by hydrolases TARG1, PARG and ARH3; ADPr-capped mRNA is protected from XRN1-mediated degradation but is not translated.","method":"Cellular RNA ADP-ribosylation assays in human cells with PARP KO/overexpression, functional RNA degradation and translation assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cellular KO/overexpression combined with functional RNA assays, replicates in-cell RNA ADP-ribosylation finding, multiple orthogonal methods","pmids":["36018800"],"is_preprint":false},{"year":2015,"finding":"PARP10 and PARP11 are auto-ADP-ribosylated on acidic amino acids (glutamate/aspartate) in cells; a novel chemical mechanism was identified whereby the ADP-ribose transfers from C1' to C2' position on these residues.","method":"Clickable aminooxy alkyne (AO-alkyne) chemical probe, click chemistry, cellular ADP-ribosylation detection","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel chemical probe used in cells, single lab, single method but novel mechanism identified","pmids":["25978521"],"is_preprint":false},{"year":2021,"finding":"PARP11 suppresses Zika virus (ZIKV) replication independently of its own ADP-ribosylation enzymatic activity; PARP11 interacts with PARP12 (by co-immunoprecipitation) and promotes PARP12-mediated degradation of ZIKV NS1 and NS3 proteins.","method":"PARP11 KO and overexpression in A549 cells, PARP11-/-/PARP12-/-/double-KO HEK293T cells, western blotting, immunofluorescence, co-immunoprecipitation","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple KO cell lines, Co-IP, loss-of-function with defined phenotype, single lab","pmids":["34187568"],"is_preprint":false},{"year":2022,"finding":"PARP11 is induced in intratumoral CD8+ CTLs by immunosuppressive TME factors (regulatory T cells, adenosine) and acts as a key regulator of IFNAR1 downregulation on CTLs; PARP11 ablation prevents IFNAR1 loss, increases CTL tumoricidal activity, and inhibits tumor growth in an IFNAR1-dependent manner.","method":"Genetic KO and pharmacologic inhibition (ITK7) in tumor-bearing mice, CAR T cell engineering, in vivo tumor models","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with pharmacologic inhibition, in vivo tumor models, IFNAR1-dependence established, multiple orthogonal approaches, multiple labs","pmids":["35637402"],"is_preprint":false},{"year":2024,"finding":"PARP11 is an essential regulator of immunosuppressive activities of tumor-infiltrating regulatory T cells (TI-Tregs); tumor-derived factors adenosine and prostaglandin E2 induce PARP11 in TI-Tregs, and PARP11 KO or inhibition with ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses.","method":"PARP11 KO in TME cells, pharmacologic inhibition with ITK7 in tumor-bearing mice, immune cell functional assays, ICB and CAR T combination experiments","journal":"Cell reports. Medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and pharmacologic inhibition in vivo, defined cellular mechanism (TI-Treg inactivation), multiple orthogonal methods, single lab with rigorous controls","pmids":["39019005"],"is_preprint":false},{"year":2022,"finding":"ACTRT1 anchors developing acrosomes to the sperm nucleus by interacting with the nuclear envelope protein PARP11 (and SPACA1/SPATA46); loss of ACTRT1 weakens this acrosome-nucleus connection during spermiogenesis.","method":"Co-immunoprecipitation, Actrt1-KO mouse model, immunofluorescence","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP demonstrating interaction, KO mouse phenotype, single lab","pmids":["35616329"],"is_preprint":false},{"year":2024,"finding":"Porcine PARP11 restricts pseudorabies virus (PRV) infection; PARP11 knockout upregulates NXF1 and CRM1 transcription, resulting in enhanced viral gene transcription, and also activates the autophagy pathway while suppressing the mTOR pathway during PRV infection.","method":"CRISPR/Cas9 PARP11-KO PK-15 cells, RT-qPCR, TCID50 assay, RNA-seq, western blot","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple readouts (transcriptomic, virological, pathway), single lab","pmids":["39445214"],"is_preprint":false}],"current_model":"PARP11 is a nuclear envelope-localized mono-ADP-ribosyltransferase (MAR transferase) that uses its WWE and catalytic domains for nuclear envelope targeting; it mono-ADP-ribosylates protein substrates (notably β-TrCP, promoting IFNAR1 degradation and viral immune evasion) and phosphorylated RNA ends (reversibly, with cellular hydrolases), auto-ribosylates on acidic residues, cooperates with PARP12 to degrade viral proteins independently of its own enzymatic activity, and plays essential roles in spermatid nuclear shaping and in regulating immunosuppression in the tumor microenvironment (in both CTLs and regulatory T cells) through IFNAR1-dependent mechanisms; its catalytic activity governs its own nuclear envelope localization, as shown by selective inhibitor ITK7."