Affinage

RNF213

E3 ubiquitin-protein ligase RNF213 · UniProt Q63HN8

Length
5207 aa
Mass
591.4 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 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

RNF213 is a giant (~591 kDa) cytosolic protein that couples a dynein-like AAA+ ATPase core to a multidomain E3 ubiquitin ligase module, functioning both as an innate immune effector and as a regulator of vascular homeostasis (PMID:21799892, PMID:32573437). Its ATPase core forms a ring-shaped oligomer whose assembly is dynamically remodeled through ATP/ADP cycles (PMID:24658080), while its E3 module catalyzes ubiquitylation through two mechanistically distinct routes: a RING-independent RZ-finger mechanism that ubiquitylates the lipid A moiety of bacterial LPS, and a RING-dependent mechanism operating with multiple E2 enzymes (UBC13/UBE2N, UBE2D2, UBE2L3, UbcH7) to build diverse chain linkages (PMID:32573437, PMID:34012115, PMID:33842849, PMID:35135845). As an interferon-inducible effector, RNF213 is recruited to pathogen-containing compartments—Salmonella, Toxoplasma parasitophorous vacuoles, and Chlamydia inclusions—where ATPase-dependent recruitment and RZ-finger-dependent ubiquitylation coat the surface in ubiquitin and recruit downstream LUBAC and autophagy machinery to restrict the pathogen (PMID:34012115, PMID:36154443, PMID:38147552, PMID:36084633); it likewise targets viral proteins such as gammaherpesvirus RTA for K48-linked proteasomal degradation (PMID:36917666) and promotes Treg differentiation via K63-linked ubiquitylation and nuclear translocation of FOXO1 (PMID:39013878). In vascular endothelium RNF213 regulates angiogenesis, cerebral blood flow, and blood-brain barrier integrity (PMID:25446450, PMID:29483617, PMID:37438553), acting in part through the UBC13 ubiquitylation axis (PMID:33842849) and through suppression of YAP/TAZ-VEGFR2 signaling (PMID:37399508). Transcription of RNF213 is induced by IFN-β, IFN-γ, and TNF-α as well as by mitochondrial dysfunction and TLR3 activation (PMID:26126547, PMID:26278786, PMID:32342250). The major moyamoya disease-associated allele p.R4810K behaves as a dominant-negative that globally impairs ubiquitylation and disrupts endothelial angiogenic function (PMID:35135845, PMID:26126547, PMID:23850618).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2011 High

    Established RNF213 as a dual-activity enzyme and linked it to vascular development, framing the central question of how a single protein bridges enzymology and angiogenesis.

    Evidence Biochemical ATPase/ubiquitin ligase assays plus zebrafish morpholino knockdown with vascular readout

    PMID:21799892

    Open questions at the time
    • No substrates identified
    • Mechanistic link between enzymatic activity and vascular phenotype undefined
  2. 2014 High

    Showed the AAA+ core assembles into a dynamic ring-shaped oligomer driven by ATP/ADP cycling, defining RNF213 as a mechanical AAA+ ATPase.

    Evidence Fluorescence correlation spectroscopy and biochemical oligomeric-state and ATPase assays

    PMID:24658080

    Open questions at the time
    • Functional consequence of oligomeric remodeling unresolved
    • No structure available at this stage
  3. 2014 Medium

    In vivo mouse models established that RNF213 loss suppresses vascular remodeling and enhances ischemic angiogenesis while being insufficient alone to cause arterial disease, defining its role as a modulator rather than sole driver.

    Evidence RNF213 knockout mice in carotid ligation and femoral ligation models with MRA, flowmetry, and MMP-9 analysis

    PMID:24440776 PMID:25383461 PMID:25446450

    Open questions at the time
    • Molecular substrate linking RNF213 to remodeling unidentified
    • MMP-9 regulation mechanism indirect
  4. 2015 High

    Connected RNF213 to interferon and inflammatory signaling, showing it mediates IFN-β antiangiogenic activity and is co-induced by IFN-γ/TNF-α, establishing it as a cytokine-responsive endothelial effector.

    Evidence Promoter/STAT analysis, AKT/PKR inhibitor studies, ATPase assays, transgenic mouse hypoxia angiogenesis model, RNAi with proliferation/tube formation readouts

    PMID:23850618 PMID:26126547 PMID:26278786

    Open questions at the time
    • Direct ubiquitylation substrate in angiogenesis not defined
    • Securin link correlative
  5. 2016 High

    Placed RNF213 in a PTP1B-dependent metabolic pathway controlling α-KG-dependent dioxygenase activity and hypoxic tumor survival, extending its role beyond vasculature.

    Evidence siRNA knockdown rescue in HER2+ breast cancer cells, oxygen consumption and α-KGDD assays, xenograft tumorigenicity

    PMID:27323329

    Open questions at the time
    • Direct enzymatic substrate in this pathway unknown
    • Mechanism of α-KGDD regulation indirect
  6. 2020 High

    The cryo-EM structure revealed the N-terminal stalk, six-unit dynein-like ATPase core, and composite E3 module, and uncovered a RING-independent, cysteine-reactive (UbcH7) ubiquitin-transfer mechanism while mapping disease mutations to the E3 region.

    Evidence Cryo-EM structure of mouse RNF213 with E2 collaboration assays and disease-variant mapping

    PMID:32573437

    Open questions at the time
    • Substrate engagement geometry not resolved
    • Coupling between ATPase cycling and ubiquitin transfer not structurally defined
  7. 2020 High

    Defined the E2 repertoire and linkage outputs and demonstrated that disease alleles, particularly p.R4810K, act as dominant-negatives that globally impair ubiquitylation without altering ATPase activity, clarifying how variants cause loss of E3 function.

