Affinage

RNF114

E3 ubiquitin-protein ligase RNF114 · UniProt Q9Y508

Length
228 aa
Mass
25.7 kDa
Annotated
2026-06-10
31 papers in source corpus 22 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF114 (ZNF313) is a RING-domain E3 ubiquitin ligase and ubiquitin-binding protein that couples recognition of ubiquitin and ADP-ribose marks to targeted substrate ubiquitination, regulating cell-cycle progression, the maternal-to-zygotic transition, innate immune signaling, and the DNA damage response (PMID:23645206, PMID:28073917, PMID:37878693). Through its RING domain it ubiquitinates and destabilizes the CIP/KIP CDK inhibitors p21, p27, and p57 to drive G1-to-S progression and suppress senescence (PMID:23645206), and this activity toward p21 is licensed by XAF1, which engages RNF114 through its ZF7 zinc finger (PMID:25313037). In early development, maternal RNF114 degrades TAB1 and the heterochromatin factor CBX5/HP1α, a step required for major zygotic genome activation and progression past the two-cell stage (PMID:28073917, PMID:34104941). In the DNA damage response, RNF114 is recruited to lesions in a PARylation-dependent manner and ubiquitinates PARP1 for K48-linked degradation, such that inhibiting its ligase activity with nimbolide traps PARP1 on chromatin and produces synthetic lethality in BRCA-mutant cells (PMID:37878693). The structural basis of this recruitment is a tandem ZnF2–ZnF3–UIM (Di19-UIM) module that preferentially reads the hybrid mono-ADP-ribose–ubiquitin (MARUbe) mark and extends K11-linked polyubiquitin chains on MARUbylated substrates such as PARP7 (PMID:40634336, PMID:41039157). RNF114 also acts on innate immune signaling, both positively—as an interferon- and dsRNA-inducible enhancer of NF-κB/IRF3-driven IFN responses (PMID:21571784)—and negatively, by targeting MAVS for polyubiquitination and degradation, with RNF114-knockout mice showing elevated basal IFN (PMID:28625874). Its NF-κB output is further shaped by stabilization of A20 (PMID:25165885) and degradation of TRAF6 during osteoclastogenesis (PMID:28708287). RNF114 can be pharmacologically engaged as a PROTAC-recruiting E3 via a reactive Cys8 (PMID:33513350).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2008 Medium

    Established that RNF114 is not merely a RING ligase but also a ubiquitin reader, raising the question of how ubiquitin recognition feeds into its catalytic output.

    Evidence Cell-free ubiquitin-binding assay of the UIM

    PMID:18364390

    Open questions at the time
    • No mutagenesis or structural validation of the UIM-ubiquitin interface
    • Functional consequence of ubiquitin binding not yet linked to substrate selection
  2. 2010 Medium

    Defined a transcriptional input to RNF114 expression by mapping a functional Sp1 site in its promoter.

    Evidence Promoter deletion, luciferase reporter, site-directed mutagenesis and mithramycin A in cells

    PMID:20515446

    Open questions at the time
    • Does not address signal-dependent regulation of the promoter
    • No link between Sp1 control and RNF114 protein activity
  3. 2011 Medium

    Positioned RNF114 within antiviral innate immunity as an interferon/dsRNA-inducible positive feedback factor for IFN production.

    Evidence Subcellular fractionation, NF-κB/IRF3 reporters, IFN mRNA quantification, siRNA/overexpression

    PMID:21571784

    Open questions at the time
    • No substrate identified to explain the positive effect
    • Reconciliation with later negative regulation of MAVS not addressed
  4. 2013 High

    Provided the first reconstituted enzymatic role by showing RING-dependent ubiquitination and degradation of CIP/KIP inhibitors p21/p27/p57, linking RNF114 to cell-cycle progression.

    Evidence In vitro ubiquitination, RING mutagenesis, co-IP, stability and cell-cycle assays

    PMID:23645206

    Open questions at the time
    • Localization shifts in carcinoma described only descriptively (#3)
    • Chain linkage type on CIP/KIP substrates not defined
  5. 2014 Medium

    Identified upstream regulators and refined the NF-κB role, showing XAF1 (via ZF7) activates p21 ubiquitination while A20 stabilization makes RNF114 a negative NF-κB regulator in T cells.

    Evidence Yeast two-hybrid, reciprocal co-IP, domain mapping, ubiquitination and reporter/T-cell assays

    PMID:24631332 PMID:25165885 PMID:25313037

    Open questions at the time
    • Opposing pro- and anti-inflammatory effects context-dependence unresolved
    • Functional role of the 23 TAP/MS interactors largely uncharacterized
  6. 2017 High

    Defined RNF114 as essential for the maternal-to-zygotic transition by degrading TAB1, and as a negative regulator of MAVS-driven IFN and of TRAF6 in osteoclastogenesis.