},"narrative":{"mechanistic_narrative":"PARP11 (ARTD11) is a nuclear envelope-localized mono-ADP-ribosyltransferase that links protein and RNA ADP-ribosylation to antiviral immunity, anti-tumor immune regulation, and spermatid development [PMID:30988430, PMID:25673562, PMID:36018800]. It is targeted to the nuclear envelope through its N-terminal WWE domain (residues Y77, Q86, R95) and the presence of its catalytic domain, where it co-localizes with the nucleoporin NUP153; this localization does not require catalytic activity per se, yet pharmacologic inhibition of its MARylation activity with the selective inhibitor ITK7 causes PARP11 to dissociate from the nuclear envelope [PMID:25673562, PMID:30344052]. Enzymatically, PARP11 mono-ADP-ribosylates the E3 ubiquitin ligase β-TrCP to promote IFNAR1 ubiquitination and degradation, dampening type I IFN signalling and facilitating viral immune evasion [PMID:30988430]. Beyond protein substrates, PARP11 ADP-ribosylates phosphorylated RNA ends in vitro and in human cells, a reversible modification removed by hydrolases such as TARG1, PARG, and ARH3; ADPr-capped mRNA is protected from XRN1-mediated degradation but is not translated [PMID:31216043, PMID:36018800]. In the tumor microenvironment, immunosuppressive factors including adenosine and prostaglandin E2 induce PARP11 in intratumoral CD8+ cytotoxic T cells and regulatory T cells, where it drives IFNAR1 downregulation and immunosuppression; genetic ablation or ITK7 inhibition restores IFNAR1, reinvigorates anti-tumor immunity, and suppresses tumor growth in an IFNAR1-dependent manner [PMID:35637402, PMID:39019005]. PARP11 also restricts viral infection through enzymatic-activity-independent routes, cooperating with PARP12 to degrade Zika virus NS1 and NS3 proteins [PMID:34187568]. In male germ cells, PARP11 is required for spermatid nuclear shaping, with its loss causing nuclear envelope structural defects, chromatin detachment, and male infertility [PMID:25673562].","teleology":[{"year":2015,"claim":"Established where PARP11 acts and what targets it there, defining the nuclear envelope as its functional site and its requirement for sperm nuclear architecture.","evidence":"Knockout mouse, WWE-domain mutagenesis, and NUP153 colocalization imaging","pmids":["25673562"],"confidence":"High","gaps":["Molecular mechanism connecting nuclear envelope localization to chromatin attachment unresolved","Substrates at the nuclear envelope not identified in this study"]},{"year":2015,"claim":"Defined the chemistry of PARP11 auto-modification, showing it auto-ADP-ribosylates acidic residues via a distinctive C1' to C2' ribose transfer.","evidence":"Clickable aminooxy alkyne chemical probe and click chemistry in cells","pmids":["25978521"],"confidence":"Medium","gaps":["Functional consequence of auto-modification unknown","Single chemical-probe method"]},{"year":2016,"claim":"Identified PARP11's protein MARylome, revealing nuclear pore complex proteins as isoform-specific targets and that targeting requires both regulatory and catalytic domains.","evidence":"Engineered orthogonal NAD+ analog, in vitro MARylation, mass spectrometry","pmids":["26774478"],"confidence":"Medium","gaps":["In vitro targets not validated in cells","Functional impact of nucleoporin MARylation unestablished"]},{"year":2018,"claim":"Provided a selective chemical tool (ITK7) and showed that PARP11 catalytic activity governs its own nuclear envelope retention.","evidence":"Structure-guided inhibitor design, in vitro inhibition assay, live-cell imaging","pmids":["30344052"],"confidence":"High","gaps":["Endogenous substrate driving localization not identified","Reconciliation with the earlier finding that catalysis is not required for NUP153 colocalization unaddressed"]},{"year":2019,"claim":"Connected PARP11 enzymatic activity to a defined physiological pathway by identifying β-TrCP as a substrate that channels IFNAR1 degradation and viral immune evasion.","evidence":"ADP-ribosylation assays, reciprocal Co-IP, loss/gain-of-function, in vivo mouse viral infection","pmids":["30988430"],"confidence":"High","gaps":["Modified residues on β-TrCP not mapped","How β-TrCP MARylation mechanistically enhances IFNAR1 ubiquitination unclear"]},{"year":2019,"claim":"Expanded the substrate class of PARP11 from proteins to RNA, showing it mono-ADP-ribosylates phosphorylated RNA ends reversibly.","evidence":"In vitro ADP-ribosylation of purified RNA substrates and hydrolase reversal assays","pmids":["31216043"],"confidence":"High","gaps":["In vitro only at this stage","Biological RNA targets not defined"]},{"year":2021,"claim":"Showed PARP11 restricts viral infection through an enzymatic-activity-independent route, cooperating with PARP12 to degrade Zika virus proteins.","evidence":"Multiple KO cell lines, Co-IP, western blot, immunofluorescence in A549 and HEK293T","pmids":["34187568"],"confidence":"Medium","gaps":["Mechanism of PARP11-PARP12 cooperation undefined","Single lab, no in vivo confirmation"]},{"year":2022,"claim":"Demonstrated RNA ADP-ribosylation by PARP11 occurs in human cells with functional consequences, protecting capped mRNA from XRN1 degradation while blocking