    Evidence In vitro ubiquitination with UBC13/Uev1A, UBE2D2, UBE2L3, linkage analysis, NF-κB and caspase reporters, dominant-negative cell assays, ATPase assays on disease alleles

    PMID:32139119 PMID:35135845

    Open questions at the time
    • Physiological substrate(s) for each E2-linkage combination not all identified
    • How dominant-negative impairment maps to vascular pathology incomplete
  8. 2020 Medium

    Identified upstream inducers beyond classical cytokines, showing mitochondrial matrix dysfunction and TLR3/dsRNA signaling drive Rnf213 expression, broadening its stress-response regulation.

    Evidence Rnf213 mRNA quantification in ClpP/Tfam/Lonp1 KO mice, Poly(I:C), IFN-γ, and PKR inhibitor experiments

    PMID:32342250

    Open questions at the time
    • Transcription factors mediating mitochondrial-stress induction undefined
    • Functional output of stress-induced RNF213 not established
  9. 2021 High

    Defined RNF213 as a direct innate immune effector that ubiquitylates non-proteinaceous LPS lipid A on cytosolic bacteria via its RZ finger (RING-independent), seeding LUBAC and autophagy recruitment to restrict pathogens.

    Evidence Biochemical ubiquitylation of LPS, RZ-finger vs RING domain mutagenesis, LUBAC Co-IP, autophagy receptor imaging, CFU assays on Salmonella; plus UBC13 yeast two-hybrid/Co-IP and autoubiquitylation analysis; plus Listeria DDAH1-NO axis and RVFV resistance models

    PMID:33420513 PMID:33842849 PMID:34012115 PMID:34804992

    Open questions at the time
    • How RNF213 recognizes diverse pathogen surfaces unclear
    • Relationship between LPS ubiquitylation and protein-substrate ubiquitylation not unified
  10. 2022 High

    Generalized RNF213 pathogen restriction to eukaryotic parasites and other bacteria, showing ATPase-dependent recruitment and RZ-finger-dependent ubiquitylation of Toxoplasma vacuoles and Chlamydia inclusions, with pathogen stealth factors (GarD) antagonizing it.

    Evidence Genome-wide and ISG CRISPR screens, domain mutagenesis (ATPase recruitment vs RZ ubiquitylation), PVM/inclusion imaging, ATG5 epistasis, garD bacterial mutants, growth restriction assays

    PMID:36084633 PMID:36154443 PMID:38147552

    Open questions at the time
    • Signal directing RNF213 to specific compartments unknown
    • Downstream effector requirements vary across pathogens
  11. 2023 High

    Extended RNF213's E3 function to protein substrates in immunity, showing K48-linked degradation of gammaherpesvirus RTA to restrict viral lytic reactivation.

    Evidence Co-IP, in vitro K48 ubiquitination, proteasome inhibitor experiments, viral infection/reactivation assays

    PMID:36917666

    Open questions at the time
    • Whether RING vs RZ finger drives RTA ubiquitylation not delineated
    • E2 partner for this event unspecified
  12. 2023 Medium

    Linked endothelial RNF213 loss to pathological angiogenesis via YAP/TAZ-driven VEGFR2 overexpression and trafficking, and to blood-brain barrier integrity through pericyte and tight-junction regulation.

    Evidence RNF213 knockdown with RNA-seq/scRNA-seq, YAP/TAZ inhibitor epistasis, VEGFR2 trafficking fractionation, in vivo mouse/zebrafish phenotyping; plus Rnf213 KO mouse BBB/pericyte analysis

    PMID:37399508 PMID:37438553

    Open questions at the time
    • Direct ubiquitylation substrate upstream of YAP/TAZ unidentified
    • Connection to immune effector function unclear
  13. 2024 High

    Defined a substrate-level immunoregulatory role, showing RNF213 promotes Treg differentiation by K63-ubiquitylating FOXO1 to drive its nuclear translocation and is required for IFN-β therapeutic efficacy.

    Evidence Co-IP, K63 ubiquitination assays, nuclear fractionation, Treg differentiation and autoimmune disease mouse models, IFN-β treatment

    PMID:39013878

    Open questions at the time
    • Whether FOXO1 ubiquitylation uses RING or RZ finger not stated
    • Structural basis of K63 vs K48 substrate selection unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RNF213's two enzymatic activities are mechanistically coupled, and how a single ligase integrates pathogen restriction, vascular homeostasis, and immunometabolic signaling through distinct substrates and linkage types, remains unresolved.
  • No unifying model connecting ATPase cycling to substrate-specific ubiquitylation
  • The full physiological substrate set is incomplete
  • Causal mechanism by which p.R4810K produces moyamoya pathology in vivo not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 7 GO:0140657 ATP-dependent activity 4 GO:0016874 ligase activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 6 R-HSA-1266738 Developmental Biology 4 R-HSA-392499 Metabolism of proteins 4
Partners
FOXO1MAD2PTP1BUBE2D2UBE2L3UBE2N

