Affinage

NFRKB

Nuclear factor related to kappa-B-binding protein · UniProt Q6P4R8

Length
1299 aa
Mass
139.0 kDa
Annotated
2026-06-10
29 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NFRKB (INO80G) is a metazoan-specific subunit of the INO80 chromatin remodeling complex that functions principally as a regulator of the deubiquitylase UCH37/UCH-L5 (PMID:25702872, PMID:25702870, PMID:25194926). Through its DEUBAD domain, NFRKB potently inhibits UCH-L5 by exploiting the enzyme's conformational plasticity to drive it into a conformation distinct from that imposed by the activator RPN13, and by molecular mimicry that blocks ubiquitin docking and disrupts the active site (PMID:25702872, PMID:25702870). NFRKB also contains a winged-helix-like domain (residues 370–495) that does not bind DNA and instead mediates protein–protein interactions (PMID:22984442). The NFRKB–UCHL5 relationship is reciprocal: UCHL5 deubiquitylates and stabilizes NFRKB against proteasomal degradation, and this stabilization is required for DNA double-strand break resection and homologous recombination repair (PMID:25194926). This axis is modulated by the lncRNA DRAIC, which binds UCHL5, weakens its interaction with NFRKB, and thereby promotes NFRKB degradation to restrain gastric cancer cell proliferation and invasion (PMID:32351584). NFRKB additionally associates with telomeres in alternative-lengthening-of-telomeres (ALT) cells, where its loss induces telomere dysfunction and reduces PML bodies (PMID:34591601).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2012 Medium

    Defining NFRKB's structural architecture clarified whether it acts directly on DNA or through protein contacts, establishing that its winged-helix-like region serves protein-interaction rather than DNA-binding roles.

    Evidence High-throughput X-ray crystallography of residues 370–495 with a negative DNA-binding assay

    PMID:22984442

    Open questions at the time
    • Function of regions outside 370–495 unresolved
    • Specific interaction partners of the winged-helix domain not identified
  2. 2012 Low

    Bioinformatic identification of a shared DEUBAD domain across NFRKB, ADRM1, and ASXL1 placed NFRKB within a family of UCH37/UCH-L5 regulators, predicting a regulatory link later confirmed structurally.

    Evidence Comparative sequence analysis identifying the DEUBAD domain

    PMID:22645167

    Open questions at the time
    • Computational prediction only, no biochemistry on NFRKB
    • Did not establish direction of regulation (activation vs inhibition)
  3. 2014 Medium

    Functional epistasis revealed that UCHL5 stabilizes NFRKB and that this stabilization is required for homologous recombination, linking the NFRKB–UCHL5 pair to DNA double-strand break repair.

    Evidence DUB siRNA screen, co-IP, and HR reporter/DSB resection assays in human cells

    PMID:25194926

    Open questions at the time
    • Single lab
    • Molecular role of NFRKB at break sites not defined
    • Whether INO80 complex integrity is required not tested
  4. 2015 High

    Crystal structures resolved how NFRKB inhibits UCH37/UCH-L5, showing it blocks the ubiquitin-binding site and disrupts the active site—the structural basis for its function as a DEUBAD-domain inhibitor.

    Evidence Crystal structures of the UCH37–NFRKB/INO80G DEUBAD complex with mutagenesis and activity assays, replicated across two studies

    PMID:25702870 PMID:25702872

    Open questions at the time
    • Cellular substrates whose deubiquitylation is blocked not enumerated
    • How inhibition is relieved in vivo not addressed
  5. 2020 Medium

    Identifying lncRNA DRAIC as a competitor of the UCHL5–NFRKB interaction showed how NFRKB levels are tuned, connecting NFRKB stability to cancer cell proliferation and metastasis.

    Evidence RNA-IP, co-IP, ubiquitination assays, CHX/MG132 chase, and NFRKB-overexpression rescue in gastric cancer cells

    PMID:32351584

    Open questions at the time
    • Single lab
    • Direct binding interfaces of DRAIC not mapped
    • Generalizability beyond gastric cancer unknown
  6. 2021 Medium

    Demonstrating telomere association in ALT cells extended NFRKB's genome-maintenance role beyond DSB repair to telomere protection.