translation.","evidence":"Cellular RNA ADP-ribosylation assays with PARP KO/overexpression and functional degradation/translation assays","pmids":["36018800"],"confidence":"High","gaps":["Endogenous mRNA targets and physiological scope unknown","Link to PARP11's nuclear envelope localization not established"]},{"year":2022,"claim":"Placed PARP11 at the center of tumor immunosuppression in cytotoxic T cells, showing TME factors induce it to downregulate IFNAR1 and that its ablation restores anti-tumor immunity.","evidence":"Genetic KO and ITK7 inhibition in tumor-bearing mice, CAR T engineering, in vivo tumor models","pmids":["35637402"],"confidence":"High","gaps":["Whether β-TrCP MARylation mediates CTL IFNAR1 loss not directly tested here","Direct enzymatic substrate in CTLs not pinpointed"]},{"year":2022,"claim":"Identified ACTRT1 as a nuclear envelope partner of PARP11 that anchors developing acrosomes to the sperm nucleus.","evidence":"Co-IP, Actrt1-KO mouse, immunofluorescence","pmids":["35616329"],"confidence":"Medium","gaps":["Direct vs indirect PARP11-ACTRT1 interaction not resolved","Role of PARP11 catalysis in acrosome anchoring untested"]},{"year":2024,"claim":"Extended PARP11's immunoregulatory role to regulatory T cells, showing TME-induced PARP11 sustains TI-Treg immunosuppression and that its inhibition reinvigorates anti-tumor responses.","evidence":"PARP11 KO and ITK7 inhibition in tumor-bearing mice, immune functional assays, ICB and CAR T combinations","pmids":["39019005"],"confidence":"High","gaps":["Molecular substrate in Tregs not identified","Relationship to IFNAR1 axis in Tregs vs CTLs not fully delineated"]},{"year":2024,"claim":"Showed PARP11 antiviral restriction extends across species and pathways, regulating nuclear export factors and autophagy/mTOR during pseudorabies virus infection.","evidence":"CRISPR/Cas9 KO PK-15 cells, RT-qPCR, TCID50, RNA-seq, western blot","pmids":["39445214"],"confidence":"Medium","gaps":["Direct PARP11 substrate driving NXF1/CRM1 and autophagy changes unknown","Whether effects require catalytic activity untested"]},{"year":null,"claim":"It remains unresolved how PARP11's catalytic and enzymatic-activity-independent functions are integrated, and which endogenous substrates mediate its distinct roles in immunity, RNA metabolism, and spermatogenesis.","evidence":"No single study reconciles the protein-MARylation, RNA-MARylation, and scaffolding activities across cell types","pmids":[],"confidence":"Low","gaps":["No unified model linking nuclear envelope localization to its diverse substrates","Physiological RNA substrates undefined","Substrate(s) underlying tumor-immune phenotypes not pinpointed in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,4,5,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[4,5]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,8,9]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[2,10]}],"complexes":[],"partners":["BTRC","NUP153","PARP12","ACTRT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NR21","full_name":"Protein mono-ADP-ribosyltransferase PARP11","aliases":["ADP-ribosyltransferase diphtheria toxin-like 11","ARTD11","Poly [ADP-ribose] polymerase 11","PARP-11"],"length_aa":338,"mass_kda":39.6,"function":"Mono-ADP-ribosyltransferase that mediates mono-ADP-ribosylation of target proteins (PubMed:25043379, PubMed:25673562). Plays a role in nuclear envelope stability and nuclear remodeling during spermiogenesis (By similarity). Inhibits the type I interferon activated signaling pathway (PubMed:30988430). Mechanistically, mono-ADP-ribosylates beta-TrCP/BTRC to promote IFNAR1 ubiquitination and protect BTRC from ubiquitin-proteasome degradation. Additionally, acts as an antiviral factor by cooperating with PARP12 to suppress Zika virus replication, independent of IFNAR1 regulation or intrinsic PARP enzymatic activity (PubMed:34187568). Instead, facilitates the degradation of viral NS1 and NS3 proteins, potentially disrupting viral replication (PubMed:34187568)","subcellular_location":"Nucleus, nuclear pore complex","url":"https://www.uniprot.org/uniprotkb/Q9NR21/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PARP11","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PARP11","total_profiled":1310},"omim":[{"mim_id":"616706","title":"POLY(ADP-RIBOSE) POLYMERASE FAMILY, MEMBER 11; PARP11","url":"https://www.omim.org/entry/616706"},{"mim_id":"300487","title":"ACTIN-RELATED PROTEIN T1; ACTRT1","url":"https://www.omim.org/entry/300487"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PARP11"},"hgnc":{"alias_symbol":["ARTD11"],"prev_symbol":["C12orf6"]},"alphafold":{"accession":"Q9NR21","domains":[{"cath_id":"3.30.720.50","chopping":"35-109","consensus_level":"high","plddt":86.4813,"start":35,"end":109},{"cath_id":"3.90.228.10","chopping":"140-252_274-338","consensus_level":"high","plddt":92.7012,"start":140,"end":338}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NR21","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NR21-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NR21-F1-predicted_aligned_error_v6.png","plddt_mean":81.