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 RNF213 encodes a 591-kDa cytosolic protein possessing a Walker motif (ATPase) and a RING finger domain that exhibit ATPase and ubiquitin ligase activities, respectively. Knockdown of RNF213 in zebrafish caused irregular wall formation in trunk arteries and abnormal sprouting vessels, establishing a role in vascular development. Exome sequencing/Sanger sequencing for variant identification; functional assays for ATPase/ubiquitin ligase activity; zebrafish morpholino knockdown with vascular phenotype readout PloS one High 21799892
2014 Mysterin/RNF213 contains two tandem AAA+ ATPase modules and forms a large ring-shaped oligomeric complex. Fluorescence correlation spectroscopy and biochemical evaluation showed that RNF213 dynamically changes its oligomeric state through ATP/ADP binding and hydrolysis cycles, consistent with a mechanical AAA+ ATPase mechanism. Fluorescence correlation spectroscopy (FCS), biochemical sedimentation/native PAGE assays for oligomeric state, ATPase activity assays Scientific reports High 24658080
2015 RNF213 is upregulated by IFN-β through STAT signaling in endothelial cells and mediates antiangiogenic activity of IFN-β. The R4810K variant decreases ATPase activity (similar to a Walker B motif stabilizing mutation WEQ) and stabilizes oligomers, causing antiangiogenic activity even without IFN-β stimulation. EC-specific Rnf213 R4757K transgenic mice showed suppressed cerebral angiogenesis under hypoxia, while wild-type overexpression did not. Promoter analysis (STAT binding), ATPase activity assays, mutagenesis of Walker B motif, transgenic mouse hypoxia model with in vivo angiogenesis readout Journal of the American Heart Association High 26126547
2015 Pro-inflammatory cytokines IFN-γ and TNF-α synergistically activate transcription of RNF213 in endothelial cells via AKT and PKR pathways. RNF213 knockdown in endothelial cells reduced expression of cell cycle-promoting genes, decreased proliferation, reduced angiogenic capacity, and down-regulated matrix metalloproteases specifically in endothelial cells. Chemical inhibitor experiments (LY294002 for AKT, C16 for PKR), RNAi knockdown, transcriptome-wide analysis, qPCR validation, proliferation and tube formation assays Scientific reports Medium 26278786
2015 RNF213 R4810K variant downregulates Securin in iPSC-derived vascular endothelial cells, inhibiting angiogenic activity. Overexpression of R4810K (but not wild-type) RNF213 reduced tube formation and proliferation in HUVECs. siRNA knockdown of Securin phenocopied the angiogenic defect. iPSC differentiation to endothelial cells, gene expression profiling, overexpression of WT vs. R4810K in HUVECs, tube formation assay, siRNA knockdown of Securin Biochemical and biophysical research communications Medium 23850618
2013 RNF213 R4810K variant induces mitotic abnormalities: overexpression in HeLa cells extended mitosis 4-fold, and co-immunoprecipitation revealed that R4810K forms a complex with MAD2 more readily than wild-type RNF213. Fibroblasts and iPSC-derived endothelial cells from patients showed desynchronized MAD2 localization and increased aneuploidy. Live-cell imaging, co-immunoprecipitation, immunofluorescence, flow cytometry for aneuploidy, MAD2 depletion epistasis experiment Biochemical and biophysical research communications Medium 23994138
2016 PTP1B negatively regulates RNF213 in HER2+ breast cancer cells. RNF213 knockdown reverses the effects of PTP1B deficiency on α-KG-dependent dioxygenase (α-KGDD) activity and non-mitochondrial oxygen consumption, establishing a PTP1B→RNF213→α-KGDD pathway required for tumor survival under hypoxia. RNF213 siRNA knockdown in PTP1B-deficient and wild-type HER2+ breast cancer cells, oxygen consumption measurements, α-KGDD activity assays, xenograft tumorigenicity rescue Nature cell biology High 27323329
2020 Cryo-EM structure of mouse RNF213 (584 kDa) revealed an N-terminal stalk, a dynein-like core with six ATPase units, and a multidomain E3 module. Collaboration with UbcH7, a cysteine-reactive E2, indicates a RING-independent ubiquitin-transfer mechanism. Pathogenic MMD mutations cluster in the composite E3 domain. Cryo-EM structure determination, biochemical E2 collaboration assays with UbcH7, mutational mapping of disease variants onto structure eLife High 32573437
2020 RING domain mutations from MMD patients reduce RNF213 ubiquitin ligase activity (using Ubc13/Uev1A as E2, generating K63-linked polyubiquitin chains in vitro). In full-length overexpression experiments in HEK293T cells, these mutations conversely enhanced NF-κB activation and caspase-3-mediated apoptosis in an AAA+ domain-dependent manner, suggesting NF-κB/apoptosis activities are negatively regulated by RNF213 E3 ligase activity. In vitro ubiquitination assays with purified RING domain, K63 linkage-specific antibodies, full-length overexpression in HEK293T, NF-κB reporter assay, caspase-3 activity assay, AAA+ domain deletion mutants Biochemical and biophysical research communications Medium 32139119
2021 RNF213 ubiquitylates the lipid A moiety of bacterial lipopolysaccharide (LPS) on cytosol-invading Salmonella, forming a ubiquitin coat. This requires the dynein-like core of RNF213 but not its RING domain; instead, an RZ finger mediates ubiquitylation. RNF213 is essential for recruitment of LUBAC (which adds M1-linked chains) and ubiquitin-dependent autophagy receptors, restricting Salmonella proliferation. Biochemical ubiquitylation assays identifying LPS as substrate, domain deletion/mutagenesis (RZ finger vs. RING domain), co-immunoprecipitation for LUBAC recruitment, bacterial colony-forming unit assays, autophagy receptor recruitment imaging Nature High 34012115
2021 UBC13 (UBE2N) is an E2 ubiquitin-conjugating enzyme for RNF213, identified by yeast two-hybrid screening with the RNF213 RING domain as bait, and confirmed by co-immunoprecipitation in vivo. RNF213 autoubiquitinates via K63-linked chains (not K48) in a UBC13-dependent manner. UBC13 knockdown and ubiquitination-dead RNF213 mutants reduced HUVEC cell migration and invasion, indicating the RNF213-UBC13 axis contributes to angiogenic activity. Yeast two-hybrid screening, co-immunoprecipitation in vivo, in vitro ubiquitination assay with K63/K48 linkage analysis, UBC13 siRNA knockdown, migration/invasion assays FASEB bioAdvances Medium 33842849