    Evidence Protein microarray substrate screen, in vitro ubiquitination, oocyte knockdown and embryo assays; KO mouse IFN phenotype; KO osteoclast differentiation

    PMID:28073917 PMID:28625874 PMID:28708287

    Open questions at the time
    • How a single ligase balances positive (#1) and negative (#7) IFN effects unresolved
    • Chain linkages differ across substrates without unifying recognition logic at this stage
  7. 2021 High

    Showed that maternal RNF114 also degrades CBX5/HP1α with TAB1 to permit zygotic genome activation, and that RNF114 is chemically tractable as a PROTAC E3 via Cys8.

    Evidence Maternal depletion with rescue and transcriptomics; chemoproteomics and cellular PROTAC degradation

    PMID:33513350 PMID:34104941

    Open questions at the time
    • Endogenous ligand/regulation of Cys8 reactivity unknown
    • Structural basis of substrate selection still undefined at this point
  8. 2023 High

    Connected RNF114 to the DNA damage response, showing PAR-dependent recruitment and K48 ubiquitination of PARP1, with therapeutic implications for BRCA-mutant cancers.

    Evidence Co-IP, in vitro ubiquitination, laser-damage recruitment imaging, nimbolide inhibition, viability and xenograft assays

    PMID:37878693

    Open questions at the time
    • Did not resolve the molecular reader for the PAR signal
    • Selectivity of PARP1 over other PARylated targets undefined
  9. 2025 High

    Resolved the mechanistic reader, establishing that a tandem Di19-UIM (M-UBD) module recognizes the hybrid MARUbe mark and that RNF114 extends K11-linked chains on MARUbylated substrates such as PARP7, defining it as a reader-writer ligase.

    Evidence Non-hydrolysable ADPr-Ub probes, proteomics, biophysical binding, domain mutagenesis, laser-damage imaging, in vitro K11 chain assembly, AlphaFold3 modeling

    PMID:40634336 PMID:41039157

    Open questions at the time
    • Full structural model of substrate engagement not experimentally solved
    • How K11 extension dictates substrate fate beyond degradation unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how RNF114's single reader-writer module is partitioned across its many substrates and opposing pathway outcomes (IFN, cell cycle, development, metastasis) within a given cell.
  • No unifying model linking MARUbe recognition to non-PAR substrates (p21, TAB1, CBX5, TRAF6)
  • Tissue- and context-specific regulation of substrate choice uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0140313 molecular sequestering activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-1474165 Reproduction 2 R-HSA-168256 Immune System 2 R-HSA-73894 DNA Repair 2 R-HSA-1640170 Cell Cycle 1
Partners
A20MAVSPARP1TAB1TRAF6TRIM28VCPXAF1

