{"gene":"ZFP91","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2003,"finding":"ZFP91 protein localizes to the nucleus and contains five zinc-finger domains, a leucine zipper, and nuclear localization signals, consistent with a transcription factor; antisense oligonucleotide-mediated suppression of ZFP91 inhibited cell growth and induced apoptosis in AML cells.","method":"Antisense oligonucleotide knockdown with cell proliferation and apoptosis readouts; nuclear localization by subcellular fractionation/imaging","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct loss-of-function with defined cellular phenotype (growth suppression, apoptosis) and localization data, single lab, single study","pmids":["12738986"],"is_preprint":false},{"year":2017,"finding":"ZFP91 is an IMiD-dependent substrate of the CRL4CRBN E3 ubiquitin ligase; lenalidomide induces CRL4CRBN-mediated ubiquitination and proteasomal degradation of ZFP91. ZFP91 harbors a zinc finger (ZnF) motif related to IKZF1/3 ZnF that is critical for IMiD-dependent CRBN binding.","method":"Pulse-chase SILAC mass spectrometry (pSILAC MS), ubiquitination assays, protein degradation assays, domain mapping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative proteomics, biochemical ubiquitination assays, domain mutagenesis, multiple orthogonal methods in a single rigorous study","pmids":["28530236"],"is_preprint":false},{"year":2016,"finding":"ZFP91 activates HIF-1α transcription through the transcription factor NF-κB/p65; ZFP91 requires NF-κB/p65 to bind the HIF-1α promoter at −197/−188 bp and drive transcriptional activation, thereby promoting colon cancer cell proliferation.","method":"Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), luciferase reporter gene assay, flow cytometry, EdU incorporation, tumor xenograft assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, luciferase reporter) in a single lab establishing direct promoter binding and transcriptional mechanism","pmids":["27144516"],"is_preprint":false},{"year":2018,"finding":"ZFP91 acts as an E3 ubiquitin ligase that ubiquitinates hnRNP F at Lys185, promoting its proteasomal degradation; ECD protein competitively binds hnRNP F via its N-terminal STG1 domain (aa 13–383), preventing hnRNP F from interacting with ZFP91 and thus blocking ZFP91-mediated degradation.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay (IP + western blot), domain mapping, in vitro and in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, domain mapping, single lab with multiple orthogonal methods","pmids":["29706618"],"is_preprint":false},{"year":2020,"finding":"ZFP91 promotes K48-linked ubiquitination of hnRNP A1 at lysine 8 and its proteasomal degradation, thereby inhibiting hnRNP A1-dependent PKM alternative splicing; this shifts PKM isoform balance toward PKM1 (away from PKM2), suppressing aerobic glycolysis (Warburg effect) in hepatocellular carcinoma.","method":"Co-IP with mass spectrometry, ubiquitination assay (IP + western blot), RT-PCR with restriction digestion for splicing analysis, lactate/glucose uptake assays, RNAi, xenograft models","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP/MS, site-specific ubiquitination, splicing readout, metabolic assays, in vivo) in a single study establishing a mechanistic axis","pmids":["32754263"],"is_preprint":false},{"year":2020,"finding":"ZFP91 ubiquitinates and destabilizes FOXA1, promoting its proteasomal degradation; ZFP91 knockdown reduces FOXA1 polyubiquitination, increases FOXA1 stability, and enhances cellular chemosensitivity in gastric cancer.","method":"Co-immunoprecipitation, ubiquitination assay (IP + western blot), ZFP91 knockdown with FOXA1 protein stability and chemoresistance readouts","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assays with functional consequence, single lab","pmids":["31046116"],"is_preprint":false},{"year":2021,"finding":"Upon TCR stimulation, ZFP91 translocates from the nucleus to the cytoplasm in regulatory T cells and mediates K63-linked ubiquitination of BECN1 (Beclin-1), promoting BECN1-PIK3C3 complex formation and autophagosome maturation; this autophagy activation restrains hyperglycolysis and maintains Treg cell homeostasis and function.","method":"T reg cell-specific Zfp91 knockout mice, TCR stimulation assays, subcellular fractionation/live imaging for translocation, Co-IP, ubiquitination assay, autophagy flux assays, in vivo colitis model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mice, direct localization with functional consequence, Co-IP, ubiquitination assay, multiple orthogonal methods across in vitro and in vivo contexts","pmids":["33355624"],"is_preprint":false},{"year":2021,"finding":"Upon TCR stimulation, ZFP91 translocates from the nucleus to the cytoplasm in tumor-infiltrating T cells and promotes PP2A complex assembly, thereby restricting mTORC1-mediated metabolic reprogramming (glycolysis); T cell-specific Zfp91 deletion increases mTORC1 activity, drives glycolysis, and enhances T cell proliferation and antitumor function.","method":"T cell-specific Zfp91 knockout mice, single-cell RNA-seq, subcellular fractionation for translocation, Co-IP for PP2A complex assembly, mTORC1 activity assays, metabolic assays, in vivo tumor models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mice, translocation experiment with functional consequence, Co-IP for complex assembly, multiple orthogonal methods","pmids":["34403361"],"is_preprint":false},{"year":2022,"finding":"ZFP91 mediates K63-linked polyubiquitination of pro-IL-1β and promotes activation of the non-canonical caspase-8 inflammasome complex assembly in macrophages; inhibiting ZFP91 (by convallatoxin) reduces K63-linked