2022 RNF213 uses E2-conjugating enzymes UBE2D2 and UBE2L3 for distinct ubiquitylation events: RNF213-UBE2D2 catalyzes K6 (and K48) poly-ubiquitylation in vitro, while RNF213-UBE2L3 catalyzes K6-, K11-, and K48-linked chains. MMD-associated SNPs encode proteins with decreased E3 activity. The most frequent MMD allele (p.R4810K) acts as a dominant-negative mutant that globally decreases ubiquitylation but does not affect ATPase activity. In vitro ubiquitination assays with purified components, ubiquitin linkage analysis, dominant-negative functional assay in cells, ATPase activity assays for MMD SNP alleles Life science alliance High 35135845
2022 RNF213 knockout in human cerebral endothelial cells (CRISPR-Cas9) caused morphological changes, increased blood-brain barrier permeability, downregulation and delocalization of PECAM-1, abnormal leukocyte transmigration, and secretion of proinflammatory cytokines, identifying RNF213 as a regulator of cerebral endothelium integrity. CRISPR-Cas9 knockout in hCMEC/D3 cells, permeability assays, immunofluorescence for junction proteins (PECAM-1), transendothelial leukocyte migration assay, cytokine ELISA Stroke Medium 34991336
2022 IFN-γ-inducible RNF213 translocates to Toxoplasma gondii parasitophorous vacuoles (PVs) and facilitates PV ubiquitylation (linear and K63-linked) in human cells independently of LUBAC. RNF213 is required for IFN-γ-mediated growth restriction of T. gondii. The ATPase domain is required for RNF213 recruitment to the PVM, while loss of a critical histidine in the RZ finger abolishes ubiquitylation; both are needed for parasite growth restriction. CRISPR loss-of-function screen, domain mutagenesis (ATPase domain, RZ finger histidine), immunofluorescence for PV localization, ubiquitin linkage analysis, intracellular parasite growth assay mBio High 36154443
2022 GarD, a Chlamydia trachomatis inclusion membrane protein, functions as a cis-acting stealth factor that bars IFN-γ-inducible RNF213 from targeting inclusions. In IFN-γ-primed human cells lacking garD, inclusions become decorated with linear ubiquitin in an RNF213-dependent manner and are destroyed, establishing RNF213 as an anti-Chlamydia E3 ligase. Genetic screen, garD loss-of-function mutants, RNF213 knockdown/knockout, immunofluorescence for ubiquitin on inclusions, bacterial growth assays Cell host & microbe High 36084633
2023 RNF213 directly interacts with the Replication and Transcription Activator (RTA) of KSHV and MHV-68, promotes K48-linked ubiquitination of RTA, and targets it for proteasome-dependent degradation, thereby inhibiting gammaherpesvirus de novo infection and lytic reactivation. Co-immunoprecipitation (RNF213-RTA interaction), in vitro ubiquitination assay (K48 linkage), proteasome inhibitor experiments, viral infection/reactivation assays with RNF213 overexpression and knockdown Proceedings of the National Academy of Sciences of the United States of America High 36917666
2023 Genome-wide CRISPR screen identified RNF213 as necessary for IFN-γ-mediated restriction of T. gondii. The ATPase domain is required for RNF213 recruitment to the parasitophorous vacuole membrane (PVM), while the RZ finger domain is required for ubiquitination. Both are required for parasite growth restriction. RNF213-mediated restriction is independent of ATG5 (non-canonical autophagy). RNF213 overexpression in naive (non-IFN-γ stimulated) cells is sufficient to restrict T. gondii growth. Genome-wide CRISPR screen, targeted ISG CRISPR screen, ATPase and RZ finger domain mutational analysis, fluorescence imaging of PVM localization, intracellular growth assays, ATG5 knockout epistasis Proceedings of the National Academy of Sciences of the United States of America High 38147552
2023 RNF213 loss-of-function activates the Hippo pathway effector YAP/TAZ, promoting overexpression of VEGFR2 downstream. Inhibition of YAP/TAZ altered VEGFR2 trafficking from Golgi to plasma membrane and reversed RNF213 knockdown-induced pathological angiogenesis in endothelial cells and in vivo (RNF213-deficient mice and zebrafish). RNF213 knockdown in human brain microvascular endothelial cells, bulk RNA-seq and single-cell RNA-seq, YAP/TAZ inhibitor experiments, VEGFR2 trafficking assay (Golgi vs. plasma membrane fractionation), in vivo RNF213-KO mouse and zebrafish vascular phenotyping Brain : a journal of neurology Medium 37399508
2024 RNF213 specifically promotes regulatory T (Treg) cell differentiation and attenuates autoimmune disease in an FOXO1-dependent manner. Mechanistically, RNF213 interacts with FOXO1 and promotes its nuclear translocation via K63-linked ubiquitination. RNF213 expression in CD4+ T cells is induced by IFN-β and is required for IFN-β therapeutic efficacy in multiple sclerosis models. Co-immunoprecipitation (RNF213-FOXO1 interaction), K63 ubiquitination assays, nuclear fractionation, Treg differentiation assays, autoimmune disease mouse models, IFN-β treatment experiments Nature communications High 39013878
2019 S-nitrosylation of RNF213 was detected in the P301S tauopathy mouse model cortex and hippocampus. S-nitrosylated RNF213 was associated with increased levels of NFAT-1 and FILAMIN-A, implicating RNF213 S-nitrosylation in activation of non-canonical Wnt/Ca²⁺ signaling in tauopathy. S-nitrosoproteome mass spectrometry, pathway analysis, immunoblotting for downstream effectors (pCaMKII, NFAT-1, FILAMIN-A) in transgenic mouse brain tissue Translational psychiatry Low 30696811
2020 Genetic ablation of mitochondrial matrix factors ClpP, Tfam, and Lonp1 potently induces Rnf213 transcript expression in multiple organs. Rnf213 is also induced by Poly(I:C)-triggered TLR3-mediated responses and IFN-γ treatment. This induction is only partially suppressed by PKR antagonist C16, suggesting RNF213 is induced by mitochondrial dysfunction/dsRNA-dependent inflammation. Rnf213 mRNA quantification in tissue from genetic KO mice (ClpP, Tfam, Lonp1), Poly(I:C) treatment, IFN-γ treatment, PKR inhibitor (C16) experiments Neurogenetics Medium 32342250