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 RNF114 (ZNF313) binds ubiquitin via an ubiquitin-interaction motif (UIM), demonstrated by cell-free ubiquitin-binding assays, identifying it as a ubiquitin-binding E3 ligase paralogue of TRAC-1. Cell-free ubiquitin-binding assay (UIM binding) Human molecular genetics Medium 18364390
2011 RNF114 is a soluble cytosolic protein that associates with ubiquitinated proteins, is induced by interferons and synthetic dsRNA, and its over-expression enhances NF-κB and IRF3 reporter activity and increases type I and type III IFN mRNA levels, indicating it positively regulates a dsRNA-induced innate immune feedback loop. Subcellular fractionation, reporter assays (NF-κB/IRF3), mRNA quantification, siRNA knockdown/overexpression Human molecular genetics Medium 21571784
2013 ZNF313/RNF114 is an E3 ubiquitin ligase that ubiquitinates and destabilizes p21(WAF1), p27(KIP1), and p57(KIP2) via its RING domain, thereby promoting G1-to-S cell cycle progression and suppressing cellular senescence; RING domain mutations abolish this activity. In vitro ubiquitination assay, RING domain mutagenesis, co-immunoprecipitation, protein stability assays, cell cycle analysis Cell death and differentiation High 23645206
2013 ZNF313/RNF114 shows both nuclear and cytoplasmic localization in normal epithelial cells but predominantly cytoplasmic distribution in carcinoma cells, as determined by immunohistochemistry and subcellular localization experiments. Immunohistochemistry, subcellular localization Cell death and differentiation Low 23645206
2014 RNF114 interacts with A20 in T cells (identified by two-hybrid screening and confirmed by co-immunoprecipitation), modulates A20 ubiquitylation, stabilizes A20 and IκBα proteins, and thereby acts as a negative regulator of NF-κB-dependent transcription, modulating T-cell activation and apoptosis. Yeast two-hybrid screening, co-immunoprecipitation, ubiquitylation assay, NF-κB reporter assay, T-cell activation assays Cell death & disease Medium 25165885
2014 XAF1 activates ZNF313/RNF114-mediated ubiquitination of p21(WAF1) to terminate p53-dependent cell-cycle arrest, and XAF1 interacts with ZNF313 through its zinc finger domain 7 (ZF7); truncated XAF1 isoforms lacking ZF7 cannot activate ZNF313. Co-immunoprecipitation, ubiquitination assays, domain deletion mapping, reporter assays Proceedings of the National Academy of Sciences of the United States of America Medium 25313037
2014 RNF114 promotes T cell activation in a dose-dependent manner; the two C2H2 domains play opposing roles (upstream C2H2 suppresses, downstream C2H2 enhances T cell activation); 23 RNF114-interacting proteins were identified by tandem affinity purification/mass spectrometry. Flow cytometry (FACS), tandem affinity purification (TAP), mass spectrometry, domain deletion constructs Immunobiology Low 24631332
2017 RNF114 is an E3 ubiquitin ligase that negatively regulates RLH/MAVS-mediated type I IFN production; MAVS is a substrate for RNF114-mediated polyubiquitination and degradation; RNF114 knockout mice exhibit increased basal IFN levels and sensitized responses to dsRNA. In vitro ubiquitination assay, co-immunoprecipitation, RNF114 knockout mouse model, IFN measurement Cytokine Medium 28625874
2017 RNF114 ubiquitinates and degrades TAB1 via the ubiquitin-proteasome pathway in mouse oocytes; RNF114-mediated TAB1 degradation activates the NF-κB pathway and is required for maternal-to-zygotic transition (MZT); knockdown of Rnf114 arrests embryo development at the two-cell stage. Protein microarray substrate screening (9,000 proteins), in vitro ubiquitination, mouse oocyte knockdown, embryo development assay EMBO reports High 28073917
2017 RNF114 suppresses RANKL-induced osteoclastogenesis by promoting K48-linked proteasomal degradation of TRAF6 and suppressing RANKL-activated NFATc1 and NFAT-regulated promoter activity, acting upstream of TAK1/TAB2 in the RANK/TRAF6/NF-κB pathway. RNF114 knockout mouse osteoclast differentiation, ectopic expression, TRAP activity assay, bone resorption assay, NF-κB/NFAT reporter assay, protein stability assay Journal of orthopaedic research Medium 28708287
2020 Sea perch LjRNF114 targets MAVS and TRAF3 for K27- and K48-linked ubiquitination and proteasomal degradation, suppressing IFN production; the RING and UIM domains of RNF114 are required for interaction with TRAF3 and MAVS. Co-immunoprecipitation, domain mapping, ubiquitination assay, IFN reporter assay, overexpression/knockdown Journal of immunology Medium 33268485
2020 Porcine RNF114 interacts with PRRSV nonstructural protein Nsp12 and promotes K27-linked polyubiquitination and proteasome-dependent degradation of Nsp12, suppressing viral replication; this activity requires RNF114 ubiquitin ligase activity. Co-immunoprecipitation, ubiquitination assay, viral titer assay, knockdown/overexpression, proteasome inhibitor Veterinary microbiology Medium 32605740
