Affinage

RNF128

E3 ubiquitin-protein ligase RNF128 · UniProt Q8TEB7

Length
428 aa
Mass
46.5 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF128 (GRAIL) is a type I transmembrane RING-finger E3 ubiquitin ligase that resides in the endocytic pathway and acts as a central negative regulator of T cell activation, immune tolerance, and inflammatory signaling (PMID:12705856, PMID:19805371). Its defining architecture separates substrate recognition from catalysis: a luminal/extracellular protease-associated (PA) domain captures the ectodomains of transmembrane substrates while the cytosolic RING domain recruits E2 enzymes and transfers ubiquitin onto cytosolic lysines, the first single-subunit E3 described with such a membrane-separated arrangement (PMID:18713730). Through this mechanism GRAIL downregulates a panel of T cell surface and signaling proteins—tetraspanins CD151/CD81 (PMID:18713730), the costimulatory ligand CD40L (PMID:18641297), CD83 (PMID:19542455), TCR-CD3 complex components (PMID:20493730), and IL-21R (PMID:28798332)—and degrades intracellular substrates including STAT6 to limit Th2 differentiation (PMID:25145352) and the actin regulators Arp2/3-5 and coronin 1A to restrain immunological-synapse formation in anergic T cells (PMID:22016387). Genetic deletion in mice abolishes T cell anergy and oral tolerance and causes CD4 T cell hyperactivation, while GRAIL is required for normal regulatory T cell suppressive function (PMID:19805371, PMID:20493730). GRAIL protein stability is set by an IL-2/CD28–Akt–mTOR axis that induces Otubain-1 translation to destabilize GRAIL during activation, with the otubain 1-ARF1 isoform conversely stabilizing it to maintain anergy (PMID:14661020, PMID:19414743). Beyond degradative K48 ubiquitination, RNF128 also catalyzes activating K63-linked ubiquitination of TBK1 to drive IRF3-dependent IFN-β antiviral responses (PMID:27776110) and K63-linked ubiquitination of scavenger receptor SRB1 to promote its Rab11-dependent recycling in macrophages (PMID:40038329). The same enzymatic logic operates outside immunity, where RNF128 ubiquitinates IL-6Rα and gp130 to suppress IL-6–STAT3 signaling and colitis-associated tumorigenesis (PMID:38964734), targets PPARγ and Sirt1 in adipogenesis and hepatic lipid metabolism (PMID:29743578, PMID:33771967), and degrades TLR4 and MPO to restrain lung inflammation (PMID:37344492). In epithelial cancers, RNF128 controls p53 fate in an isoform-dependent manner: the active isoform 2, paired with the E2 UBE2D3, degrades mutant p53, whereas the N-glycosylated isoform 1 is catalytically impaired and stabilizes it, a switch that accompanies Barrett's esophagus progression to adenocarcinoma (PMID:23370271, PMID:31715145, PMID:34416429).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Established RNF128/GRAIL as a transmembrane E3 ligase whose catalytic activity and endocytic trafficking are jointly required to restrain T cell cytokine production, defining its core role as a brake on T cell activation.

    Evidence In vitro ubiquitination plus retroviral transduction of T cell hybridomas with cytokine readouts; companion study defining Otubain-1 control of GRAIL stability

    PMID:12705856 PMID:14661020

    Open questions at the time
    • Direct transmembrane substrates not yet identified at this stage
    • Mechanism linking endocytic trafficking to cytokine transcription unresolved
  2. 2007 Medium

    Linked GRAIL to the regulatory T cell program by showing its enrichment in Tregs and sufficiency to confer a suppressive phenotype, framing GRAIL as more than a generic activation brake.