2014 RNF213-deficient mice show suppressed vascular remodeling after common carotid artery ligation: the intima and medial layers were significantly thinner in RNF213-/- than wild-type mice after ligation. Under normal conditions, no spontaneous arterial abnormalities were observed up to 64 weeks, indicating RNF213 loss is insufficient alone to cause moyamoya disease. Cre-lox RNF213 knockout mouse generation, 9.4-T MRA, common carotid artery ligation model, Elastica-Masson staining of arterial wall Brain research Medium 24440776
2014 RNF213-deficient mice showed enhanced angiogenesis and improved blood flow recovery after permanent femoral artery ligation compared to wild-type, indicating RNF213 functions to suppress angiogenesis under chronic ischemic conditions. RNF213-/- knockout mice, femoral artery ligation model, laser speckle flowmetry, vascular density quantification, ambulatory impairment scoring Brain research Medium 25446450
2014 RNF213-deficient mice showed significantly increased vascular MMP-9 expression at 1 and 7 days after common carotid artery ligation, and thinner vascular walls at 14 days, linking RNF213 loss to dysregulated MMP-9-dependent vascular remodeling. RNF213-/- knockout mice, common carotid artery ligation, immunohistochemistry/immunoblotting for MMP-9, Elastica-Masson staining Neuroreport Medium 25383461
2015 Mysterin/RNF213 is required for proper fast muscle formation and neuromuscular regulation in zebrafish. Morpholino-mediated knockdown caused significant reduction in fast myofibrils and immature projection of primary motoneurons, leading to severe motor deficits. Rescue with fast muscle-specific RNF213 expression reversed these phenotypes. Both AAA+ ATPase and ubiquitin ligase activities were indispensable for proper fast muscle formation. Zebrafish antisense morpholino knockdown, tissue-specific mRNA rescue, immunofluorescence for myofibrils and motoneuron projections, behavioral motor assays, ATPase-dead and RING-dead rescue constructs Scientific reports High 26530008
2018 RNF213 is required for maintenance of cerebral blood flow under hypoperfusion. RNF213 knockout mice showed significantly more severe CBF reduction and impaired CBF restoration compared to wild-type after bilateral carotid stenosis. EC-specific Rnf213 mutant (R4810K ortholog) transgenic mice also showed impaired CBF restoration and reduced angiogenesis, establishing a vascular endothelial cell-autonomous role. Bilateral carotid artery stenosis surgery, arterial spin-labeling MRI for quantitative CBF measurements, histological angiogenesis analysis in RNF213 KO and EC-specific transgenic mice Scientific reports Medium 29483617
2021 RNF213 is required for resistance to Rift Valley fever virus in mice. CRISPR/Cas9 Rnf213-deficient C57BL/6 mice were significantly more susceptible to RVF than controls, with reduced average survival time post-infection. CRISPR/Cas9 Rnf213 knockout mouse, Rift Valley fever virus infection, survival analysis Mammalian genome Medium 33420513
2021 RNF213 knockdown in macrophages and adipocytes reduces its expression, which is enhanced by pro-inflammatory TNF-α stimuli (LPS) and suppressed by PPARγ-mediated anti-inflammatory stimuli. PTP1B inactivation abolished RNF213 expression and enhanced adipogenesis through PPARγ. Constitutive RNF213 expression suppressed adipocyte differentiation by inhibiting PPARγ, establishing a TNF-α/PTP1B/RNF213/PPARγ pathway in adipogenesis. RNF213 knockdown in macrophages/adipocytes, LPS stimulation, PPARγ inhibitor/activator treatment, PTP1B inhibitor experiments, adipogenesis assays (Oil Red O staining), qPCR Gene Low 33333224
2021 RNF213 knockdown in bone marrow-derived mesenchymal stem cells upregulates TGF-β1 at both protein and mRNA levels but does not affect VEGF expression, suggesting RNF213 normally suppresses TGF-β1 in these cells. Lentivirus-mediated shRNA knockdown of RNF213 in rat BMSCs, RT-qPCR, ELISA for TGF-β1 and VEGF expression Experimental and therapeutic medicine Low 34373710
2022 RNF213 knockdown in HUVECs disrupts angiogenesis partly through downregulation of DNA replication/proliferation pathways. Endothelial cells sensitized to LPS-induced inflammation after RNF213 KD showed retarded migration and enhanced macrophage transmigration. RNF213 KD also caused extensive changes in mRNA splicing. In vascular smooth muscle cells, RNF213 KD altered cytoskeletal organization and contractility. RNF213 siRNA knockdown in HUVECs and vSMCs, transcriptome sequencing, splicing analysis, angiogenesis assays, LPS stimulation, macrophage transmigration assays, co-culture models Journal of cerebral blood flow and metabolism Medium 35754359
2023 RNF213 knockout in mice causes significant pericyte reduction, blood-brain barrier impairment in cortex, microglia activation, elevated proinflammatory cytokines, and reduced tight junction proteins (Occludin, Claudin-5, ZO-1). Rnf213 knockout mice, immunofluorescence for pericyte markers and tight junction proteins, cytokine quantification, BBB permeability assays Molecular neurobiology Medium 37438553
2020 RNF213 R4810K variant-expressing HUVECs show autophagy inhibition (increased SQSTM1/p62 and LC3-II) and impaired endothelial function (tube formation) after oxygen-glucose deprivation (OGD). Rapamycin and cilostazol as autophagy inducers restored RNF213 R4810K cell function, linking R4810K to autophagic impairment under ischemic stress. Transfection of RNF213 WT vs. R4810K in HUVECs, OGD model, immunoblotting for autophagy markers (p62, LC3-II), tube formation assay, transmission electron microscopy for autophagic vesicles, rapamycin/cilostazol pharmacological rescue Journal of cerebral blood flow and metabolism Medium 38573771
2021 RNF213 controls Listeria monocytogenes infection through regulation of DDAH1 transcription and production of nitric oxide (NO). RNF213 knockdown downregulates DDAH1, reducing NO production in macrophages from RNF213 KO mice, thereby impairing anti-Listeria defense. Mass spectrometry-based proteomics of RNF213-depleted cells, RT-qPCR validation, DDAH1 knockdown, NO production measurements, Listeria growth assays in RNF213 KO mouse macrophages Frontiers in cellular and infection microbiology Medium 34804992