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PARP11","jax_strain_url":"https://www.jax.org/strain/search?query=PARP11"},"sequence":{"accession":"Q9NR21","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NR21.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NR21/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NR21"}},"corpus_meta":[{"pmid":"31216043","id":"PMC_31216043","title":"Reversible ADP-ribosylation of RNA.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31216043","citation_count":134,"is_preprint":false},{"pmid":"30988430","id":"PMC_30988430","title":"ADP-ribosyltransferase PARP11 modulates the interferon antiviral response by mono-ADP-ribosylating the ubiquitin E3 ligase β-TrCP.","date":"2019","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30988430","citation_count":89,"is_preprint":false},{"pmid":"26774478","id":"PMC_26774478","title":"Identifying Family-Member-Specific Targets of Mono-ARTDs by Using a Chemical Genetics Approach.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26774478","citation_count":74,"is_preprint":false},{"pmid":"30344052","id":"PMC_30344052","title":"A Potent and Selective PARP11 Inhibitor Suggests Coupling between Cellular Localization and Catalytic Activity.","date":"2018","source":"Cell chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/30344052","citation_count":54,"is_preprint":false},{"pmid":"25673562","id":"PMC_25673562","title":"Spermatid head elongation with normal nuclear shaping requires ADP-ribosyltransferase PARP11 (ARTD11) in mice.","date":"2015","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/25673562","citation_count":49,"is_preprint":false},{"pmid":"35637402","id":"PMC_35637402","title":"Targeting PARP11 to avert immunosuppression and improve CAR T therapy in solid tumors.","date":"2022","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35637402","citation_count":45,"is_preprint":false},{"pmid":"36018800","id":"PMC_36018800","title":"ADP-ribosylation of RNA in mammalian cells is mediated by TRPT1 and multiple PARPs.","date":"2022","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36018800","citation_count":44,"is_preprint":false},{"pmid":"25978521","id":"PMC_25978521","title":"A Clickable Aminooxy Probe for Monitoring Cellular ADP-Ribosylation.","date":"2015","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/25978521","citation_count":37,"is_preprint":false},{"pmid":"34187568","id":"PMC_34187568","title":"ADP-ribosyltransferase PARP11 suppresses Zika virus in synergy with PARP12.","date":"2021","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/34187568","citation_count":30,"is_preprint":false},{"pmid":"35616329","id":"PMC_35616329","title":"Loss of perinuclear theca ACTRT1 causes acrosome detachment and severe male subfertility in mice.","date":"2022","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35616329","citation_count":29,"is_preprint":false},{"pmid":"35461273","id":"PMC_35461273","title":"SARS-COV-2 as potential microRNA sponge in COVID-19 patients.","date":"2022","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/35461273","citation_count":28,"is_preprint":false},{"pmid":"36598465","id":"PMC_36598465","title":"[1,2,4]Triazolo[3,4-b]benzothiazole Scaffold as Versatile Nicotinamide Mimic Allowing Nanomolar Inhibition of Different PARP Enzymes.","date":"2023","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36598465","citation_count":20,"is_preprint":false},{"pmid":"16548914","id":"PMC_16548914","title":"Deregulation of cyclin D2 by juxtaposition with T-cell receptor alpha/delta locus in t(12;14)(p13;q11)-positive childhood T-cell acute lymphoblastic leukemia.","date":"2006","source":"European journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/16548914","citation_count":19,"is_preprint":false},{"pmid":"24923327","id":"PMC_24923327","title":"Evolutionary origin and methylation status of human intronic CpG islands that are not present in mouse.","date":"2014","source":"Genome biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/24923327","citation_count":16,"is_preprint":false},{"pmid":"37801755","id":"PMC_37801755","title":"Immunomodulatory roles of PARPs: Shaping the tumor microenvironment, one ADP-ribose at a time.","date":"2023","source":"Current opinion in chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/37801755","citation_count":14,"is_preprint":false},{"pmid":"24780630","id":"PMC_24780630","title":"Genotype-phenotype relationship in a child with 2.3 Mb de novo interstitial 12p13.33-p13.32 deletion.","date":"2014","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24780630","citation_count":12,"is_preprint":false},{"pmid":"39965743","id":"PMC_39965743","title":"Parps in immune response: Potential targets for cancer immunotherapy.","date":"2025","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39965743","citation_count":11,"is_preprint":false},{"pmid":"39019005","id":"PMC_39019005","title":"PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies.","date":"2024","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39019005","citation_count":8,"is_preprint":false},{"pmid":"37809963","id":"PMC_37809963","title":"A seven-immune-genes risk model predicts the survival and suitable treatments for patients with skin cutaneous melanoma.