polyubiquitination of pro-IL-1β, caspase-8 inflammasome assembly, and IL-1β production.","method":"Co-immunoprecipitation, ubiquitination assay (IP + western blot), immunofluorescence, ELISA, in vivo inflammatory models (D-GalN/LPS liver injury, DSS colitis, alum peritonitis)","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, site-specific ubiquitination assay, inflammasome complex assembly assay, in vivo validation, single lab","pmids":["34825365"],"is_preprint":false},{"year":2022,"finding":"ZFP91 functions as a bona fide transcription factor in T-cell lymphomas, co-regulating cell survival with IKZF1 by directly activating genes from WNT, NF-κB, and MAP kinase signaling pathways; ZFP91 is selectively degraded by the next-generation IMiD degrader CC-92480 via CRL4CRBN with greater potency than pomalidomide, and ZFP91 rewiring involving casein kinase 2-mediated c-Jun inactivation confers acquired resistance to lenalidomide.","method":"Mass spectrometry proteomics for target identification of CC-92480, transcription factor chromatin binding assays, in vivo TCL models (4 models), epistasis analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based target ID, functional transcription factor evidence, multiple in vivo models, single lab","pmids":["34936696"],"is_preprint":false},{"year":2022,"finding":"ZFP91 promotes the molecular glue bufalin-induced E2F2 ubiquitination via K48-linked ubiquitin chains and proteasomal degradation; bufalin promotes E2F2-ZFP91 complex formation, establishing ZFP91 as an atypical E3 ligase for E2F2.","method":"Human proteome microarray, Co-IP with SILAC-based quantitative proteomics, ubiquitination assay (K48-linked chain specificity), in vitro and in vivo cancer models","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteome microarray, quantitative Co-IP proteomics, ubiquitination assay, single lab with multiple orthogonal methods","pmids":["36375317"],"is_preprint":false},{"year":2022,"finding":"ZFP91 interacts with RIP1 and inhibits K48-linked ubiquitination of RIP1, thereby protecting RIP1 from proteasomal degradation in AML cells and promoting cell proliferation while inhibiting apoptosis.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linked chain specificity), ZFP91 knockdown with proliferation/apoptosis readouts","journal":"International journal of medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and ubiquitination assay, single lab, limited mechanistic follow-up","pmids":["35165513"],"is_preprint":false},{"year":2020,"finding":"ZFP91 is directly targeted by miR-640; Ang-1-induced downregulation of miR-640 upregulates ZFP91 expression, and ZFP91 knockdown inhibits Ang-1-induced endothelial cell migration and tube formation, placing ZFP91 downstream of Ang-1/Tie-2 signaling in angiogenesis.","method":"Pull-down assay of biotinylated miR-640, ZFP91 siRNA knockdown, Ang-1 stimulation assays, migration and tube formation assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA pull-down for target validation, loss-of-function with defined angiogenic phenotype, single lab","pmids":["32630670"],"is_preprint":false},{"year":2021,"finding":"ZFP91 ubiquitinates TSPYL2 and promotes its poly-ubiquitination and proteasomal degradation; this ZFP91-mediated TSPYL2 destabilization contributes to gemcitabine resistance in pancreatic adenocarcinoma.","method":"Co-immunoprecipitation, ubiquitination assay, PANC-1 gemcitabine-resistant cell model, xenograft in vivo model","journal":"Journal of ginseng research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and ubiquitination assay, single lab, limited mechanistic detail in abstract","pmids":["36090681"],"is_preprint":false},{"year":2026,"finding":"ZFP91 directly binds the EVI1 promoter and enhances H3K4me3/H3K27ac histone marks and chromatin accessibility to activate EVI1 transcription in myeloid leukemia; ZFP91 was identified as the leading activator of EVI1 in a genome-wide CRISPR screen.","method":"Genome-wide CRISPR screen (GFP knock-in reporter at EVI1 locus), ChIP-seq for ZFP91 promoter binding and histone marks, ATAC-seq for chromatin accessibility, ZFP91 knockout","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — unbiased genome-wide CRISPR screen followed by ChIP-seq and chromatin accessibility assays establishing direct promoter binding and epigenetic mechanism, single lab but multiple orthogonal methods","pmids":["42034869"],"is_preprint":false},{"year":2025,"finding":"ZFP91 positively regulates HIF-1α protein expression in non-small cell lung cancer cells; CuB treatment inhibits HIF-1α expression through ZFP91 as shown by co-immunoprecipitation and molecular binding studies.","method":"Co-immunoprecipitation, western blot, molecular docking, siRNA knockdown, in vivo xenograft model","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and molecular docking, single lab, limited mechanistic detail; mechanism of how ZFP91 regulates HIF-1α not fully resolved","pmids":["40860815"],"is_preprint":false}],"current_model":"ZFP91 is an atypical RING-type E3 ubiquitin ligase and transcription factor that, depending on cellular context, ubiquitinates substrates including hnRNP A1 (K48-linked, at Lys8), hnRNP F (K48-linked, at Lys185), FOXA1, BECN1 (K63-linked), pro-IL-1β (K63-linked), E2F2 (K48-linked), and TSPYL2, while also functioning in the nucleus to directly activate gene transcription (e.g., HIF-1α via NF-κB/p65, EVI1); upon TCR stimulation ZFP91 translocates from the nucleus to the cytoplasm where it promotes PP2A assembly and BECN1-driven autophagy to restrain mTORC1 glycolytic reprogramming in T cells, and ZFP91 is itself a substrate of the CRL4CRBN E3 ligase complex whose degradation is induced by IMiD drugs (lenalidomide, pomalidomide) through a ZnF motif related to IKZF1/3."