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Showing ZRANB1 — TRABID is a alias.

ZRANB1

Ubiquitin thioesterase ZRANB1 · UniProt Q9UGI0

Length
708 aa
Mass
81.0 kDa
Annotated
2026-06-11
24 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZRANB1 (TRABID) is an OTU-family deubiquitinase that uses three tandem NZF zinc-finger domains to bind atypical polyubiquitin chains and its OTU catalytic domain to cleave them, with biochemical preference for K29-, K33-, and K63-linked linkages (PMID:18281465, PMID:33853758). Its principal cellular function is to stabilize a broad set of substrates by removing degradative or regulatory ubiquitin chains, thereby controlling diverse downstream programs. In chromatin and transcription it deubiquitinates and stabilizes the histone demethylase Jmjd2d to license TLR-induced IL-12/IL-23 expression and inflammatory T-cell differentiation (PMID:26808229), the methyltransferase SUV39H1 to shape the H3K9me3 landscape [PMID:bio_10.1101_2024.10.29.620783], and the polycomb subunit EZH2 to support cancer cell growth (PMID:29669287, PMID:41949670). It also operates at the ubiquitin-proteasome/autophagy interface, where it opposes the E3 ligase UBE3C by removing K29/K48-branched chains from VPS34 to promote autophagosome formation and govern liver lipid metabolism (PMID:33637724), and stabilizes the E3 ligase HECTD1 (PMID:33853758). In mitosis ZRANB1 stabilizes the chromosomal passenger complex by stripping K29-linked chains from Aurora B and Survivin, and its inhibition couples mitotic defects to cGAS/STING innate-immune activation (PMID:37237031). In the DNA damage response it removes SPOP-deposited K29 chains from 53BP1 to prolong 53BP1 retention at double-strand breaks and bias repair away from homologous recombination (PMID:37002234). Beyond canonical DUB activity, ZRANB1 unexpectedly acts as an E3 ligase toward SLC7A11, targeting it for degradation to sensitize cells to ferroptosis (PMID:37831441). ZRANB1 mediates STRIPAK-directed deubiquitination of APC to enable APC trafficking to microtubule plus-ends; patient missense mutations that impair either DUB activity or STRIPAK binding disrupt growth-cone formation and neurite outgrowth (PMID:38099646).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2008 High

    Established the founding biochemical logic of the enzyme: how it recognizes and cleaves ubiquitin chains and links that activity to a transcriptional output.

    Evidence In vitro DUB assays with domain-deletion/point mutants, Co-IP, and epistasis across mammalian and Drosophila cells

    PMID:18281465

    Open questions at the time
    • Chain-linkage preference beyond K63 not yet resolved
    • Direct substrate underlying the TCF effect not fully defined
  2. 2012 Medium

    Challenged the proposed Wnt/beta-catenin role by showing DUB inhibition and catalytic-dead mutants had little effect on beta-catenin transcription, indicating context dependence of the early model.

    Evidence Structure-based virtual screening, in vitro DUB assay, beta-catenin reporter, shRNA and DUB-dead mutant (negative result)

    PMID:22584113

    Open questions at the time
    • Negative result; does not exclude cell-type-specific Wnt regulation
    • Inhibitor potency/selectivity in cells not established
  3. 2014 Medium

    Extended the enzyme into innate immune signalling, showing it tunes K63-ubiquitination of TAK1 and immune output in vivo.

    Evidence Co-IP, ubiquitin site-mapping, Drosophila loss-of-function genetics

    PMID:24586180

    Open questions at the time
    • Mammalian conservation of TAK1 regulation not shown here
    • Single lab
  4. 2016 High

    Provided the first mammalian genetic proof that DUB-mediated substrate stabilization (Jmjd2d) controls a defined chromatin and immune phenotype.

    Evidence Conditional KO mouse, Co-IP, ubiquitination assay, ChIP, T-cell differentiation assays

    PMID:26808229

    Open questions at the time
    • Chain linkage on Jmjd2d not specified
    • Direct vs indirect promoter effects not fully separated
  5. 2018 Medium

    Defined regulated substrate selection — AKT phosphorylation activates the enzyme to edit K63 chains on Twist1, redirecting it toward K48 degradation — and added EZH2 stabilization as an oncogenic axis.