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37809963","citation_count":4,"is_preprint":false},{"pmid":"41292883","id":"PMC_41292883","title":"Cross-Species Transcriptomic Integration Reveals a Conserved, MIRO1-Mediated Macrophage-to-T Cell Signaling Axis Driving Immunosuppression in Glioma.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41292883","citation_count":1,"is_preprint":false},{"pmid":"39445214","id":"PMC_39445214","title":"Identification of porcine PARP11 as a restricted factor for pseudorabies virus.","date":"2024","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39445214","citation_count":0,"is_preprint":false},{"pmid":"41997320","id":"PMC_41997320","title":"Single-cell transcriptomic analysis reveals novel lncRNA macromolecules associated with PARP11, LMF1, and RRM2 regulatory axes in non-small cell lung cancer.","date":"2026","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41997320","citation_count":0,"is_preprint":false},{"pmid":"40454210","id":"PMC_40454210","title":"Identification of Ferroptosis-Related Genes Associated With Cryptorchidism via Bioinformatics and Experimental Verification.","date":"2025","source":"Genetics research","url":"https://pubmed.ncbi.nlm.nih.gov/40454210","citation_count":0,"is_preprint":false},{"pmid":"42128668","id":"PMC_42128668","title":"Cross-species transcriptomic integration reveals a MIRO1-mediated macrophage-T cell axis in glioma.","date":"2026","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/42128668","citation_count":0,"is_preprint":false},{"pmid":"42017899","id":"PMC_42017899","title":"Bidirectional Mendelian randomization analysis reveals significant associations between Serum DNA repair proteins and liver cancer.","date":"2026","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/42017899","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.10.686781","title":"Cross-Species Transcriptomic Integration Reveals a MIRO1-Mediated Macrophage–T Cell Axis in Glioma","date":"2025-11-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.10.686781","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14726,"output_tokens":3024,"usd":0.044769,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10446,"output_tokens":3920,"usd":0.075115,"stage2_stop_reason":"end_turn"},"total_usd":0.119884,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"PARP11 (ARTD11) mono-ADP-ribosylates the ubiquitin E3 ligase β-TrCP, which promotes IFNAR1 ubiquitination and degradation, thereby inhibiting IFN-I-activated signalling and facilitating viral immune evasion.\",\n      \"method\": \"Biochemical ADP-ribosylation assays, Co-IP, loss-of-function and overexpression in cell lines, in vivo mouse viral infection model\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, enzymatic assay identifying substrate, defined cellular phenotype (IFNAR1 degradation), in vivo validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"30988430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Chemical genetic profiling using an engineered NAD+ analog identified ARTD11 (PARP11) MARylome targets in vitro, revealing nuclear pore complex proteins as isoform-specific targets; targeting was dependent on both the regulatory and catalytic domains of ARTD11.\",\n      \"method\": \"Chemical genetics (orthogonal NAD+ analog), in vitro MARylation assay, mass spectrometry\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution with engineered enzyme and domain mutagenesis, single lab, novel chemical genetic strategy\",\n      \"pmids\": [\"26774478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PARP11 localizes to the nuclear envelope in spermatids and somatic cells by co-localizing with NUP153; its N-terminal WWE domain residues Y77, Q86, R95 and the presence of the catalytic domain are required for nuclear envelope colocalization, but catalytic activity itself is not required for colocalization with NUP153. Loss of PARP11 in mice causes teratozoospermia with nuclear envelope structural defects and chromatin detachment in elongating spermatids, resulting in male infertility.\",\n      \"method\": \"Knockout mouse model, immunofluorescence colocalization, site-directed mutagenesis of WWE domain, in vitro mono-ADP-ribosylation assay (auto-ribosylation), transfection of somatic cells\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined cellular phenotype, mutagenesis-based domain mapping, direct localization experiments, multiple orthogonal methods\",\n      \"pmids\": [\"25673562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Structure-guided design of ITK7, a selective inhibitor (>200-fold selective over other PARPs) of PARP11 MARylation activity; live-cell imaging showed that ITK7 causes PARP11 to dissociate from the nuclear envelope, indicating that PARP11's catalytic activity regulates its nuclear envelope localization.