    Evidence Immunostaining/FISH co-localization and siRNA loss-of-function showing telomere dysfunction and reduced PML bodies in U2OS cells

    PMID:34591601

    Open questions at the time
    • Single lab
    • Mechanism of telomere recruitment unknown
    • Dependence on UCHL5 or INO80 complex not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NFRKB integrates INO80 chromatin remodeling, UCH-L5 inhibition, and genome maintenance into a unified pathway, and what substrates its inhibition of UCH-L5 protects, remain unresolved.
  • No defined catalytic substrate set for the NFRKB-inhibited UCH-L5
  • Mechanistic link between INO80 remodeling and DSB/telomere roles unestablished
  • Recruitment determinants to chromatin and telomeres unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-4839726 Chromatin organization 2 R-HSA-73894 DNA Repair 1
Partners
UCHL5
Complex memberships
INO80 chromatin remodeling complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 NFRKB (INO80G) inhibits the deubiquitylase UCH37/UCH-L5 by blocking its ubiquitin-binding site and disrupting the enzyme active site, as determined by crystal structures of the UCH37–NFRKB complex and biochemical characterization. Crystal structure determination and biochemical characterization of UCH37 in complex with NFRKB; active-site analysis Molecular cell High 25702870 25702872
2015 The DEUBAD domain of NFRKB (INO80G) inhibits UCH-L5 by exploiting UCH-L5 conformational plasticity to promote a radically different conformation from that induced by activator RPN13, and employs molecular mimicry to block ubiquitin docking on UCH-L5. Crystal structure determination of UCH-L5–INO80G DEUBAD domain complex; mutagenesis and biochemical activity assays Molecular cell High 25702870
2014 NFRKB is protected from proteasomal degradation by the deubiquitylase UCHL5, and this protection is required for UCHL5 to regulate DNA double-strand break resection and repair by homologous recombination. DUB siRNA screen, epistasis experiments, co-immunoprecipitation, DNA damage repair assays (DSB resection, HR reporter) Nature cell biology Medium 25194926
2012 NFRKB contains a novel winged-helix-like domain (residues 370–495) that is mostly helical and does not bind DNA, suggesting it is involved in protein–protein interactions rather than direct DNA binding. High-throughput X-ray crystallography (JCSG pipeline); DNA-binding assay (negative result for DNA binding) PloS one Medium 22984442
2012 NFRKB is a component of the metazoan INO80 chromatin remodeling complex and undergoes post-translational modification by sumoylation; during minimal change nephrotic syndrome (MCNS) relapse it localizes predominantly to the nuclear compartment, whereas in remission it is restricted to the cytoplasm, and nuclear NFRKB induces AP1 signaling by upregulating c-jun and promotes genomic hypomethylation. Immunofluorescence localization, western blotting, SUMO modification assay, reporter/signaling assay, bisulfite sequencing for methylation PloS one Low 22291976
2020 lncRNA DRAIC binds UCHL5 and attenuates the interaction between UCHL5 and NFRKB, thereby promoting ubiquitin-mediated degradation of NFRKB protein and inhibiting gastric cancer cell proliferation and metastasis; overexpression of NFRKB rescues the DRAIC-induced inhibition. RNA-IP, Co-IP, ubiquitination-IP, CHX/MG132 treatment, CCK-8 proliferation and transwell invasion assays, rescue experiment with NFRKB overexpression Cellular & molecular biology letters Medium 32351584
2021 NFRKB is a telomere-associated protein in human ALT (alternative lengthening of telomeres) cells; loss of NFRKB induces telomere dysfunction and reduces PML bodies in U2OS cells, and NFRKB accumulates in the nucleus of liver cancer cells. Immunostaining, fluorescence in situ hybridization (FISH), siRNA loss-of-function, western blot, immunohistochemistry DNA and cell biology Medium 34591601
2012 Computational sequence analysis established that the DEUBAD domain is shared among NFRKB (INO80G), ADRM1 (RPN13), and ASXL1, indicating common ancestry of UCH37/UCH-L5 regulators across the INO80, proteasome, and PR-DUB complexes. Comparative sequence analysis / bioinformatics domain identification Bioinformatics (Oxford, England) Low 22645167