},"narrative":{"mechanistic_narrative":"ZFP91 is a dual-function nuclear zinc-finger protein that operates both as a sequence-specific transcriptional activator and as an atypical RING-type E3 ubiquitin ligase, with its activities shaping cancer cell metabolism, immune homeostasis, and inflammatory signaling [PMID:12738986, PMID:32754263, PMID:33355624]. As a transcription factor it binds target promoters directly: it activates HIF-1α transcription in a manner requiring NF-κB/p65 promoter binding [PMID:27144516], and it occupies the EVI1 promoter to deposit activating H3K4me3/H3K27ac marks and increase chromatin accessibility in myeloid leukemia [PMID:42034869]. As an E3 ligase, ZFP91 governs substrate stability through distinct chain linkages: it directs K48-linked ubiquitination and proteasomal degradation of hnRNP A1 at Lys8—thereby redirecting PKM alternative splicing toward PKM1 and suppressing aerobic glycolysis in hepatocellular carcinoma [PMID:32754263]—as well as of hnRNP F at Lys185, FOXA1, and E2F2 [PMID:29706618, PMID:31046116, PMID:36375317], while assembling K63-linked chains on BECN1 to promote autophagosome maturation [PMID:33355624] and on pro-IL-1β to drive non-canonical caspase-8 inflammasome assembly in macrophages [PMID:34825365]. Upon TCR stimulation in T cells, ZFP91 relocates from nucleus to cytoplasm, where it promotes PP2A complex assembly to restrain mTORC1-driven glycolytic reprogramming and supports BECN1-dependent autophagy to maintain regulatory T-cell homeostasis [PMID:33355624, PMID:34403361]. ZFP91 is itself a target of the CRL4CRBN E3 ligase: lenalidomide and next-generation IMiD degraders induce its CRBN-dependent ubiquitination and degradation through a zinc-finger motif related to IKZF1/3 [PMID:28530236, PMID:34936696].","teleology":[{"year":2003,"claim":"Establishing ZFP91's basic identity and cellular importance, this work showed it is a nuclear multi-zinc-finger protein with transcription-factor architecture whose loss impairs leukemia cell survival.","evidence":"Antisense knockdown with proliferation/apoptosis readouts and subcellular localization in AML cells","pmids":["12738986"],"confidence":"Medium","gaps":["No direct DNA targets identified","Ligase activity not yet known","Phenotype not linked to a defined molecular mechanism"]},{"year":2016,"claim":"The first direct transcriptional target was defined, showing ZFP91 drives HIF-1α expression but only via cooperation with NF-κB/p65 at a specific promoter element.","evidence":"ChIP, EMSA, and luciferase reporter assays with xenograft validation in colon cancer","pmids":["27144516"],"confidence":"Medium","gaps":["Whether ZFP91 contacts DNA directly or only through p65 unresolved","No genome-wide binding map"]},{"year":2017,"claim":"ZFP91 was identified as an IMiD-dependent neosubstrate of CRL4CRBN, explaining how it is selectively degraded by lenalidomide and linking it to the IKZF1/3 zinc-finger degron family.","evidence":"Pulse-chase SILAC MS, ubiquitination/degradation assays, and degron domain mapping","pmids":["28530236"],"confidence":"High","gaps":["Functional consequence of ZFP91 degradation in patients not addressed here","Endogenous role separate from IMiD context unexplored"]},{"year":2018,"claim":"ZFP91 was reframed as an E3 ligase itself, ubiquitinating hnRNP F at a defined lysine to drive its degradation, with ECD acting as a competitive protective factor.","evidence":"Reciprocal Co-IP, MS, site-mapped ubiquitination assays, and domain mapping","pmids":["29706618"],"confidence":"Medium","gaps":["Direct vs. adaptor-mediated ligase activity not distinguished","No reconstitution of minimal ubiquitination reaction"]},{"year":2020,"claim":"A coherent metabolic axis emerged: ZFP91 ubiquitinates hnRNP A1 at Lys8 to alter PKM splicing and suppress the Warburg effect, connecting its ligase activity to tumor glycolysis.","evidence":"Co-IP/MS, site-specific K48 ubiquitination, splicing and metabolic assays, and xenografts in HCC","pmids":["32754263"],"confidence":"High","gaps":["Whether splicing control is the dominant tumor-suppressive function unclear","Context-dependence across tumor types not resolved"]},{"year":2020,"claim":"Additional substrates (FOXA1) and an upstream regulator (miR-640) broadened the ligase target set and placed ZFP91 within angiogenic and chemoresistance pathways.","evidence":"Co-IP and ubiquitination assays for FOXA1; biotinylated miR-640 pull-down and angiogenesis assays","pmids":["31046116","32630670"],"confidence":"Medium","gaps":["Substrate selectivity determinants unknown","Whether multiple substrates are degraded simultaneously in the same cell unaddressed"]},{"year":2021,"claim":"The pivotal mechanistic insight was that TCR signaling triggers nuclear-to-cytoplasmic relocation of ZFP91, switching it to a cytoplasmic role that restrains mTORC1 glycolysis via PP2A assembly and BECN1 K63-ubiquitination-driven autophagy to maintain T-cell homeostasis.","evidence":"T-cell- and Treg-specific Zfp91 knockout mice, translocation imaging, Co-IP, K63 ubiquitination, autophagy flux, and in vivo colitis/tumor models","pmids":["33355624","34403361"],"confidence":"High","gaps":["Signal that drives nucleocytoplasmic shuttling unknown","How ZFP91 promotes PP2A assembly mechanistically not resolved"]},{"year":2022,"claim":"ZFP91's repertoire expanded to inflammatory and additional oncogenic substrates and confirmed its standalone transcription-factor role in lymphoma alongside refined IMiD pharmacology.","evidence":"Co-IP/ubiquitination for pro-IL-1β (K63), E2F2 (K48), and RIP1; chromatin binding and CC-92480 degrader proteomics in T-cell lymphoma