\",\n      \"method\": \"Structure-guided inhibitor design, in vitro MARylation inhibition assay, live-cell imaging\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structure-guided inhibitor with crystal structure data, enzymatic assay, live-cell imaging showing functional consequence of catalytic inhibition, single lab multiple methods\",\n      \"pmids\": [\"30344052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PARP10, PARP11, and PARP15 (as well as TRPT1) ADP-ribosylate phosphorylated ends of RNA in vitro, identifying RNA as a novel substrate for mono-ADP-ribosylation; this modification can be reversed by cellular ADP-ribosylhydrolases (PARG, TARG1, MACROD1, MACROD2, ARH3).\",\n      \"method\": \"Biochemical in vitro ADP-ribosylation assays using purified proteins and RNA substrates, hydrolase reversal assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified components, replicated across multiple enzymes and hydrolases, orthogonal biochemical methods\",\n      \"pmids\": [\"31216043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PARP11 mediates ADP-ribosylation of RNA in human cells (not only in vitro), counteracted by hydrolases TARG1, PARG and ARH3; ADPr-capped mRNA is protected from XRN1-mediated degradation but is not translated.\",\n      \"method\": \"Cellular RNA ADP-ribosylation assays in human cells with PARP KO/overexpression, functional RNA degradation and translation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cellular KO/overexpression combined with functional RNA assays, replicates in-cell RNA ADP-ribosylation finding, multiple orthogonal methods\",\n      \"pmids\": [\"36018800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PARP10 and PARP11 are auto-ADP-ribosylated on acidic amino acids (glutamate/aspartate) in cells; a novel chemical mechanism was identified whereby the ADP-ribose transfers from C1' to C2' position on these residues.\",\n      \"method\": \"Clickable aminooxy alkyne (AO-alkyne) chemical probe, click chemistry, cellular ADP-ribosylation detection\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel chemical probe used in cells, single lab, single method but novel mechanism identified\",\n      \"pmids\": [\"25978521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PARP11 suppresses Zika virus (ZIKV) replication independently of its own ADP-ribosylation enzymatic activity; PARP11 interacts with PARP12 (by co-immunoprecipitation) and promotes PARP12-mediated degradation of ZIKV NS1 and NS3 proteins.\",\n      \"method\": \"PARP11 KO and overexpression in A549 cells, PARP11-/-/PARP12-/-/double-KO HEK293T cells, western blotting, immunofluorescence, co-immunoprecipitation\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple KO cell lines, Co-IP, loss-of-function with defined phenotype, single lab\",\n      \"pmids\": [\"34187568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PARP11 is induced in intratumoral CD8+ CTLs by immunosuppressive TME factors (regulatory T cells, adenosine) and acts as a key regulator of IFNAR1 downregulation on CTLs; PARP11 ablation prevents IFNAR1 loss, increases CTL tumoricidal activity, and inhibits tumor growth in an IFNAR1-dependent manner.\",\n      \"method\": \"Genetic KO and pharmacologic inhibition (ITK7) in tumor-bearing mice, CAR T cell engineering, in vivo tumor models\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with pharmacologic inhibition, in vivo tumor models, IFNAR1-dependence established, multiple orthogonal approaches, multiple labs\",\n      \"pmids\": [\"35637402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PARP11 is an essential regulator of immunosuppressive activities of tumor-infiltrating regulatory T cells (TI-Tregs); tumor-derived factors adenosine and prostaglandin E2 induce PARP11 in TI-Tregs, and PARP11 KO or inhibition with ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses.\",\n      \"method\": \"PARP11 KO in TME cells, pharmacologic inhibition with ITK7 in tumor-bearing mice, immune cell functional assays, ICB and CAR T combination experiments\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and pharmacologic inhibition in vivo, defined cellular mechanism (TI-Treg inactivation), multiple orthogonal methods, single lab with rigorous controls\",\n      \"pmids\": [\"39019005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACTRT1 anchors developing acrosomes to the sperm nucleus by interacting with the nuclear envelope protein PARP11 (and SPACA1/SPATA46); loss of ACTRT1 weakens this acrosome-nucleus connection during spermiogenesis.\",\n      \"method\": \"Co-immunoprecipitation, Actrt1-KO mouse model, immunofluorescence\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP demonstrating interaction, KO mouse phenotype, single lab\",\n      \"pmids\": [\"35616329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Porcine PARP11 restricts pseudorabies virus (PRV) infection; PARP11 knockout upregulates NXF1 and CRM1 transcription, resulting in enhanced viral gene transcription, and also activates the autophagy pathway while suppressing the mTOR pathway during PRV infection.