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PloS one 569 21799892
2021 Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection. Nature 292 34012115
2012 Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology 249 22377813
2014 Genetics and Biomarkers of Moyamoya Disease: Significance of RNF213 as a Susceptibility Gene. Journal of stroke 132 24949311
2014 RNF213 rare variants in an ethnically diverse population with Moyamoya disease. Stroke 130 25278557
2015 Biochemical and Functional Characterization of RNF213 (Mysterin) R4810K, a Susceptibility Mutation of Moyamoya Disease, in Angiogenesis In Vitro and In Vivo. Journal of the American Heart Association 128 26126547
2015 Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells. Scientific reports 118 26278786
2020 Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism. eLife 110 32573437
2012 Molecular analysis of RNF213 gene for moyamoya disease in the Chinese Han population. PloS one 110 23110205
2016 PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia. Nature cell biology 107 27323329
2013 Downregulation of Securin by the variant RNF213 R4810K (rs112735431, G>A) reduces angiogenic activity of induced pluripotent stem cell-derived vascular endothelial cells from moyamoya patients. Biochemical and biophysical research communications 107 23850618
2015 A new horizon of moyamoya disease and associated health risks explored through RNF213. Environmental health and preventive medicine 103 26662949
2017 Rare RNF213 variants in the C-terminal region encompassing the RING-finger domain are associated with moyamoya angiopathy in Caucasians. European journal of human genetics : EJHG 96 28635953
2014 Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213: a susceptibility gene for moyamoya disease. Brain research 93 24440776
2014 Moyamoya disease-associated protein mysterin/RNF213 is a novel AAA+ ATPase, which dynamically changes its oligomeric state. Scientific reports 92 24658080
2019 Moyamoya Disease and Spectrums of RNF213 Vasculopathy. Translational stroke research 90 31650369
2015 Importance of RNF213 polymorphism on clinical features and long-term outcome in moyamoya disease. Journal of neurosurgery 85 26430847
2016 RNF213 as the major susceptibility gene for Chinese patients with moyamoya disease and its clinical relevance. Journal of neurosurgery 71 27128593
2021 RNF213 and GUCY1A3 in Moyamoya Disease: Key Regulators of Metabolism, Inflammation, and Vascular Stability. Frontiers in neurology 70 34381413
2020 Predictive role of heterozygous p.R4810K of RNF213 in the phenotype of Chinese moyamoya disease. Neurology 67 31949090
2014 Enhanced post-ischemic angiogenesis in mice lacking RNF213; a susceptibility gene for moyamoya disease. Brain research 63 25446450
2012 P.R4810K, a polymorphism of RNF213, the susceptibility gene for moyamoya disease, is associated with blood pressure. Environmental health and preventive medicine 61 22878964
2022 Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function. Stroke 53 34991336
2023 RNF213 loss-of-function promotes pathological angiogenesis in moyamoya disease via the Hippo pathway. Brain : a journal of neurology 52 37399508
2022 The bacterial effector GarD shields Chlamydia trachomatis inclusions from RNF213-mediated ubiquitylation and destruction. Cell host & microbe 52 36084633
2020 Moyamoya disease patient mutations in the RING domain of RNF213 reduce its ubiquitin ligase activity and enhance NFκB activation and apoptosis in an AAA+ domain-dependent manner. Biochemical and biophysical research communications 52 32139119
2016 RNF213 Is Associated with Intracranial Aneurysms in the French-Canadian Population. American journal of human genetics 49 27745834
2015 Temporal profile of the vascular anatomy evaluated by 9.4-tesla magnetic resonance angiography and histological analysis in mice with the R4859K mutation of RNF213, the susceptibility gene for moyamoya disease. Brain research 48 26315378
2013 The moyamoya disease susceptibility variant RNF213 R4810K (rs112735431) induces genomic instability by mitotic abnormality. Biochemical and biophysical research communications 48 23994138
2017 Rare variants of RNF213 and moyamoya/non-moyamoya intracranial artery stenosis/occlusion disease risk: a meta-analysis and systematic review. Environmental health and preventive medicine 47 29165161
2016 A Polymorphism in RNF213 Is a Susceptibility Gene for Intracranial Atherosclerosis. PloS one 47 27253870
2019 S-nitrosylation of E3 ubiquitin-protein ligase RNF213 alters non-canonical Wnt/Ca+2 signaling in the P301S mouse model of tauopathy. Translational psychiatry 46 30696811
2019 Prevalence of RNF213 p.R4810K Variant in Early-Onset Stroke With Intracranial Arterial Stenosis. Stroke 46 31060437
2013 Impacts and interactions of PDGFRB, MMP-3, TIMP-2, and RNF213 polymorphisms on the risk of Moyamoya disease in Han Chinese human subjects. Gene 46 23769926
2022 Interferon-Inducible E3 Ligase RNF213 Facilitates Host-Protective Linear and K63-Linked Ubiquitylation of Toxoplasma gondii Parasitophorous Vacuoles. mBio 41 36154443
2018 Rare variants in RNF213, a susceptibility gene for moyamoya disease, are found in patients with pulmonary hypertension and aggravate hypoxia-induced pulmonary hypertension in mice. Pulmonary circulation 41 29718794