    Evidence In vitro DUB and chain-discrimination assays, phosphosite mutagenesis, Co-IP, xenografts

    PMID:29669287 PMID:29748601

    Open questions at the time
    • Upstream regulation generalizability beyond AKT unknown
    • Single-lab substrate sets
  6. 2021 High

    Pinned down K29/K33 chain-cleavage preference and embedded the enzyme in UPS-autophagy crosstalk by showing reciprocal control of branched VPS34 ubiquitination with UBE3C and stabilization of E3 ligases (HECTD1) and transcription factors (Sox9, SP1).

    Evidence Catalytic-dead interactome trapping/MS, UbiCREST, Ub-AQUA, reciprocal E3/DUB perturbation, autophagy flux and liver mouse models

    PMID:33637724 PMID:33853758 PMID:34765294 PMID:34798260

    Open questions at the time
    • How branched-chain specificity is achieved structurally unclear
    • Substrate-recruitment determinants not mapped
  7. 2022 Medium

    Used a catalytic-dead knock-in mouse to show DUB activity is physiologically required for MUC2 mucin production and intestinal barrier protection.

    Evidence C443S knock-in mouse, colonic organoids, DSS colitis model

    PMID:36087511

    Open questions at the time
    • Direct substrate driving MUC2 phenotype not identified
    • Single lab
  8. 2023 High

    Expanded the enzyme into genome maintenance, mitosis, ferroptosis, and neurodevelopment, and overturned its classification as a pure DUB by demonstrating E3 ligase activity toward SLC7A11.

    Evidence K29-specific ubiquitination/DUB assays, HR/NHEJ reporters, CPC/cGAS-STING analyses, whole-DUB sgRNA screen with in vitro ubiquitination, patient-mutation knock-in mice and neuronal imaging

    PMID:37002234 PMID:37237031 PMID:37831441 PMID:38099646

    Open questions at the time
    • Mechanism switching between DUB and E3 modes unresolved
    • STRIPAK-mediated recruitment to APC structurally undefined
  9. 2025 Medium

    Added mitochondrial (mt-ND5/complex I) and epigenetic (SUV39H1) substrates, showing scaffold-dependent restriction (PTRH2) and K29-linkage editing against specific E3 ligases.

    Evidence IP-MS, co-IP, ubiquitination assays, PTRH2 KO/re-expression, complex I and Ca2+ assays; engineered ubiquitin-replacement system with ChIP (preprint)

    PMID:40496187 PMID:bio_10.1101_2024.10.29.620783

    Open questions at the time
    • Mitochondrial localization mechanism of the enzyme unclear
    • SUV39H1 finding is a preprint, single lab
  10. 2026 Medium

    Linked the enzyme to splicing control via SF3B3 stabilization and CHEK2 isoform choice, and added EZH2-MYCN and CTSB axes plus an upstream stabilizer (UCHL5).

    Evidence IP-MS, ubiquitination assays, splicing analysis, ternary-complex pull-downs, CHX chase, tumor models

    PMID:41035046 PMID:41949670 PMID:42037453 PMID:42265067

    Open questions at the time
    • UCHL5 and CTSB axes rest on single Co-IP/CHX without reconstitution
    • Direct vs indirect splicing effects not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single enzyme switches between deubiquitinase and E3 ligase activity, and what governs its substrate and chain-linkage selectivity in each cellular context, remains unresolved.
  • No structural model of DUB-vs-E3 mode switching
  • Determinants of substrate targeting across compartments unknown
  • Physiological hierarchy among the many reported substrates undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 3 GO:0016874 ligase activity 1
Localization
GO:0005634 nucleus 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-168256 Immune System 2 R-HSA-4839726 Chromatin organization 2 R-HSA-9612973 Autophagy 2 R-HSA-1640170 Cell Cycle 1 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1
Partners
53BP1APCEZH2HECTD1PTRH2SF3B3UBE3CVPS34
Complex memberships
STRIPAKchromosomal passenger complex (CPC)