\",\n      \"method\": \"CRISPR/Cas9 PARP11-KO PK-15 cells, RT-qPCR, TCID50 assay, RNA-seq, western blot\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple readouts (transcriptomic, virological, pathway), single lab\",\n      \"pmids\": [\"39445214\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PARP11 is a nuclear envelope-localized mono-ADP-ribosyltransferase (MAR transferase) that uses its WWE and catalytic domains for nuclear envelope targeting; it mono-ADP-ribosylates protein substrates (notably β-TrCP, promoting IFNAR1 degradation and viral immune evasion) and phosphorylated RNA ends (reversibly, with cellular hydrolases), auto-ribosylates on acidic residues, cooperates with PARP12 to degrade viral proteins independently of its own enzymatic activity, and plays essential roles in spermatid nuclear shaping and in regulating immunosuppression in the tumor microenvironment (in both CTLs and regulatory T cells) through IFNAR1-dependent mechanisms; its catalytic activity governs its own nuclear envelope localization, as shown by selective inhibitor ITK7.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PARP11 (ARTD11) is a nuclear envelope-localized mono-ADP-ribosyltransferase that links protein and RNA ADP-ribosylation to antiviral immunity, anti-tumor immune regulation, and spermatid development [#0, #2, #5]. It is targeted to the nuclear envelope through its N-terminal WWE domain (residues Y77, Q86, R95) and the presence of its catalytic domain, where it co-localizes with the nucleoporin NUP153; this localization does not require catalytic activity per se, yet pharmacologic inhibition of its MARylation activity with the selective inhibitor ITK7 causes PARP11 to dissociate from the nuclear envelope [#2, #3]. Enzymatically, PARP11 mono-ADP-ribosylates the E3 ubiquitin ligase \\u03b2-TrCP to promote IFNAR1 ubiquitination and degradation, dampening type I IFN signalling and facilitating viral immune evasion [#0]. Beyond protein substrates, PARP11 ADP-ribosylates phosphorylated RNA ends in vitro and in human cells, a reversible modification removed by hydrolases such as TARG1, PARG, and ARH3; ADPr-capped mRNA is protected from XRN1-mediated degradation but is not translated [#4, #5]. In the tumor microenvironment, immunosuppressive factors including adenosine and prostaglandin E2 induce PARP11 in intratumoral CD8+ cytotoxic T cells and regulatory T cells, where it drives IFNAR1 downregulation and immunosuppression; genetic ablation or ITK7 inhibition restores IFNAR1, reinvigorates anti-tumor immunity, and suppresses tumor growth in an IFNAR1-dependent manner [#8, #9]. PARP11 also restricts viral infection through enzymatic-activity-independent routes, cooperating with PARP12 to degrade Zika virus NS1 and NS3 proteins [#7]. In male germ cells, PARP11 is required for spermatid nuclear shaping, with its loss causing nuclear envelope structural defects, chromatin detachment, and male infertility [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established where PARP11 acts and what targets it there, defining the nuclear envelope as its functional site and its requirement for sperm nuclear architecture.\",\n      \"evidence\": \"Knockout mouse, WWE-domain mutagenesis, and NUP153 colocalization imaging\",\n      \"pmids\": [\"25673562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism connecting nuclear envelope localization to chromatin attachment unresolved\", \"Substrates at the nuclear envelope not identified in this study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the chemistry of PARP11 auto-modification, showing it auto-ADP-ribosylates acidic residues via a distinctive C1' to C2' ribose transfer.\",\n      \"evidence\": \"Clickable aminooxy alkyne chemical probe and click chemistry in cells\",\n      \"pmids\": [\"25978521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of auto-modification unknown\", \"Single chemical-probe method\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified PARP11's protein MARylome, revealing nuclear pore complex proteins as isoform-specific targets and that targeting requires both regulatory and catalytic domains.\",\n      \"evidence\": \"Engineered orthogonal NAD+ analog, in vitro MARylation, mass spectrometry\",\n      \"pmids\": [\"26774478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro targets not validated in cells\", \"Functional impact of nucleoporin MARylation unestablished\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided a selective chemical tool (ITK7) and showed that PARP11 catalytic activity governs its own nuclear envelope retention.