models","pmids":["34825365","36375317","34936696","35165513"],"confidence":"Medium","gaps":["RIP1 protection (anti-degradation) mechanism single-Co-IP only","How one protein both activates and represses substrate ubiquitination context-dependently unexplained"]},{"year":2026,"claim":"Unbiased screening positioned ZFP91 as a leading transcriptional activator of EVI1 acting through chromatin remodeling, cementing its epigenetic-regulator function in myeloid leukemia.","evidence":"Genome-wide CRISPR reporter screen, ChIP-seq for promoter binding and histone marks, and ATAC-seq with ZFP91 knockout","pmids":["42034869"],"confidence":"High","gaps":["Whether ZFP91 recruits histone-modifying machinery directly or indirectly unknown","Relationship between its ligase and transcriptional activities at the same loci unexplored"]},{"year":null,"claim":"The central unresolved question is how a single zinc-finger protein partitions between catalytically distinct activities (E3 ligase vs. transcriptional activator) and subcellular compartments, and what determines its substrate and promoter selectivity.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate or DNA engagement","Determinants of K48 vs K63 chain choice unknown","Signal controlling nuclear/cytoplasmic switching uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,4,5,6,8,10]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[3,4,6,8,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,14]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,14]},{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,4,5,6,8,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,7,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,7]}],"complexes":["CRL4CRBN (as substrate)","PP2A (assembly promoter)","caspase-8 non-canonical inflammasome"],"partners":["CRBN","HNRNP A1","HNRNP F","FOXA1","BECN1","E2F2","IKZF1","RIPK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96JP5","full_name":"E3 ubiquitin-protein ligase ZFP91","aliases":["RING-type E3 ubiquitin transferase ZFP91","Zinc finger protein 757","Zinc finger protein 91 homolog","Zfp-91"],"length_aa":570,"mass_kda":63.4,"function":"DNA-binding transcription factor (PubMed:34936696, PubMed:40608935). Also acts as an atypical E3 ubiquitin-protein ligase that mediates 'Lys-63'-linked ubiquitination of MAP3K14/NIK, leading to stabilize and activate MAP3K14/NIK (PubMed:20682767). It thereby acts as an activator of the non-canonical NF-kappa-B2/NFKB2 pathway (PubMed:20682767). May also play an important role in cell proliferation and/or anti-apoptosis (PubMed:12738986)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96JP5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZFP91","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZFP91","total_profiled":1310},"omim":[{"mim_id":"621325","title":"VERVERI-BRADY SYNDROME 2; VERBRAS2","url":"https://www.omim.org/entry/621325"},{"mim_id":"619289","title":"ZINC FINGER PROTEIN 91, ATYPICAL E3 UBIQUITIN LIGASE; ZFP91","url":"https://www.omim.org/entry/619289"},{"mim_id":"617387","title":"GLUTAMINE-RICH PROTEIN 1; QRICH1","url":"https://www.omim.org/entry/617387"},{"mim_id":"600902","title":"SELENOPHOSPHATE SYNTHETASE 1; SEPHS1","url":"https://www.omim.org/entry/600902"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nucleoli","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZFP91"},"hgnc":{"alias_symbol":["PZF","ZNF757"],"prev_symbol":[]},"alphafold":{"accession":"Q96JP5","domains":[{"cath_id":"-","chopping":"308-349","consensus_level":"medium","plddt":70.9407,"start":308,"end":349}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JP5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JP5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JP5-F1-predicted_aligned_error_v6.png","plddt_mean":51.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZFP91","jax_strain_url":"https://www.jax.org/strain/search?query=ZFP91"},"sequence":{"accession":"Q96JP5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96JP5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96JP5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JP5"}},"corpus_meta":[{"pmid":"28530236","id":"PMC_28530236","title":"pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28530236","citation_count":145,"is_preprint":false},{"pmid":"32754263","id":"PMC_32754263","title":"E3 ligase ZFP91 inhibits Hepatocellular Carcinoma Metabolism Reprogramming by regulating PKM splicing.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32754263","citation_count":65,"is_preprint":false},{"pmid":"36375317","id":"PMC_36375317","title":"Atypical E3 ligase ZFP91 promotes small-molecule-induced E2F2 transcription factor degradation for cancer therapy.","date":"2022","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/36375317","citation_count":54,"is_preprint":false},{"pmid":"12738986","id":"PMC_12738986","title":"Identification of a novel human gene, ZFP91, involved in acute myelogenous leukemia.","date":"2003","source":"International journal of 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promotes gastric cancer metastasis by blocking E3 ligase ZFP91-mediated hnRNP F ubiquitination and degradation.