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Trabid/ZRANB1 binds K63-linked ubiquitin chains with its three tandem NZF (Npl4 zinc finger) domains and cleaves these chains via its OTU domain; both activities are required for efficient TCF-mediated transcription in cells with high Wnt pathway activity. Epistasis experiments showed Trabid acts below the stabilization of beta-catenin, suggesting it affects the TCF-beta-catenin transcription complex. Trabid also binds to and deubiquitylates APC, a negative regulator of Wnt transcription. In vitro DUB assay, domain-deletion/point-mutation analysis, Co-IP, epistasis in mammalian and Drosophila cells Genes & development High 18281465
2014 Drosophila Trabid interacts with TAK1, reduces its K63-linked ubiquitination (at Lys142) and immune signalling output. The three tandem NZF fingers and catalytic cysteine (C518) are required for Trabid activity. TAB2 participates in the TAK1-Trabid interaction via its zinc finger domain. Loss of Trabid causes chronic IMD pathway activation and reduced lifespan. Co-IP, ubiquitin site-mapping by mutagenesis, genetic loss-of-function in Drosophila, cell culture screen PLoS genetics Medium 24586180
2016 TRABID/ZRANB1 deubiquitinates and stabilizes the histone demethylase Jmjd2d in dendritic cells, thereby facilitating TLR-induced histone modifications at the Il12 and Il23 promoters. Deletion of Zranb1 in dendritic cells inhibited TLR-induced IL-12 and IL-23 expression, impaired inflammatory T cell differentiation, and protected mice from autoimmune inflammation. Conditional knockout mouse model, co-IP, ubiquitination assay, ChIP (histone modification), T cell differentiation assays Nature immunology High 26808229
2018 ZRANB1 binds, deubiquitinates, and stabilizes EZH2 protein; depletion of ZRANB1 leads to EZH2 destabilization and growth inhibition in breast cancer cells. Co-IP, ubiquitination assay, siRNA knockdown, small-molecule inhibitor, in vivo xenograft model Cell reports Medium 29669287
2018 Trabid/ZRANB1 forms a complex with Twist1 and specifically cleaves RNF8-induced K63-linked polyubiquitin chains from Twist1, which promotes subsequent K48-linked ubiquitination and proteasomal degradation of Twist1. TRABID activity is activated by AKT-mediated phosphorylation at Ser78/Thr117. Knockdown of Trabid increases Twist1 K63-ubiquitination while abrogating K48-ubiquitination, enhancing HCC growth and metastasis. Co-IP, in vitro deubiquitination assay, ubiquitin chain-type discrimination assay, phosphorylation site mutagenesis, in vivo xenograft model Cell death and differentiation Medium 29748601
2021 TRABID and E3 ligase UBE3C reciprocally regulate K29/K48-branched ubiquitination of VPS34. This branched ubiquitination enhances VPS34 binding to proteasomes for degradation, suppressing autophagosome formation and maturation. Under ER/proteotoxic stress, UBE3C shifts from phagophores to proteasomes, reducing VPS34 ubiquitination and elevating autophagy. TRABID-mediated VPS34 stabilization is critical for liver lipid metabolism. Co-IP, ubiquitin chain-type analysis (UBE3C/TRABID knockdown and overexpression), autophagy flux assays, liver-specific mouse models Nature communications High 33637724
2021 TRABID/ZRANB1 stabilizes the E3 ubiquitin ligase HECTD1 by deubiquitinating it; TRABID depletion leads to rapid HECTD1 degradation. HECTD1 preferentially assembles K29- and K48-linked ubiquitin chains and requires K29/K48 branching for full ligase activity. TRABID prefers cleavage of K29- and K33-linked chains. Catalytic-dead TRABID interactome trapping (MS), Co-IP, UbiCREST, Ub-AQUA proteomics, in vitro autoubiquitination with Ub mutants, siRNA knockdown and CRISPR KO in mammalian cells The Journal of biological chemistry High 33853758
2021 ZRANB1 deubiquitinates Sox9 in colorectal cancer cells, decelerating its ubiquitination and increasing Sox9 stability; stabilized Sox9 then transcriptionally activates USP22 to promote Wnt/β-catenin pathway activity and cancer stem cell features. Co-IP, ubiquitination assay, CHX chase, reporter assay, xenograft mouse model Cellular signalling Medium 34798260
2021 ZRANB1 directly binds SP1 and stabilizes it by deubiquitination, which in turn upregulates LOXL2 transcription to promote HCC growth and metastasis. Co-IP, ubiquitination assay, CHX chase, RNA-seq, in vivo xenograft American journal of cancer research Medium 34765294
2022 ZRANB1 deubiquitinase activity (demonstrated via C443S catalytic knock-in mice) is required for normal MUC2 mucin expression in colonic goblet cells; Zranb1 C443S mutant mice show decreased MUC2 production and exacerbated DSS-induced colitis. CRISPR/Cas9 knock-in mouse model (catalytic dead C443S), colonic organoids, DSS colitis model Biochemical and biophysical research communications Medium 36087511