2021 Covalent small molecules that react with RNF114 at Cys8 can be used as PROTAC E3 ligase recruiters to degrade therapeutic targets (BRD4, BCR-ABL) in cells, demonstrating that RNF114 can be engaged as an E3 ligase in targeted protein degradation. Activity-based protein profiling, covalent ligand screening, PROTAC synthesis and cellular degradation assays Cell chemical biology Medium 33513350
2021 Maternal RNF114 ubiquitinates and degrades CBX5 (HP1α) in mouse oocytes; accumulation of CBX5 or TAB1 in RNF114-depleted two-cell embryos impedes major zygotic genome activation; knockdown of either CBX5 or TAB1 partially rescues the developmental arrest caused by RNF114 depletion. Maternal protein depletion, immunofluorescence, transcriptome analysis, in vitro ubiquitination, rescue experiments Development High 34104941
2022 Human RNF114 interacts with MAVS and inhibits type I interferon production, thereby promoting VSV replication; overexpression promotes and depletion reduces viral replication both in vitro and in vivo. Co-immunoprecipitation, overexpression/knockdown, viral replication assays, in vivo mouse experiment Microbial pathogenesis Medium 35545202
2022 RNF114 mediates ubiquitylation and degradation of EGR1, as demonstrated by ubiquitylation experiments in gastric cancer cells. Ubiquitylation assay, knockdown, western blot Journal of Cancer Low 35069903
2023 RNF114 is a PARylation-dependent E3 ubiquitin ligase recruited to DNA lesions in a PAR-dependent manner, where it targets PARP1 for K48-linked ubiquitination and degradation; blockade of RNF114 (by nimbolide, which inhibits its E3 activity) causes PARP1 trapping at DNA lesions and synthetic lethality with BRCA mutations. Co-immunoprecipitation, in vitro ubiquitination, laser-induced DNA damage recruitment imaging, nimbolide-RNF114 inhibition, cellular viability assays, in vivo xenograft Science advances High 37878693
2023 XAF1 acts as an adaptor for VCP-mediated deubiquitination of RNF114, which activates RNF114 to promote K48-linked ubiquitination and degradation of junction plakoglobin (JUP), facilitating colorectal cancer cell migration and metastasis. Co-immunoprecipitation, ubiquitination assay, VCP inhibition, migration/invasion assay, in vivo metastasis model The Journal of cell biology Medium 38095639
2024 XAF1 facilitates ZNF313/RNF114-mediated K48-linked polyubiquitination and proteasomal degradation of TRIM28 by interacting with the RING domain of ZNF313 through XAF1's ZF7 domain, thereby suppressing TRIM28 oncogenic activity; XAF1 mutants lacking ZF7 cannot promote TRIM28 ubiquitination. Co-immunoprecipitation, ubiquitination assay, domain deletion mapping, tumor growth assays Molecular biomedicine Medium 39532800
2025 RNF114 preferentially recognizes ubiquitinated ADP-ribose (ADPr-Ub / MARUbe) over non-modified ubiquitin, and extends K11-linked polyubiquitin chains on MARUbylated substrates; the tandem ZnF2+ZnF3+UIM (Di19-UIM) domain module is required for recognizing MARUbylated species and for RNF114 recruitment to sites of laser-induced DNA damage. Non-hydrolysable ADPr-Ub probe, proteomics pull-down, biophysical binding assays (biochemical), domain deletion analysis, laser-induced DNA damage recruitment imaging, in vitro K11 ubiquitin chain assembly Nature communications High 40634336
2025 RNF114 (and RNF166) act as reader-writer E3 ligases that recognize the MARUbe hybrid mark on PARP7 (generated by DTX2) through a tandem Di19-UIM module (M-UBD) and extend K11-linked polyubiquitin chains at those sites; this places RNF114 in a PARP7 MARUbylation-K11 polyUb pathway. Fluorescent Ub-ADPr chemoenzymatic probe, in vitro ubiquitination, AlphaFold3 structural modeling, cellular PARP7 MARUbylation assays The EMBO journal High 41039157
2025 RNF114 and RNF166 recognize a monoubiquitin-MAR hybrid mark on tankyrase (generated by Deltex ligases DTX2/DTX3) via a hybrid reader domain containing two binding sites (one for MAR, one for ubiquitin), and further diubiquitylate this mark; this blocks PAR formation and antagonizes RNF146-mediated tankyrase degradation, stabilizing tankyrase. Cellular ubiquitylation assays, immunoprecipitation, domain mapping bioRxivpreprint Medium
2025 RNF114 promotes K48-linked polyubiquitination and proteasomal degradation of PRRSV nsp12 at lysine residues 89, 91, 127, and 130; mutations at these lysines enable PRRSV to evade RNF114-mediated degradation and enhance viral replication. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis of nsp12 lysines, reverse genetics viral replication assay, mass spectrometry bioRxivpreprint Medium
2025 SPP1 interacts with RNF114 and facilitates RNF114-mediated ubiquitination of P85α, promoting PI3K/AKT/mTOR signaling and NSCLC brain metastasis. Co-immunoprecipitation, LC-MS, shRNA knockdown, in vitro/in vivo metastasis assays Molecular carcinogenesis Low 39918025
2010 The ZNF313 promoter has a functional Sp1 binding site within the fragment from nt -157 to +8, confirmed by site-directed mutation and mithramycin A treatment, identifying Sp1 as a transcriptional regulator of RNF114. Promoter deletion constructs, luciferase reporter assay, site-directed mutagenesis, mithramycin A treatment Cell biology international Medium 20515446