    Evidence Quantitative RT-PCR and retroviral gain-of-function with functional suppression assay in a T cell line

    PMID:17259178

    Open questions at the time
    • Foxp3-independent mechanism of suppression unexplained
    • Endogenous requirement not tested (gain-of-function only)
  3. 2008 High

    Resolved the biochemical logic of GRAIL by demonstrating that the luminal PA domain captures substrate ectodomains while the cytosolic RING catalyzes K48 ubiquitination, the first membrane-separated single-subunit E3 mechanism, and identified tetraspanins and CD40L as substrates.

    Evidence Yeast two-hybrid, co-IP, in vitro ubiquitination, and surface-downregulation flow cytometry

    PMID:18641297 PMID:18713730

    Open questions at the time
    • Structural basis of PA-domain substrate selectivity not defined
    • Full substrate repertoire unknown
  4. 2009 High

    Genetic deletion proved GRAIL is required in vivo for T cell anergy and oral tolerance, and defined the IL-2/CD28-Akt-mTOR-Otubain-1 axis that times GRAIL degradation, while extending substrates to CD83.

    Evidence Grail knockout mice with proliferation, tolerance and autoimmunity models; pharmacological mTOR pathway dissection; CD83 lysine mutagenesis

    PMID:19414743 PMID:19542455 PMID:19805371

    Open questions at the time
    • Mechanism connecting GRAIL loss to elevated baseline ERK1/2 not established
    • How mTOR selectively translates Otubain-1 mRNA unresolved
  5. 2010 High

    Identified the TCR-CD3 complex as a GRAIL substrate and tied GRAIL to Treg suppressive function, mechanistically connecting receptor downregulation to NFATc1 control and Th17 restraint.

    Evidence Co-IP for CD3 ubiquitination and GRAIL-deficient mouse autoimmune and Treg suppression assays

    PMID:20493730

    Open questions at the time
    • Which CD3 chain lysines are modified not mapped
    • Causal link between TCR downregulation and Th17 program incomplete
  6. 2011 Medium

    Extended GRAIL's reach to the actin cytoskeleton by showing it ubiquitinates Arp2/3-5 and coronin 1A, explaining impaired immunological-synapse F-actin in anergic T cells.

    Evidence In vitro ubiquitination with K48/K63 linkage analysis and confocal imaging of actin structures

    PMID:22016387

    Open questions at the time
    • How a transmembrane/endocytic E3 accesses cytosolic actin regulators not explained
    • Single-lab finding
  7. 2013 Medium

    Showed GRAIL targets p53 for degradation in a Mdm2-like negative feedback loop, opening a non-immune, tumor-relevant function in apoptosis and cell-cycle control.

    Evidence Co-IP, ubiquitination assay, and apoptosis/cell-cycle assays after overexpression and knockdown in cultured cells

    PMID:23370271

    Open questions at the time
    • Isoform-dependence not yet appreciated here
    • Wild-type vs mutant p53 specificity unaddressed
  8. 2014 High

    Demonstrated GRAIL degrades STAT6 to control Th2 development, embedding GRAIL in a STAT6/GATA3 transcriptional feedback loop relevant to allergic asthma.

    Evidence Co-IP, ubiquitination, Grail-deficient mice, in vitro Th2 differentiation, asthma model, and promoter binding assays

    PMID:25145352

    Open questions at the time
    • STAT6 ubiquitination sites not mapped
    • Cytosolic-substrate access mechanism unresolved
  9. 2016 High

    Revealed a non-degradative mode in which RNF128 catalyzes K63-linked ubiquitination of TBK1 to activate IRF3 and IFN-β, establishing RNF128 as a positive regulator of antiviral innate immunity.

    Evidence Co-IP through the PA domain, in vitro ubiquitination, and RNF128-deficient cells/mice in viral infection models

    PMID:27776110

    Open questions at the time
    • How linkage specificity (K63 vs K48) is selected per substrate unknown
    • TBK1 ubiquitination sites not defined
  10. 2017 High

    Identified IL-21R as a GRAIL substrate in CD8+ T cells, showing GRAIL loss boosts IL-21 signaling and antitumor T cell function.