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29706618","citation_count":35,"is_preprint":false},{"pmid":"34936696","id":"PMC_34936696","title":"Overcoming IMiD resistance in T-cell lymphomas through potent degradation of ZFP91 and IKZF1.","date":"2022","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/34936696","citation_count":31,"is_preprint":false},{"pmid":"30375338","id":"PMC_30375338","title":"Thromboresistance and functional healing in the COBRA PzF stent versus competitor DES: implications for dual antiplatelet therapy.","date":"2019","source":"EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/30375338","citation_count":24,"is_preprint":false},{"pmid":"34403361","id":"PMC_34403361","title":"ZFP91 disturbs metabolic fitness and antitumor activity of tumor-infiltrating T cells.","date":"2021","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/34403361","citation_count":23,"is_preprint":false},{"pmid":"33355624","id":"PMC_33355624","title":"ZFP91 is required for the maintenance of regulatory T cell homeostasis and function.","date":"2021","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33355624","citation_count":20,"is_preprint":false},{"pmid":"34825365","id":"PMC_34825365","title":"Convallatoxin inhibits IL-1β production by suppressing zinc finger protein 91 (ZFP91)-mediated pro-IL-1β ubiquitination and caspase-8 inflammasome activity.","date":"2022","source":"British journal of 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research","url":"https://pubmed.ncbi.nlm.nih.gov/32913509","citation_count":12,"is_preprint":false},{"pmid":"20434516","id":"PMC_20434516","title":"A retroviral vector common integration site between leupaxin and zinc finger protein 91 (ZFP91) observed in baboon hematopoietic repopulating cells.","date":"2010","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/20434516","citation_count":6,"is_preprint":false},{"pmid":"38597324","id":"PMC_38597324","title":"LncRNA EBLN3P Accelerates Cell Proliferation and Invasion of Colon Cancer through Modulating the miR-519d-3p/ZFP91 Axis.","date":"2024","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/38597324","citation_count":5,"is_preprint":false},{"pmid":"34925523","id":"PMC_34925523","title":"Breviscapine Participates in the Progression of Prostate Cancer by Inhibiting ZFP91 Expression through Upregulation of MicroRNA-129-5p.","date":"2021","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/34925523","citation_count":5,"is_preprint":false},{"pmid":"35165513","id":"PMC_35165513","title":"ZFP91 promotes cell proliferation and inhibits cell apoptosis in AML via inhibiting the proteasome-dependent degradation of RIP1.","date":"2022","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35165513","citation_count":4,"is_preprint":false},{"pmid":"35399733","id":"PMC_35399733","title":"Silencing LINC00491 Inhibits Pancreatic Cancer Progression through MiR-188-5p-induced Inhibition of ZFP91.","date":"2022","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35399733","citation_count":4,"is_preprint":false},{"pmid":"40860815","id":"PMC_40860815","title":"Cucurbitacin B inhibits HIF-1α and attenuates non-small cell lung cancer via ZFP91.","date":"2025","source":"Frontiers in 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oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40978051","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15316,"output_tokens":4255,"usd":0.054886,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12137,"output_tokens":3732,"usd":0.076993,"stage2_stop_reason":"end_turn"},"total_usd":0.131879,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"ZFP91 protein localizes to the nucleus and contains five zinc-finger domains, a leucine zipper, and nuclear localization signals, consistent with a transcription factor; antisense oligonucleotide-mediated suppression of ZFP91 inhibited cell growth and induced apoptosis in AML cells.\",\n      \"method\": \"Antisense oligonucleotide knockdown with cell proliferation and apoptosis readouts; nuclear localization by subcellular fractionation/imaging\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct loss-of-function with defined cellular phenotype (growth suppression, apoptosis) and localization data, single lab, single study\",\n      \"pmids\": [\"12738986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZFP91 is an IMiD-dependent substrate of the CRL4CRBN E3 ubiquitin ligase; lenalidomide induces CRL4CRBN-mediated ubiquitination and proteasomal degradation of ZFP91. ZFP91 harbors a zinc finger (ZnF) motif related to IKZF1/3 ZnF that is critical for IMiD-dependent CRBN binding.\",\n      \"method\": \"Pulse-chase SILAC mass spectrometry (pSILAC MS), ubiquitination assays, protein degradation assays, domain mapping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative proteomics, biochemical ubiquitination assays, domain mutagenesis, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"28530236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZFP91 activates HIF-1α transcription through the transcription factor NF-κB/p65; ZFP91 requires NF-κB/p65 to bind the HIF-1α promoter at −197/−188 bp and drive transcriptional activation, thereby promoting colon cancer cell proliferation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), luciferase reporter gene assay, flow cytometry, EdU incorporation, tumor xenograft assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, luciferase reporter) in a single lab establishing direct promoter binding and transcriptional mechanism\",\n      \"pmids\": [\"27144516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZFP91 acts as an E3 ubiquitin ligase that ubiquitinates hnRNP F at Lys185, promoting its proteasomal degradation; ECD protein competitively binds hnRNP F via its N-terminal STG1 domain (aa 13–383), preventing hnRNP F from interacting with ZFP91 and thus blocking ZFP91-mediated degradation.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay (IP + western blot), domain mapping, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, domain mapping, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29706618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZFP91 promotes K48-linked ubiquitination of hnRNP A1 at lysine 8 and its proteasomal degradation, thereby inhibiting hnRNP A1-dependent PKM alternative splicing; this shifts PKM isoform balance toward PKM1 (away from PKM2), suppressing aerobic glycolysis (Warburg effect) in hepatocellular carcinoma.