2023 TRABID deubiquitinates K29-linked polyubiquitin chains on 53BP1 (placed by E3 ligase SPOP), preventing 53BP1 dissociation from DNA double-strand breaks. This prolongs 53BP1 retention at DSBs, suppresses homologous recombination, and causes chromosomal instability. TRABID overexpression in prostate cancer cells sensitizes them to PARP inhibitors. Co-IP, ubiquitination assay (K29-specific), TRABID knockdown/overexpression, HR/NHEJ reporter assays, PARP inhibitor sensitivity assays Nature communications Medium 37002234
2023 TRABID is upregulated in mitosis and stabilizes the chromosomal passenger complex (CPC) by removing K29-linked polyubiquitin chains from Aurora B and Survivin. TRABID inhibition causes micronuclei through combined mitotic and autophagy defects, protects cGAS from autophagic degradation, and activates the cGAS/STING innate immunity pathway. Co-IP, ubiquitin chain-type assay, TRABID KO/knockdown, mitotic cell analysis, cGAS/STING reporter, in vivo tumor immunotherapy models Nature communications High 37237031
2023 ZRANB1 functions as an E3 ubiquitin ligase (not only a DUB) for SLC7A11: it ubiquitinates and targets SLC7A11 for degradation, thereby inhibiting glutathione synthesis and sensitizing cancer cells to ferroptosis. The region spanning residues 463–584 is required for this E3 ligase activity. sgRNA whole-DUB screen, co-IP, in vitro ubiquitination assay, domain-deletion mutagenesis, GSH measurement, lipid peroxidation assay The Journal of cell biology Medium 37831441
2023 Patient missense mutations in ZRANB1 impair either its DUB catalytic activity or its binding to STRIPAK complex. Both defects impede trafficking of APC to microtubule plus-ends, causing APC hyperubiquitylation and mislocalization, and severely compromise neuronal growth cone formation and neurite outgrowth trajectory. The proposed model is that STRIPAK recruits Trabid to deubiquitylate APC. Knock-in mouse models (patient mutations), live-cell imaging, neuronal culture, immunofluorescence, DUB activity assay, Co-IP with STRIPAK components, APC localization analysis eLife High 38099646
2012 Small molecules identified as TRABID DUB inhibitors via virtual screening and in vitro DUB assay did not inhibit β-catenin-mediated transcription. Furthermore, shRNA knockdown of TRABID or expression of a DUB-activity-deficient TRABID mutant showed little effect on β-catenin-mediated transcription (negative result). Structure-based virtual screening, in vitro DUB assay, β-catenin transcription reporter, shRNA knockdown, DUB-dead mutant overexpression BMC chemical biology Medium 22584113
2025 Mitochondrial PTRH2 interacts with TRABID and mt-ND5 (complex I subunit). In cells lacking PTRH2, TRABID aberrantly deubiquitylates mt-ND5, increasing its stability and promoting complex I activity and ATP production, leading to mitochondrial Ca2+ overload under stress. Re-expression of PTRH2 blocks TRABID-mediated mt-ND5 deubiquitylation, resulting in mt-ND5 polyubiquitylation and proteasomal degradation. Immunoprecipitation/mass spectrometry proteomics, co-IP, ubiquitination assay, PTRH2 knockout/re-expression, mitochondrial Ca2+ measurement, complex I activity assay PNAS nexus Medium 40496187
2025 TRABID removes K29-linked ubiquitination from the H3K9me3 methyltransferase SUV39H1, antagonizing the TRIP12 E3 ligase. K29-linked ubiquitination is essential for proteasomal degradation of SUV39H1, and TRABID-mediated reversal of this modification stabilizes SUV39H1, thereby controlling the H3K9me3 epigenetic landscape. Cell-based ubiquitin replacement strategy (conditional chain-type abrogation), ubiquitination assays, TRABID/TRIP12 genetic manipulation, H3K9me3 ChIP bioRxivpreprint Medium bio_10.1101_2024.10.29.620783
2025 ZRANB1 regulates K33-linked deubiquitination of cathepsin B (CTSB), stabilizing CTSB expression. In HBV-positive HCC cells, the MINPP1-ZRANB1-CTSB axis promotes ferroptosis; this axis is inactive in HBV-negative cells unless HBV is introduced. Co-immunoprecipitation, ubiquitin modification analysis (K33-linkage), immunofluorescence, in vivo tumor experiments Biology direct Low 41035046
2026 ZRANB1 deubiquitinates and stabilizes SF3B3 (a spliceosomal protein), preventing its UPS-dependent degradation. Stabilization of SF3B3 by ZRANB1 modulates alternative splicing of CHEK2, specifically suppressing production of the tumor-suppressive exon-4-skipped isoform in urothelial bladder cancer. Co-immunoprecipitation coupled with mass spectrometry, ubiquitination assay, alternative splicing analysis, in vitro and in vivo tumor models Cell death & disease Medium 42265067
2026 UCHL5 directly interacts with ZRANB1 (co-IP) and extends ZRANB1 protein half-life by more than 2-fold through deubiquitination, establishing UCHL5 as an upstream stabilizer of ZRANB1. Co-immunoprecipitation, CHX chase, protein half-life measurement, CRISPR KO and overexpression Cancer biology & therapy Low 42037453
2026 ZRANB1 directly binds EZH2 (confirmed by in vitro pull-down) and deubiquitinates EZH2 to stabilize it; stabilized EZH2 in turn maintains MYCN stability in a ternary ZRANB1-EZH2-MYCN complex. DUB activity is required for MYCN stabilization. Co-IP, in vitro pull-down, CHX chase, ubiquitination assay, catalytic-dead mutant, xenograft model Cell biology and toxicology Medium 41949670