    Evidence Co-IP, ubiquitination assay, Grail-deficient mice, and transplantable lymphoma and adoptive-transfer therapy models

    PMID:28798332

    Open questions at the time
    • IL-21R ubiquitination sites not mapped
    • Relative contribution among multiple T cell substrates unquantified
  11. 2018 Medium

    Expanded GRAIL function to metabolism by showing it degrades PPARγ to regulate adipogenesis and body weight, indicating roles beyond immune cells.

    Evidence Co-IP, ubiquitination assay, Grail KO mice on high-fat diet with glucose/insulin tolerance and in vitro adipogenesis assays

    PMID:29743578

    Open questions at the time
    • Paradoxical reduction of PPARγ by both knockdown and overexpression unexplained
    • Single lab
  12. 2019 High

    Resolved the p53 link mechanistically as isoform-dependent: catalytically active isoform 2 degrades mutant p53 while N-glycosylated isoform 1 stabilizes it, a switch tracking Barrett's progression and additional cancer-promoting substrates (CD44, cortactin) and EGFR/MAPK signaling.

    Evidence Isoform-specific constructs, ubiquitination assays, glycosylation/proline mutagenesis, xenografts, and co-IP across esophageal and melanoma models

    PMID:30832692 PMID:31216681 PMID:31715145

    Open questions at the time
    • Tissue-specific regulation of isoform balance incompletely defined
    • Reconciliation of tumor-suppressive vs tumor-promoting roles across cancers unresolved
  13. 2021 High

    Defined the E2-E3 pairing controlling p53 fate (Iso2-UBE2D3 active vs Iso1-UBE2D1 inactive) and broadened substrates to Sirt1 in hepatic lipid metabolism and β-catenin in colorectal cancer.

    Evidence Single-cell RNA-seq, co-IP, ubiquitination with residue mutagenesis, clonogenic assays, and Grail KO/overexpression metabolic and cancer models

    PMID:33771967 PMID:34416429 PMID:35035697

    Open questions at the time
    • Why E2 partner switching occurs during disease progression unknown
    • β-catenin regulation supported only by limited mechanistic detail
  14. 2024 High

    Mapped specific degradative ubiquitination of IL-6Rα and gp130 with defined lysines, showing RNF128 suppresses IL-6-STAT3 signaling, colitis, and colorectal tumorigenesis.

    Evidence Co-IP, site-directed lysine mutagenesis, ubiquitination assay, and RNF128-deficient DSS colitis and AOM/DSS CRC models

    PMID:38964734

    Open questions at the time
    • Whether IL-6Rα/gp130 are captured via the PA domain not directly tested
    • Crosstalk with the EGFR/MAPK cancer-promoting axis unresolved
  15. 2025 High

    Established a recycling-promoting K63 function in macrophages, where RNF128 ubiquitinates SRB1 at K478 to block lysosomal degradation and drive Rab11 endosome recycling, aggravating atherosclerosis.

    Evidence Co-IP, K63-linkage-specific ubiquitination, K478 mutagenesis, macrophage-specific KO in ApoE/LDLR-deficient mice, and scRNA-seq

    PMID:40038329

    Open questions at the time
    • Determinants selecting K63-recycling vs K48-degradative outcomes per substrate unknown
    • Generalizability of recycling function to other receptors untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what governs RNF128's choice of ubiquitin linkage type and substrate fate (degradation, recycling, or activation) across its diverse substrate panel, and how a transmembrane endocytic ligase engages cytosolic substrates such as p53, STAT6, and actin regulators.
  • No unifying structural model of PA-domain vs cytosolic substrate engagement
  • Linkage-determining cofactors/E2 selection rules undefined
  • Context determining tumor-suppressive vs tumor-promoting output unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016874 ligase activity 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 2
Pathway
R-HSA-168256 Immune System 5 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 3
Partners
CD40LCD83IL21RIL6RSCARB1STAT6TBK1TP53