\",\n      \"evidence\": \"Structure-guided inhibitor design, in vitro inhibition assay, live-cell imaging\",\n      \"pmids\": [\"30344052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous substrate driving localization not identified\", \"Reconciliation with the earlier finding that catalysis is not required for NUP153 colocalization unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected PARP11 enzymatic activity to a defined physiological pathway by identifying \\u03b2-TrCP as a substrate that channels IFNAR1 degradation and viral immune evasion.\",\n      \"evidence\": \"ADP-ribosylation assays, reciprocal Co-IP, loss/gain-of-function, in vivo mouse viral infection\",\n      \"pmids\": [\"30988430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Modified residues on \\u03b2-TrCP not mapped\", \"How \\u03b2-TrCP MARylation mechanistically enhances IFNAR1 ubiquitination unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded the substrate class of PARP11 from proteins to RNA, showing it mono-ADP-ribosylates phosphorylated RNA ends reversibly.\",\n      \"evidence\": \"In vitro ADP-ribosylation of purified RNA substrates and hydrolase reversal assays\",\n      \"pmids\": [\"31216043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro only at this stage\", \"Biological RNA targets not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed PARP11 restricts viral infection through an enzymatic-activity-independent route, cooperating with PARP12 to degrade Zika virus proteins.\",\n      \"evidence\": \"Multiple KO cell lines, Co-IP, western blot, immunofluorescence in A549 and HEK293T\",\n      \"pmids\": [\"34187568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PARP11-PARP12 cooperation undefined\", \"Single lab, no in vivo confirmation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated RNA ADP-ribosylation by PARP11 occurs in human cells with functional consequences, protecting capped mRNA from XRN1 degradation while blocking translation.\",\n      \"evidence\": \"Cellular RNA ADP-ribosylation assays with PARP KO/overexpression and functional degradation/translation assays\",\n      \"pmids\": [\"36018800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous mRNA targets and physiological scope unknown\", \"Link to PARP11's nuclear envelope localization not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed PARP11 at the center of tumor immunosuppression in cytotoxic T cells, showing TME factors induce it to downregulate IFNAR1 and that its ablation restores anti-tumor immunity.\",\n      \"evidence\": \"Genetic KO and ITK7 inhibition in tumor-bearing mice, CAR T engineering, in vivo tumor models\",\n      \"pmids\": [\"35637402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether \\u03b2-TrCP MARylation mediates CTL IFNAR1 loss not directly tested here\", \"Direct enzymatic substrate in CTLs not pinpointed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified ACTRT1 as a nuclear envelope partner of PARP11 that anchors developing acrosomes to the sperm nucleus.\",\n      \"evidence\": \"Co-IP, Actrt1-KO mouse, immunofluorescence\",\n      \"pmids\": [\"35616329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect PARP11-ACTRT1 interaction not resolved\", \"Role of PARP11 catalysis in acrosome anchoring untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended PARP11's immunoregulatory role to regulatory T cells, showing TME-induced PARP11 sustains TI-Treg immunosuppression and that its inhibition reinvigorates anti-tumor responses.\",\n      \"evidence\": \"PARP11 KO and ITK7 inhibition in tumor-bearing mice, immune functional assays, ICB and CAR T combinations\",\n      \"pmids\": [\"39019005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrate in Tregs not identified\", \"Relationship to IFNAR1 axis in Tregs vs CTLs not fully delineated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed PARP11 antiviral restriction extends across species and pathways, regulating nuclear export factors and autophagy/mTOR during pseudorabies virus infection.\",\n      \"evidence\": \"CRISPR/Cas9 KO PK-15 cells, RT-qPCR, TCID50, RNA-seq, western blot\",\n      \"pmids\": [\"39445214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PARP11 substrate driving NXF1/CRM1 and autophagy changes unknown\", \"Whether effects require catalytic activity untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PARP11's catalytic and enzymatic-activity-independent functions are integrated, and which endogenous substrates mediate its distinct roles in immunity, RNA metabolism, and spermatogenesis.\",\n      \"evidence\": \"No single study reconciles the protein-MARylation, RNA-MARylation, and scaffolding activities across cell types\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking nuclear envelope localization to its diverse substrates\", \"Physiological RNA substrates undefined\", \"Substrate(s) underlying tumor-immune phenotypes not pinpointed in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 4, 5, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 8, 9]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BTRC\", \"NUP153\", \"PARP12\", \"ACTRT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}