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Trabid, a new positive regulator of Wnt-induced transcription with preference for binding and cleaving K63-linked ubiquitin chains. Genes & development 98 18281465
2016 Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid. Nature immunology 87 26808229
2021 VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism. Nature communications 73 33637724
2018 ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer. Cell reports 51 29669287
2014 Loss of Trabid, a new negative regulator of the drosophila immune-deficiency pathway at the level of TAK1, reduces life span. PLoS genetics 49 24586180
2018 Trabid inhibits hepatocellular carcinoma growth and metastasis by cleaving RNF8-induced K63 ubiquitination of Twist1. Cell death and differentiation 43 29748601
2018 Targeting circular RNA-ZRANB1 for therapeutic intervention in retinal neurodegeneration. Cell death & disease 43 29748605
2023 TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation. Nature communications 39 37237031
2021 ZRANB1 enhances stem-cell-like features and accelerates tumor progression by regulating Sox9-mediated USP22/Wnt/β-catenin pathway in colorectal cancer. Cellular signalling 30 34798260
2020 Downregulated circular RNA zRANB1 mediates Wnt5a/β-Catenin signaling to promote neuropathic pain via miR-24-3p/LPAR3 axis in CCI rat models. Gene 28 32777532
2021 The deubiquitinase TRABID stabilizes the K29/K48-specific E3 ubiquitin ligase HECTD1. The Journal of biological chemistry 24 33853758
2023 TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks. Nature communications 22 37002234
2021 Deubiquitinase ZRANB1 drives hepatocellular carcinoma progression through SP1-LOXL2 axis. American journal of cancer research 19 34765294
2023 The deubiquitinase ZRANB1 is an E3 ubiquitin ligase for SLC7A11 and regulates ferroptotic resistance. The Journal of cell biology 18 37831441
2012 Identification Of Small Molecule TRABID Deubiquitinase Inhibitors By Computation-Based Virtual Screen. BMC chemical biology 15 22584113
2013 UBE3B and ZRANB1 polymorphisms and transcript abundance are associated with water holding capacity of porcine M. longissimus dorsi. Meat science 12 23743024
2023 Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth. eLife 2 38099646
2025 MINPP1 promotes ferroptosis in HBV-related hepatocellular carcinoma by regulating CTSB K33-linked deubiquitination via ZRANB1. Biology direct 1 41035046
2026 ZRANB1 depletion inhibits neuroblastoma progression by destabilizing MYCN through EZH2-mediated deubiquitination. Cell biology and toxicology 0 41949670
2026 UCHL5 suppresses thyroid carcinoma progression via ZRANB1 stabilization and ferroptosis regulation. Cancer biology & therapy 0 42037453
2026 ZRANB1 promotes cell proliferation and lymph node metastasis through SF3B3-mediated alternative splicing of CHEK2 in urothelial bladder cancer. Cell death & disease 0 42265067
2025 Mitochondrial PTRH2 controls the deubiquitinase TRABID to regulate mt-ND5 stability and metabolism. PNAS nexus 0 40496187
2025 Chronic airway inflammation in Drosophila lacking the A20-like protein Trabid. Frontiers in immunology 0 40977741
2022 Zranb1-mutant mice display abnormal colonic mucus production and exacerbation of DSS-induced colitis. Biochemical and biophysical research communications 0 36087511

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