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 GRAIL (RNF128) is a type I transmembrane E3 ubiquitin ligase that localizes to the endocytic pathway and limits activation-induced IL-2 and IL-4 cytokine production in T cells; both E3 ubiquitin ligase activity and intact endocytic trafficking are required for cytokine transcriptional regulation. In vitro ubiquitination assay, retroviral transduction of T cell hybridomas, cytokine production assays, subcellular localization studies Immunity High 12705856
2003 GRAIL is associated with and regulated by two isoforms of the deubiquitinase otubain 1: otubain 1 destabilizes GRAIL and promotes T cell proliferation and IL-2 production, whereas the alternatively spliced isoform otubain 1-ARF1 stabilizes GRAIL and maintains CD4 T cell anergy. These two proteins have opposing epistatic functions in controlling GRAIL stability. Retroviral transduction in bone marrow chimeric mice, flow cytometry for proliferation, IL-2 production assays, Western blot for GRAIL protein levels Nature immunology High 14661020
2008 GRAIL uses its luminal protease-associated (PA) domain to capture the extracellular/luminal portions of transmembrane substrates (tetraspanins CD151 and CD81), and its cytosolic RING finger domain then catalyzes K48-linked ubiquitination of cytosolic lysine residues on those substrates, promoting their proteasomal degradation and cell surface downregulation. GRAIL is identified as the first single-subunit E3 ligase with a membrane-separated substrate-binding domain and E2-recruitment domain. Yeast two-hybrid screen for PA domain interactors, co-immunoprecipitation, in vitro ubiquitination assay, flow cytometry for cell surface levels, proteasome inhibitor experiments The Journal of biological chemistry High 18713730
2008 GRAIL ubiquitinates the costimulatory molecule CD40L on CD4 T cells: using its luminal PA domain it binds the extracellular portion of CD40L, and its intracellular RING finger transfers ubiquitin to the small cytosolic tail of CD40L, leading to CD40L downregulation. Expression of GRAIL in bone marrow chimeric mice was associated with diminished lymphoid follicle formation. Co-immunoprecipitation, retroviral transduction, flow cytometry for CD40L surface expression, bone marrow chimera experiments Journal of immunology High 18641297
2009 GRAIL ubiquitinates and promotes proteasomal degradation of CD83 on CD4 T cells, dependent on an intact PA domain (extracellular) and active RING domain (cytosolic); ubiquitination of lysine residues K168 and K183 (but not K192) in the cytoplasmic domain of CD83 is required. GRAIL-mediated CD83 downregulation reduces a CD4 T cell costimulatory signal. Retroviral transduction, RNAi knockdown, site-directed mutagenesis of CD83 lysines, flow cytometry, co-immunoprecipitation, 26S proteasome inhibitor experiments Journal of immunology High 19542455
2009 Genetic deletion of Grail in mice leads to loss of T cell anergy, hyperactivation of primary CD4+ T cells (hyperproliferation, cytokine hypersecretion, costimulation-independent effector generation), and abrogation of oral tolerance; Grail-deficient T cells show elevated baseline ERK1/2 but unchanged ZAP70, PLCγ1, p38, or JNK levels. Grail knockout mouse generation, in vitro proliferation and cytokine assays, oral tolerance models (OT-II transgenic mice), experimental allergic encephalitis, Western blot for signaling molecules Proceedings of the National Academy of Sciences of the United States of America High 19805371
2009 GRAIL expression in naive CD4 T cells is maintained during quiescence; CD28 costimulation leads to IL-2 production, which activates the Akt-mTOR pathway, inducing selective translation of Otubain-1 mRNA, causing GRAIL degradation and allowing T cell proliferation. CTLA4-Ig, rapamycin, and anti-IL-2 all block mTOR, maintain GRAIL, and inhibit proliferation. In vitro T cell activation assays, rapamycin/CTLA4-Ig/anti-IL-2 treatment, Western blot for GRAIL and Otubain-1, proliferation assays Journal of immunology High 19414743