2019 Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 40 31542298
2016 Whole genome sequencing of "Faecalibaculum rodentium" ALO17, isolated from C57BL/6J laboratory mouse feces. Gut pathogens 39 26877770
2014 Increased vascular MMP-9 in mice lacking RNF213: moyamoya disease susceptibility gene. Neuroreport 39 25383461
2022 Novel Multifaceted Roles for RNF213 Protein. International journal of molecular sciences 38 35562882
2013 Ablation of Rnf213 retards progression of diabetes in the Akita mouse. Biochemical and biophysical research communications 38 23410753
2013 RNF213 polymorphism and Moyamoya disease: A systematic review and meta-analysis. Neurology India 38 23466837
2018 Dysregulation of RNF213 promotes cerebral hypoperfusion. Scientific reports 37 29483617
2020 New insights into TNFα/PTP1B and PPARγ pathway through RNF213- a link between inflammation, obesity, insulin resistance, and Moyamoya disease. Gene 36 33333224
2016 RNF213 Rare Variants in Slovakian and Czech Moyamoya Disease Patients. PloS one 35 27736983
2021 The ring finger protein 213 gene (Rnf213) contributes to Rift Valley fever resistance in mice. Mammalian genome : official journal of the International Mammalian Genome Society 31 33420513
2016 Significant Association of the RNF213 p.R4810K Polymorphism with Quasi-Moyamoya Disease. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 31 27476341
2024 RNF213 promotes Treg cell differentiation by facilitating K63-linked ubiquitination and nuclear translocation of FOXO1. Nature communications 29 39013878
2016 Temporal profile of magnetic resonance angiography and decreased ratio of regulatory T cells after immunological adjuvant administration to mice lacking RNF213, a susceptibility gene for moyamoya disease. Brain research 29 26972532
2022 RNF213-Associated Vascular Disease: A Concept Unifying Various Vasculopathies. Life (Basel, Switzerland) 27 35455046
2016 Association between moyamoya syndrome and the RNF213 c.14576G>A variant in patients with neurofibromatosis Type 1. Journal of neurosurgery. Pediatrics 27 26849809
2023 Genome-wide and targeted CRISPR screens identify RNF213 as a mediator of interferon gamma-dependent pathogen restriction in human cells. Proceedings of the National Academy of Sciences of the United States of America 26 38147552
2017 Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with the variant RNF213-, ATIC- and TPM3-ALK fusions is characterized by copy number gain of the rearranged ALK gene. Haematologica 26 28659337
2018 RNF213 p.R4810K Polymorphism and the Risk of Moyamoya Disease, Intracranial Major Artery Stenosis/Occlusion, and Quasi-Moyamoya Disease: A Meta-Analysis. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 25 29752070
2015 Mutation genotypes of RNF213 gene from moyamoya patients in Taiwan. Journal of the neurological sciences 25 25956231
2018 Posterior circulation involvement and collateral flow pattern in moyamoya disease with the RNF213 polymorphism. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 24 30283986
2017 Genetic Analysis of Ring Finger Protein 213 (RNF213) c.14576G>A in Intracranial Atherosclerosis of the Anterior and Posterior Circulations. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 24 28797616
2020 Role of the RNF213 Variant in Vascular Outcomes in Patients With Intracranial Atherosclerosis. Journal of the American Heart Association 23 33356381
2015 Genetic Analysis of RNF213 c.14576G>A Variant in Nonatherosclerotic Quasi-Moyamoya Disease. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 23 25817623
2022 RNF213 loss of function reshapes vascular transcriptome and spliceosome leading to disrupted angiogenesis and aggravated vascular inflammatory responses. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 22 35754359
2022 RNF213 Loss-of-Function Promotes Angiogenesis of Cerebral Microvascular Endothelial Cells in a Cellular State Dependent Manner. Cells 22 36611871
2021 Absence of the RNF213 p.R4810K variant may indicate a severe form of pediatric moyamoya disease in Japanese patients. Journal of neurosurgery. Pediatrics 22 34624841
2017 RNF213 p.R4810K Variant and Intracranial Arterial Stenosis or Occlusion in Relatives of Patients with Moyamoya Disease. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 22 28506590
2011 C-MYC rearrangement may induce an aggressive phenotype in anaplastic lymphoma kinase positive anaplastic large cell lymphoma: Identification of a novel fusion gene ALO17/C-MYC. American journal of hematology 22 21080342
2022 MMD-associated RNF213 SNPs encode dominant-negative alleles that globally impair ubiquitylation. Life science alliance 21 35135845
2020 RNF213 gene mutation in circulating tumor DNA detected by targeted next-generation sequencing in the assisted discrimination of early-stage lung cancer from pulmonary nodules. Thoracic cancer 21 33200540
2024 RNF213 Variants, Vasospastic Angina, and Risk of Fatal Myocardial Infarction. JAMA cardiology 20 38888930
2023 RNF213 modulates γ-herpesvirus infection and reactivation via targeting the viral Replication and Transcription Activator. Proceedings of the National Academy of Sciences of the United States of America 20 36917666
2020 Prolonged/delayed cerebral hyperperfusion in adult patients with moyamoya disease with RNF213 gene polymorphism c.14576G>A (rs112735431) after superficial temporal artery-middle cerebral artery anastomosis. Journal of neurosurgery 20 33096527