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene. Human molecular genetics 159 18364390
2021 Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function. Cell chemical biology 136 33513350
2011 Functional analysis of the RNF114 psoriasis susceptibility gene implicates innate immune responses to double-stranded RNA in disease pathogenesis. Human molecular genetics 70 21571784
2013 ZNF313 is a novel cell cycle activator with an E3 ligase activity inhibiting cellular senescence by destabilizing p21(WAF1.). Cell death and differentiation 62 23645206
2014 XAF1 directs apoptotic switch of p53 signaling through activation of HIPK2 and ZNF313. Proceedings of the National Academy of Sciences of the United States of America 61 25313037
2017 The E3 ubiquitin ligase RNF114 and TAB1 degradation are required for maternal-to-zygotic transition. EMBO reports 55 28073917
2014 The RING ubiquitin E3 RNF114 interacts with A20 and modulates NF-κB activity and T-cell activation. Cell death & disease 50 25165885
2023 Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in BRCA-mutated cancer. Science advances 47 37878693
2020 E3 Ubiquitin Ligase RNF114 Inhibits Innate Immune Response to Red-Spotted Grouper Nervous Necrosis Virus Infection in Sea Perch by Targeting MAVS and TRAF3 to Mediate Their Degradation. Journal of immunology (Baltimore, Md. : 1950) 36 33268485
2020 Proteasomal degradation of nonstructural protein 12 by RNF114 suppresses porcine reproductive and respiratory syndrome virus replication. Veterinary microbiology 21 32605740
2017 Negative regulation of the RLH signaling by the E3 ubiquitin ligase RNF114. Cytokine 21 28625874
2025 Identification of RNF114 as ADPr-Ub reader through non-hydrolysable ubiquitinated ADP-ribose. Nature communications 17 40634336
2021 Maternal RNF114-mediated target substrate degradation regulates zygotic genome activation in mouse embryos. Development (Cambridge, England) 17 34104941
2023 XAF1 promotes colorectal cancer metastasis via VCP-RNF114-JUP axis. The Journal of cell biology 16 38095639
2014 Identification of RNF114 as a novel positive regulatory protein for T cell activation. Immunobiology 16 24631332
2022 RNF114 Silencing Inhibits the Proliferation and Metastasis of Gastric Cancer. Journal of Cancer 14 35069903
2003 Identification of a novel human zinc finger protein gene ZNF313. Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica 14 12621547
2017 Regulation of RANKL-induced osteoclastogenesis by RING finger protein RNF114. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 13 28708287
2014 A RING finger protein 114 (RNF114) homolog from Chinese sturgeon (Acipenser sinensis) possesses immune-regulation properties via modulating RIG-I signaling pathway-mediated interferon expression. Fish & shellfish immunology 11 25290666
2007 Cloning and expression analysis of a novel mouse zinc finger protein gene Znf313 abundantly expressed in testis. Journal of biochemistry and molecular biology 11 17394778
2022 E3 ubiquitin ligase RNF114 promotes vesicular stomatitis virus replication via inhibiting type I interferon production. Microbial pathogenesis 8 35545202
2025 RNF114 and RNF166 exemplify reader-writer E3 ligases that extend K11 polyubiquitin onto sites of MARUbylation. The EMBO journal 7 41039157
2023 RNF114 facilitates the proliferation, stemness, and metastasis of colorectal cancer. Pathology, research and practice 7 37523804
2023 DCAF13 and RNF114 participate in the regulation of early porcine embryo development. Reproduction (Cambridge, England) 5 37855431
2024 XAF1 antagonizes TRIM28 activity through the assembly of a ZNF313-mediated destruction complex to suppress tumor malignancy. Molecular biomedicine 4 39532800
2025 SPP1 Promotes NSCLC Brain Metastasis Via Sequestration of Ubiquitin Ligase RNF114 to Facilitate P85α Ubiquitination. Molecular carcinogenesis 2 39918025
2025 RNF114 Interacts with EWSR1 to Regulate VEGFR2 in HER2-positive Breast Cancer. Journal of Cancer 1 40092691
2010 Sp1 plays an important role in regulating the transcription of ZNF313. Cell biology international 1 20515446
2025 Computational Identification of RNF114 nsSNPs with Potential Roles in Psoriasis and Immune Dysregulation. Medical sciences (Basel, Switzerland) 0 40981192
2025 RNF114, a RING E3 ligase that reads and extends the hybrid ADP-ribose-ubiquitin signal. The EMBO journal 0 41039156
2025 Emerging role of the E3 ubiquitin ligase RNF114 in health and disease. Human cell 0 41046487

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