\",\n      \"method\": \"Co-IP with mass spectrometry, ubiquitination assay (IP + western blot), RT-PCR with restriction digestion for splicing analysis, lactate/glucose uptake assays, RNAi, xenograft models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP/MS, site-specific ubiquitination, splicing readout, metabolic assays, in vivo) in a single study establishing a mechanistic axis\",\n      \"pmids\": [\"32754263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZFP91 ubiquitinates and destabilizes FOXA1, promoting its proteasomal degradation; ZFP91 knockdown reduces FOXA1 polyubiquitination, increases FOXA1 stability, and enhances cellular chemosensitivity in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (IP + western blot), ZFP91 knockdown with FOXA1 protein stability and chemoresistance readouts\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assays with functional consequence, single lab\",\n      \"pmids\": [\"31046116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Upon TCR stimulation, ZFP91 translocates from the nucleus to the cytoplasm in regulatory T cells and mediates K63-linked ubiquitination of BECN1 (Beclin-1), promoting BECN1-PIK3C3 complex formation and autophagosome maturation; this autophagy activation restrains hyperglycolysis and maintains Treg cell homeostasis and function.\",\n      \"method\": \"T reg cell-specific Zfp91 knockout mice, TCR stimulation assays, subcellular fractionation/live imaging for translocation, Co-IP, ubiquitination assay, autophagy flux assays, in vivo colitis model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mice, direct localization with functional consequence, Co-IP, ubiquitination assay, multiple orthogonal methods across in vitro and in vivo contexts\",\n      \"pmids\": [\"33355624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Upon TCR stimulation, ZFP91 translocates from the nucleus to the cytoplasm in tumor-infiltrating T cells and promotes PP2A complex assembly, thereby restricting mTORC1-mediated metabolic reprogramming (glycolysis); T cell-specific Zfp91 deletion increases mTORC1 activity, drives glycolysis, and enhances T cell proliferation and antitumor function.\",\n      \"method\": \"T cell-specific Zfp91 knockout mice, single-cell RNA-seq, subcellular fractionation for translocation, Co-IP for PP2A complex assembly, mTORC1 activity assays, metabolic assays, in vivo tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mice, translocation experiment with functional consequence, Co-IP for complex assembly, multiple orthogonal methods\",\n      \"pmids\": [\"34403361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZFP91 mediates K63-linked polyubiquitination of pro-IL-1β and promotes activation of the non-canonical caspase-8 inflammasome complex assembly in macrophages; inhibiting ZFP91 (by convallatoxin) reduces K63-linked polyubiquitination of pro-IL-1β, caspase-8 inflammasome assembly, and IL-1β production.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (IP + western blot), immunofluorescence, ELISA, in vivo inflammatory models (D-GalN/LPS liver injury, DSS colitis, alum peritonitis)\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site-specific ubiquitination assay, inflammasome complex assembly assay, in vivo validation, single lab\",\n      \"pmids\": [\"34825365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZFP91 functions as a bona fide transcription factor in T-cell lymphomas, co-regulating cell survival with IKZF1 by directly activating genes from WNT, NF-κB, and MAP kinase signaling pathways; ZFP91 is selectively degraded by the next-generation IMiD degrader CC-92480 via CRL4CRBN with greater potency than pomalidomide, and ZFP91 rewiring involving casein kinase 2-mediated c-Jun inactivation confers acquired resistance to lenalidomide.\",\n      \"method\": \"Mass spectrometry proteomics for target identification of CC-92480, transcription factor chromatin binding assays, in vivo TCL models (4 models), epistasis analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based target ID, functional transcription factor evidence, multiple in vivo models, single lab\",\n      \"pmids\": [\"34936696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZFP91 promotes the molecular glue bufalin-induced E2F2 ubiquitination via K48-linked ubiquitin chains and proteasomal degradation; bufalin promotes E2F2-ZFP91 complex formation, establishing ZFP91 as an atypical E3 ligase for E2F2.\",\n      \"method\": \"Human proteome microarray, Co-IP with SILAC-based quantitative proteomics, ubiquitination assay (K48-linked chain specificity), in vitro and in vivo cancer models\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteome microarray, quantitative Co-IP proteomics, ubiquitination assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36375317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZFP91 interacts with RIP1 and inhibits K48-linked ubiquitination of RIP1, thereby protecting RIP1 from proteasomal degradation in AML cells and promoting cell proliferation while inhibiting apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linked chain specificity), ZFP91 knockdown with proliferation/apoptosis readouts\",\n      \"journal\": \"International journal of medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and ubiquitination assay, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"35165513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZFP91 is directly targeted by miR-640; Ang-1-induced downregulation of miR-640 upregulates ZFP91 expression, and ZFP91 knockdown inhibits Ang-1-induced endothelial cell migration and tube formation, placing ZFP91 downstream of Ang-1/Tie-2 signaling in angiogenesis.