2018 RNF213 Variant Diversity Predisposes Distinct Populations to Dissimilar Cerebrovascular Diseases. BioMed research international 20 30671466
2017 The Association of the RNF213 p.R4810K Polymorphism with Quasi-Moyamoya Disease and a Review of the Pertinent Literature. World neurosurgery 20 28063898
2015 Neuromuscular regulation in zebrafish by a large AAA+ ATPase/ubiquitin ligase, mysterin/RNF213. Scientific reports 20 26530008
2024 RNF213 in moyamoya disease: Genotype-phenotype association and the underlying mechanism. Chinese medical journal 19 38243713
2022 Association of RNF213 Variants With Periventricular Anastomosis in Moyamoya Disease. Stroke 19 35543128
2020 RNF213 suppresses carcinogenesis in glioblastoma by affecting MAPK/JNK signaling pathway. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 19 31953610
2019 Association of single nucleotide polymorphisms of MTHFR, TCN2, RNF213 with susceptibility to hypertension and blood pressure. Bioscience reports 19 31815282
2015 Frequency of the moyamoya-related RNF213 p.Arg4810Lys variant in 1,516 Korean individuals. BMC medical genetics 19 26590131
2021 UBC13 is an RNF213-associated E2 ubiquitin-conjugating enzyme, and Lysine 63-linked ubiquitination by the RNF213-UBC13 axis is responsible for angiogenic activity. FASEB bioAdvances 18 33842849
2017 The Role of RNF213 4810G>A and 4950G>A Variants in Patients with Moyamoya Disease in Korea. International journal of molecular sciences 18 29160859
2020 Loss of mitochondrial ClpP, Lonp1, and Tfam triggers transcriptional induction of Rnf213, a susceptibility factor for moyamoya disease. Neurogenetics 17 32342250
2020 Mutations of RNF213 are responsible for sporadic cerebral cavernous malformation and lead to a mulberry-like cluster in zebrafish. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 16 32248732
2019 Rare RNF213 variants and the risk of intracranial artery stenosis/occlusion disease in Chinese population: a case-control study. BMC medical genetics 16 30925911
2012 Identification of a novel gene fusion RNF213‑SLC26A11 in chronic myeloid leukemia by RNA-Seq. Molecular medicine reports 16 23151810
2017 Frequency and significance of rare RNF213 variants in patients with adult moyamoya disease. PloS one 15 28617845
2015 Transient middle cerebral artery occlusion in mice induces neuronal expression of RNF213, a susceptibility gene for moyamoya disease. Brain research 15 26556774
2022 Impact of RNF213 c.14576G>A Variant on the Development of Direct and Indirect Revascularization in Pediatric Moyamoya Disease. Cerebrovascular diseases (Basel, Switzerland) 14 36063804
2021 RNF213 p.R4810K Variant Carriers with Intracranial Arterial Stenosis Have a Low Atherosclerotic Burden. Journal of atherosclerosis and thrombosis 14 34955493
2019 The Impact of Moyamoya Disease and RNF213 Mutations on the Spectrum of Plasma Protein and MicroRNA. Journal of clinical medicine 14 31658621
2019 A histopathological report of a 16-year-old male with peripheral pulmonary artery stenosis and Moyamoya disease with a homozygous RNF213 mutation. Respiratory medicine case reports 14 31908915
2016 The association between the ring finger protein 213 (RNF213) polymorphisms and moyamoya disease susceptibility: a meta-analysis based on case-control studies. Molecular genetics and genomics : MGG 14 26847828
2023 De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke. Genetics in medicine : official journal of the American College of Medical Genetics 13 37924258
2019 Genetic analysis of ring finger protein 213 (RNF213) c.14576G>A polymorphism in patients with vertebral artery dissection: a comparative study with moyamoya disease. Neurological research 13 31064275
2024 RNF213 variant and autophagic impairment: A pivotal link to endothelial dysfunction in moyamoya disease. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 12 38573771
2023 Rnf-213 Knockout Induces Pericyte Reduction and Blood-Brain Barrier Impairment in Mouse. Molecular neurobiology 12 37438553
2023 The emerging role of E3 ubiquitin ligase RNF213 as an antimicrobial host determinant. Frontiers in cellular and infection microbiology 12 37655297
2022 RNF213 R4810K Variant in Suspected Unilateral Moyamoya Disease Predicts Contralateral Progression. Journal of the American Heart Association 12 35876407
2021 RNF213 gene silencing upregulates transforming growth factor β1 expression in bone marrow-derived mesenchymal stem cells and is involved in the onset of Moyamoya disease. Experimental and therapeutic medicine 12 34373710
2021 Proteome Profiling of RNF213 Depleted Cells Reveals Nitric Oxide Regulator DDAH1 Antilisterial Activity. Frontiers in cellular and infection microbiology 12 34804992
2017 Transient Global Cerebral Ischemia Induces RNF213, a Moyamoya Disease Susceptibility Gene, in Vulnerable Neurons of the Rat Hippocampus CA1 Subregion and Ischemic Cortex. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 12 28734662
2016 Association between the rs112735431 polymorphism of the RNF213 gene and moyamoya disease: A case-control study and meta-analysis. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 12 27515544

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