Affinage

ZFP91

E3 ubiquitin-protein ligase ZFP91 · UniProt Q96JP5

Length
570 aa
Mass
63.4 kDa
Annotated
2026-06-11
27 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2003 Medium

    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

    PMID:12738986

    Open questions at the time
    • No direct DNA targets identified
    • Ligase activity not yet known
    • Phenotype not linked to a defined molecular mechanism
  2. 2016 Medium

    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

    PMID:27144516

    Open questions at the time
    • Whether ZFP91 contacts DNA directly or only through p65 unresolved
    • No genome-wide binding map
  3. 2017 High

    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

    PMID:28530236

    Open questions at the time
    • Functional consequence of ZFP91 degradation in patients not addressed here
    • Endogenous role separate from IMiD context unexplored
  4. 2018 Medium

    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

    PMID:29706618

    Open questions at the time
    • Direct vs. adaptor-mediated ligase activity not distinguished
    • No reconstitution of minimal ubiquitination reaction
  5. 2020 High

    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

    PMID:32754263

    Open questions at the time
    • Whether splicing control is the dominant tumor-suppressive function unclear
    • Context-dependence across tumor types not resolved
  6. 2020 Medium

    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

    PMID:31046116 PMID:32630670

    Open questions at the time
    • Substrate selectivity determinants unknown
    • Whether multiple substrates are degraded simultaneously in the same cell unaddressed
  7. 2021 High

    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

    PMID:33355624 PMID:34403361

    Open questions at the time
    • Signal that drives nucleocytoplasmic shuttling unknown
    • How ZFP91 promotes PP2A assembly mechanistically not resolved
  8. 2022 Medium

    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

    PMID:34825365 PMID:34936696 PMID:35165513 PMID:36375317

    Open questions at the time
    • RIP1 protection (anti-degradation) mechanism single-Co-IP only
    • How one protein both activates and represses substrate ubiquitination context-dependently unexplained
  9. 2026 High

    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

    PMID:42034869

    Open questions at the time
    • Whether ZFP91 recruits histone-modifying machinery directly or indirectly unknown
    • Relationship between its ligase and transcriptional activities at the same loci unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No structural model of substrate or DNA engagement
  • Determinants of K48 vs K63 chain choice unknown
  • Signal controlling nuclear/cytoplasmic switching uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016874 ligase activity 5 GO:0003677 DNA binding 2 GO:0140110 transcription regulator activity 2 GO:0031386 protein tag activity 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-168256 Immune System 3 R-HSA-1430728 Metabolism 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-9612973 Autophagy 1
Partners
BECN1CRBNE2F2FOXA1HNRNP A1HNRNP FIKZF1RIPK1
Complex memberships
CRL4CRBN (as substrate)PP2A (assembly promoter)caspase-8 non-canonical inflammasome

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Antisense oligonucleotide knockdown with cell proliferation and apoptosis readouts; nuclear localization by subcellular fractionation/imaging International journal of oncology Medium 12738986
2017 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. Pulse-chase SILAC mass spectrometry (pSILAC MS), ubiquitination assays, protein degradation assays, domain mapping Nature communications High 28530236
2016 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. Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), luciferase reporter gene assay, flow cytometry, EdU incorporation, tumor xenograft assay Oncotarget Medium 27144516
2018 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. Co-immunoprecipitation, mass spectrometry, ubiquitination assay (IP + western blot), domain mapping, in vitro and in vivo functional assays Cell death & disease Medium 29706618
2020 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. 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 Theranostics High 32754263
2020 ZFP91 ubiquitinates and destabilizes FOXA1, promoting its proteasomal degradation; ZFP91 knockdown reduces FOXA1 polyubiquitination, increases FOXA1 stability, and enhances cellular chemosensitivity in gastric cancer. Co-immunoprecipitation, ubiquitination assay (IP + western blot), ZFP91 knockdown with FOXA1 protein stability and chemoresistance readouts Carcinogenesis Medium 31046116
2021 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. 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 The Journal of experimental medicine High 33355624
2021 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. 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 The Journal of clinical investigation High 34403361
2022 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. Co-immunoprecipitation, ubiquitination assay (IP + western blot), immunofluorescence, ELISA, in vivo inflammatory models (D-GalN/LPS liver injury, DSS colitis, alum peritonitis) British journal of pharmacology Medium 34825365
2022 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. Mass spectrometry proteomics for target identification of CC-92480, transcription factor chromatin binding assays, in vivo TCL models (4 models), epistasis analysis Blood Medium 34936696
2022 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. Human proteome microarray, Co-IP with SILAC-based quantitative proteomics, ubiquitination assay (K48-linked chain specificity), in vitro and in vivo cancer models EBioMedicine Medium 36375317
2022 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. Co-immunoprecipitation, ubiquitination assay (K48-linked chain specificity), ZFP91 knockdown with proliferation/apoptosis readouts International journal of medical sciences Low 35165513
2020 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. Pull-down assay of biotinylated miR-640, ZFP91 siRNA knockdown, Ang-1 stimulation assays, migration and tube formation assays Cells Medium 32630670
2021 ZFP91 ubiquitinates TSPYL2 and promotes its poly-ubiquitination and proteasomal degradation; this ZFP91-mediated TSPYL2 destabilization contributes to gemcitabine resistance in pancreatic adenocarcinoma. Co-immunoprecipitation, ubiquitination assay, PANC-1 gemcitabine-resistant cell model, xenograft in vivo model Journal of ginseng research Low 36090681
2026 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. 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 Oncogene High 42034869
2025 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. Co-immunoprecipitation, western blot, molecular docking, siRNA knockdown, in vivo xenograft model Frontiers in oncology Low 40860815