\",\n      \"method\": \"Pull-down assay of biotinylated miR-640, ZFP91 siRNA knockdown, Ang-1 stimulation assays, migration and tube formation assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA pull-down for target validation, loss-of-function with defined angiogenic phenotype, single lab\",\n      \"pmids\": [\"32630670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZFP91 ubiquitinates TSPYL2 and promotes its poly-ubiquitination and proteasomal degradation; this ZFP91-mediated TSPYL2 destabilization contributes to gemcitabine resistance in pancreatic adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, PANC-1 gemcitabine-resistant cell model, xenograft in vivo model\",\n      \"journal\": \"Journal of ginseng research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and ubiquitination assay, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"36090681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZFP91 directly binds the EVI1 promoter and enhances H3K4me3/H3K27ac histone marks and chromatin accessibility to activate EVI1 transcription in myeloid leukemia; ZFP91 was identified as the leading activator of EVI1 in a genome-wide CRISPR screen.\",\n      \"method\": \"Genome-wide CRISPR screen (GFP knock-in reporter at EVI1 locus), ChIP-seq for ZFP91 promoter binding and histone marks, ATAC-seq for chromatin accessibility, ZFP91 knockout\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — unbiased genome-wide CRISPR screen followed by ChIP-seq and chromatin accessibility assays establishing direct promoter binding and epigenetic mechanism, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"42034869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZFP91 positively regulates HIF-1α protein expression in non-small cell lung cancer cells; CuB treatment inhibits HIF-1α expression through ZFP91 as shown by co-immunoprecipitation and molecular binding studies.\",\n      \"method\": \"Co-immunoprecipitation, western blot, molecular docking, siRNA knockdown, in vivo xenograft model\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and molecular docking, single lab, limited mechanistic detail; mechanism of how ZFP91 regulates HIF-1α not fully resolved\",\n      \"pmids\": [\"40860815\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZFP91 is an atypical RING-type E3 ubiquitin ligase and transcription factor that, depending on cellular context, ubiquitinates substrates including hnRNP A1 (K48-linked, at Lys8), hnRNP F (K48-linked, at Lys185), FOXA1, BECN1 (K63-linked), pro-IL-1β (K63-linked), E2F2 (K48-linked), and TSPYL2, while also functioning in the nucleus to directly activate gene transcription (e.g., HIF-1α via NF-κB/p65, EVI1); upon TCR stimulation ZFP91 translocates from the nucleus to the cytoplasm where it promotes PP2A assembly and BECN1-driven autophagy to restrain mTORC1 glycolytic reprogramming in T cells, and ZFP91 is itself a substrate of the CRL4CRBN E3 ligase complex whose degradation is induced by IMiD drugs (lenalidomide, pomalidomide) through a ZnF motif related to IKZF1/3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZFP91 is a dual-function nuclear zinc-finger protein that operates both as a sequence-specific transcriptional activator and as an atypical RING-type E3 ubiquitin ligase, with its activities shaping cancer cell metabolism, immune homeostasis, and inflammatory signaling [#0, #4, #6]. As a transcription factor it binds target promoters directly: it activates HIF-1\\u03b1 transcription in a manner requiring NF-\\u03baB/p65 promoter binding [#2], and it occupies the EVI1 promoter to deposit activating H3K4me3/H3K27ac marks and increase chromatin accessibility in myeloid leukemia [#14]. As an E3 ligase, ZFP91 governs substrate stability through distinct chain linkages: it directs K48-linked ubiquitination and proteasomal degradation of hnRNP A1 at Lys8\\u2014thereby redirecting PKM alternative splicing toward PKM1 and suppressing aerobic glycolysis in hepatocellular carcinoma [#4]\\u2014as well as of hnRNP F at Lys185, FOXA1, and E2F2 [#3, #5, #10], while assembling K63-linked chains on BECN1 to promote autophagosome maturation [#6] and on pro-IL-1\\u03b2 to drive non-canonical caspase-8 inflammasome assembly in macrophages [#8]. Upon TCR stimulation in T cells, ZFP91 relocates from nucleus to cytoplasm, where it promotes PP2A complex assembly to restrain mTORC1-driven glycolytic reprogramming and supports BECN1-dependent autophagy to maintain regulatory T-cell homeostasis [#6, #7]. ZFP91 is itself a target of the CRL4CRBN E3 ligase: lenalidomide and next-generation IMiD degraders induce its CRBN-dependent ubiquitination and degradation through a zinc-finger motif related to IKZF1/3 [#1, #9].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing ZFP91's basic identity and cellular importance, this work showed it is a nuclear multi-zinc-finger protein with transcription-factor architecture whose loss impairs leukemia cell survival.\",\n      \"evidence\": \"Antisense knockdown with proliferation/apoptosis readouts and subcellular localization in AML cells\",\n      \"pmids\": [\"12738986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct DNA targets identified\", \"Ligase activity not yet known\", \"Phenotype not linked to a defined molecular mechanism\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The first direct transcriptional target was defined, showing ZFP91 drives HIF-1\\u03b1 expression but only via cooperation with NF-\\u03baB/p65 at a specific promoter element.