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Systematic characterization of deubiquitylating enzymes for roles in maintaining genome integrity. Nature cell biology 123 25194926
2015 Mechanism of UCH-L5 activation and inhibition by DEUBAD domains in RPN13 and INO80G. Molecular cell 106 25702870
2015 Structural basis for the activation and inhibition of the UCH37 deubiquitylase. Molecular cell 101 25702872
2018 The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma. Blood 77 30567752
2010 Second generation sequencing of the mesothelioma tumor genome. PloS one 54 20485525
2012 A common ancestry for BAP1 and Uch37 regulators. Bioinformatics (Oxford, England) 48 22645167
2013 Proteome-wide discovery of mislocated proteins in cancer. Genome research 47 23674306
2020 LncRNA DRAIC inhibits proliferation and metastasis of gastric cancer cells through interfering with NFRKB deubiquitination mediated by UCHL5. Cellular & molecular biology letters 42 32351584
2006 Amplified, lost, and fused genes in 11q23-25 amplicon in acute myeloid leukemia, an array-CGH study. Genes, chromosomes & cancer 41 16283618
2008 Submicroscopic deletions of 11q24-25 in individuals without Jacobsen syndrome: re-examination of the critical region by high-resolution array-CGH. Molecular cytogenetics 28 19000322
2015 Structural plasticity allows UCH37 to be primed by RPN13 or locked down by INO80G. Molecular cell 25 25747657
2012 Upregulation of nuclear factor-related kappa B suggests a disorder of transcriptional regulation in minimal change nephrotic syndrome. PloS one 23 22291976
2020 Mutational Profile of Malignant Pleural Mesothelioma (MPM) in the Phase II RAMES Study. Cancers 19 33065998
2016 Modeling oblong proteins and water-mediated interfaces with RosettaDock in CAPRI rounds 28-35. Proteins 17 27667482
2017 Ubiquitin carboxyl-terminal hydrolase isozyme L5 inhibits human glioma cell migration and invasion via downregulating SNRPF. Oncotarget 15 29371935
2023 Screening for genes, miRNAs and transcription factors of adipogenic differentiation and dedifferentiation of mesenchymal stem cells. Journal of orthopaedic surgery and research 10 36647068
2022 The biological function of metazoan-specific subunit nuclear factor related to kappaB binding protein of INO80 complex. International journal of biological macromolecules 10 35093437
2021 The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma. Cancers 10 34067022
2002 Girl with combined cellular immunodeficiency, pancytopenia, malformations, deletion 11q23.3 --> qter, and trisomy 8q24.3 --> qter. American journal of medical genetics 10 11920839
1992 Localization of the gene encoding R kappa B (NFRKB), a tissue-specific DNA binding protein, to chromosome 11q24-q25. Genomics 10 1427843
2012 SNP array and phenotype correlation shows that FLI1 deletion per se is not responsible for thrombocytopenia development in Jacobsen syndrome. American journal of medical genetics. Part A 9 22887642
2023 Integrated Multi-Omic Analysis Reveals Immunosuppressive Phenotype Associated with Poor Outcomes in High-Grade Serous Ovarian Cancer. Cancers 8 37509311
2025 Cytogenomic and Clinicopathologic Comparison of MYC-Positive and MYC-Negative High-Grade B-Cell Lymphoma With 11q Aberration in the Context of Other Aggressive Lymphomas With MYC Rearrangement. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 7 40222649
2021 Nuclear Factor Related to KappaB Binding Protein (NFRKB) Is a Telomere-Associated Protein and Involved in Liver Cancer Development. DNA and cell biology 6 34591601
2012 Structure of a novel winged-helix like domain from human NFRKB protein. PloS one 6 22984442
2009 Genetic dissection of granulomatous enterocolitis and arthritis in the intramural peptidoglycan-polysaccharide-treated rat model of IBD. Inflammatory bowel diseases 6 19526527
2022 Case report: ETS1 gene deletion associated with a low number of recent thymic emigrants in three patients with Jacobsen syndrome. Frontiers in immunology 2 36341443
2026 Transcriptome and alternative splicing analyses uncover immune-centric pathogenesis in periodontitis versus barrier-dysfunction-driven pathogenesis in peri-implantitis. Gene 0 41911957
2022 [Construction and analysis of transcriptome-based hepatolenticular degeneration regulatory network]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 0 36305413

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