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase. Nature communications 145 28530236
2020 E3 ligase ZFP91 inhibits Hepatocellular Carcinoma Metabolism Reprogramming by regulating PKM splicing. Theranostics 65 32754263
2022 Atypical E3 ligase ZFP91 promotes small-molecule-induced E2F2 transcription factor degradation for cancer therapy. EBioMedicine 54 36375317
2003 Identification of a novel human gene, ZFP91, involved in acute myelogenous leukemia. International journal of oncology 52 12738986
2018 miR-188-5p Suppresses Gastric Cancer Cell Proliferation and Invasion via Targeting ZFP91. Oncology research 51 29471891
2016 Zinc finger protein 91 (ZFP91) activates HIF-1α via NF-κB/p65 to promote proliferation and tumorigenesis of colon cancer. Oncotarget 48 27144516
2021 Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91. Journal of medicinal chemistry 47 33506674
2018 ECD promotes gastric cancer metastasis by blocking E3 ligase ZFP91-mediated hnRNP F ubiquitination and degradation. Cell death & disease 35 29706618
2022 Overcoming IMiD resistance in T-cell lymphomas through potent degradation of ZFP91 and IKZF1. Blood 31 34936696
2019 Thromboresistance and functional healing in the COBRA PzF stent versus competitor DES: implications for dual antiplatelet therapy. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 24 30375338
2021 ZFP91 disturbs metabolic fitness and antitumor activity of tumor-infiltrating T cells. The Journal of clinical investigation 23 34403361
2022 Convallatoxin inhibits IL-1β production by suppressing zinc finger protein 91 (ZFP91)-mediated pro-IL-1β ubiquitination and caspase-8 inflammasome activity. British journal of pharmacology 20 34825365
2021 ZFP91 is required for the maintenance of regulatory T cell homeostasis and function. The Journal of experimental medicine 20 33355624
2016 ZFP91: A Noncanonical NF-κB Signaling Pathway Regulator with Oncogenic Properties Is Overexpressed in Prostate Cancer. BioMed research international 18 27975057
2020 The ubiquitinase ZFP91 promotes tumor cell survival and confers chemoresistance through FOXA1 destabilization. Carcinogenesis 16 31046116
2013 ZFP91-a newly described gene potentially involved in prostate pathology. Pathology oncology research : POR 16 24272675
2020 Roles of miR-640 and Zinc Finger Protein 91 (ZFP91) in Angiopoietin-1-Induced In Vitro Angiogenesis. Cells 15 32630670
2021 Ginsenoside Rg3 increases gemcitabine sensitivity of pancreatic adenocarcinoma via reducing ZFP91 mediated TSPYL2 destabilization. Journal of ginseng research 13 36090681
2020 Overexpression of lncRNA Gm43050 alleviates apoptosis and inflammation response induced by sevoflurane treatment by regulating miR-640/ZFP91. American journal of translational research 12 32913509
2010 A retroviral vector common integration site between leupaxin and zinc finger protein 91 (ZFP91) observed in baboon hematopoietic repopulating cells. Experimental hematology 6 20434516
2024 LncRNA EBLN3P Accelerates Cell Proliferation and Invasion of Colon Cancer through Modulating the miR-519d-3p/ZFP91 Axis. Cancer biotherapy & radiopharmaceuticals 5 38597324
2021 Breviscapine Participates in the Progression of Prostate Cancer by Inhibiting ZFP91 Expression through Upregulation of MicroRNA-129-5p. Evidence-based complementary and alternative medicine : eCAM 5 34925523
2022 ZFP91 promotes cell proliferation and inhibits cell apoptosis in AML via inhibiting the proteasome-dependent degradation of RIP1. International journal of medical sciences 4 35165513
2022 Silencing LINC00491 Inhibits Pancreatic Cancer Progression through MiR-188-5p-induced Inhibition of ZFP91. Journal of Cancer 4 35399733
2026 Genome-wide screening identifies ZFP91 as a key regulator of EVI1 in myeloid leukemia. Oncogene 0 42034869
2025 Cucurbitacin B inhibits HIF-1α and attenuates non-small cell lung cancer via ZFP91. Frontiers in oncology 0 40860815
2025 Correction: Cucurbitacin B inhibits HIF-1α and attenuates non-small cell lung cancer via ZFP91. Frontiers in oncology 0 40978051

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