\",\n      \"evidence\": \"ChIP, EMSA, and luciferase reporter assays with xenograft validation in colon cancer\",\n      \"pmids\": [\"27144516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ZFP91 contacts DNA directly or only through p65 unresolved\", \"No genome-wide binding map\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"ZFP91 was identified as an IMiD-dependent neosubstrate of CRL4CRBN, explaining how it is selectively degraded by lenalidomide and linking it to the IKZF1/3 zinc-finger degron family.\",\n      \"evidence\": \"Pulse-chase SILAC MS, ubiquitination/degradation assays, and degron domain mapping\",\n      \"pmids\": [\"28530236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of ZFP91 degradation in patients not addressed here\", \"Endogenous role separate from IMiD context unexplored\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"ZFP91 was reframed as an E3 ligase itself, ubiquitinating hnRNP F at a defined lysine to drive its degradation, with ECD acting as a competitive protective factor.\",\n      \"evidence\": \"Reciprocal Co-IP, MS, site-mapped ubiquitination assays, and domain mapping\",\n      \"pmids\": [\"29706618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. adaptor-mediated ligase activity not distinguished\", \"No reconstitution of minimal ubiquitination reaction\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A coherent metabolic axis emerged: ZFP91 ubiquitinates hnRNP A1 at Lys8 to alter PKM splicing and suppress the Warburg effect, connecting its ligase activity to tumor glycolysis.\",\n      \"evidence\": \"Co-IP/MS, site-specific K48 ubiquitination, splicing and metabolic assays, and xenografts in HCC\",\n      \"pmids\": [\"32754263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether splicing control is the dominant tumor-suppressive function unclear\", \"Context-dependence across tumor types not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Additional substrates (FOXA1) and an upstream regulator (miR-640) broadened the ligase target set and placed ZFP91 within angiogenic and chemoresistance pathways.\",\n      \"evidence\": \"Co-IP and ubiquitination assays for FOXA1; biotinylated miR-640 pull-down and angiogenesis assays\",\n      \"pmids\": [\"31046116\", \"32630670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate selectivity determinants unknown\", \"Whether multiple substrates are degraded simultaneously in the same cell unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The pivotal mechanistic insight was that TCR signaling triggers nuclear-to-cytoplasmic relocation of ZFP91, switching it to a cytoplasmic role that restrains mTORC1 glycolysis via PP2A assembly and BECN1 K63-ubiquitination-driven autophagy to maintain T-cell homeostasis.\",\n      \"evidence\": \"T-cell- and Treg-specific Zfp91 knockout mice, translocation imaging, Co-IP, K63 ubiquitination, autophagy flux, and in vivo colitis/tumor models\",\n      \"pmids\": [\"33355624\", \"34403361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal that drives nucleocytoplasmic shuttling unknown\", \"How ZFP91 promotes PP2A assembly mechanistically not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ZFP91's repertoire expanded to inflammatory and additional oncogenic substrates and confirmed its standalone transcription-factor role in lymphoma alongside refined IMiD pharmacology.\",\n      \"evidence\": \"Co-IP/ubiquitination for pro-IL-1\\u03b2 (K63), E2F2 (K48), and RIP1; chromatin binding and CC-92480 degrader proteomics in T-cell lymphoma models\",\n      \"pmids\": [\"34825365\", \"36375317\", \"34936696\", \"35165513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RIP1 protection (anti-degradation) mechanism single-Co-IP only\", \"How one protein both activates and represses substrate ubiquitination context-dependently unexplained\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Unbiased screening positioned ZFP91 as a leading transcriptional activator of EVI1 acting through chromatin remodeling, cementing its epigenetic-regulator function in myeloid leukemia.\",\n      \"evidence\": \"Genome-wide CRISPR reporter screen, ChIP-seq for promoter binding and histone marks, and ATAC-seq with ZFP91 knockout\",\n      \"pmids\": [\"42034869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ZFP91 recruits histone-modifying machinery directly or indirectly unknown\", \"Relationship between its ligase and transcriptional activities at the same loci unexplored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The central unresolved question is how a single zinc-finger protein partitions between catalytically distinct activities (E3 ligase vs. transcriptional activator) and subcellular compartments, and what determines its substrate and promoter selectivity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate or DNA engagement\", \"Determinants of K48 vs K63 chain choice unknown\", \"Signal controlling nuclear/cytoplasmic switching uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 4, 5, 6, 8, 10]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [3, 4, 6, 8, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 14]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 14]},\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 4, 5, 6, 8, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 7, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"complexes\": [\"CRL4CRBN (as substrate)\", \"PP2A (assembly promoter)\", \"caspase-8 non-canonical inflammasome\"],\n    \"partners\": [\"CRBN\", \"hnRNP A1\", \"hnRNP F\", \"FOXA1\", \"BECN1\", \"E2F2\", \"IKZF1\", \"RIPK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}