2010 GRAIL mediates ubiquitination and degradation of TCR-CD3 complex components in naive and regulatory T cells; GRAIL-deficient T cells are less efficient at downregulating TCR-CD3 expression after activation and exhibit increased NFATc1 expression. GRAIL-deficient Treg cells show reduced suppressive function associated with increased Th17-related gene expression. GRAIL-deficient mouse analysis, autoimmune disease models, co-immunoprecipitation for CD3 ubiquitinylation, Western blot for NFATc1, flow cytometry, Treg suppression assays Immunity High 20493730
2011 GRAIL ubiquitinates Arp2/3 subunit 5 (Arp2/3-5) and coronin 1A via K48 and K63 linkages, leading to their degradation and impairing lamellipodium formation and F-actin accumulation at the immunological synapse in anergic T cells. In vitro ubiquitination assays, Western blot for substrate levels in anergic/GRAIL-overexpressing T cells, confocal microscopy for actin structures The Journal of biological chemistry Medium 22016387
2013 GRAIL physically interacts with the N-terminus of p53, targets it for ubiquitination and degradation, and modulates p53 transactivation activity through a negative feedback loop similar to Mdm2. Overexpression of GRAIL inhibits p53-induced apoptosis by increasing p53 degradation, whereas cells lacking GRAIL fail to undergo p53-dependent apoptosis and undergo p21-dependent G1 arrest instead. Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown in cultured cells, apoptosis and cell cycle assays Cell death and differentiation Medium 23370271
2014 Grail controls Th2 cell development by interacting with STAT6 and targeting it for ubiquitination and degradation; Grail deficiency increases STAT6 and IL-4 receptor α expression, leading to enhanced Th2 effector cytokine production and increased susceptibility to allergic asthma. STAT6 and GATA3 were found to bind the Grail promoter and transactivate it, forming a negative feedback loop. Co-immunoprecipitation, ubiquitination assay, Grail-deficient mice, in vitro Th2 differentiation, allergic asthma model, promoter binding assays Nature communications High 25145352
2016 RNF128 directly interacts with TBK1 through its protease-associated (PA) domain and catalyzes K63-linked polyubiquitination of TBK1, leading to TBK1 activation, IRF3 activation, and IFN-β production. RNF128 deficiency attenuates innate antiviral immune responses to RNA and DNA viruses in vitro and in vivo. Co-immunoprecipitation, in vitro ubiquitination assay, RNF128-deficient cells and mice, viral infection models, IRF3 and IFN-β reporter assays Nature immunology High 27776110
2017 Grail promotes IL-21 receptor (IL-21R) ubiquitination and degradation in CD8+ T cells; Grail deficiency increases IL-21R expression and enhances IL-21 signaling, conferring improved anti-tumor CD8+ T cell function and long-term tumor control. Co-immunoprecipitation, ubiquitination assay, Grail-deficient mice, transplanted lymphoma tumor models, therapeutic T cell transfer Nature communications High 28798332
2018 Grail interacts with PPARγ, targeting it for ubiquitination and degradation, thereby regulating adipogenesis; both Grail knockdown and overexpression reduce PPARγ expression and inhibit adipogenesis. Grail KO mice have lower adipose mass and body weight and improved glucose and insulin tolerance on high-fat diet. Co-immunoprecipitation, ubiquitination assay, Grail KO mice, high-fat diet model, glucose/insulin tolerance tests, in vitro adipogenesis assays Cell death & disease Medium 29743578
2019 RNF128 ubiquitinates CD44 and cortactin (CTTN), leading to their degradation; loss of RNF128 stabilizes CD44 and CTTN, activating Wnt/β-catenin signaling, increasing c-Myc and CD44 transcription, and promoting EMT and stemness in melanoma cells. Co-immunoprecipitation, ubiquitination assay, RNF128 knockdown/overexpression functional assays, Western blot Journal of hematology & oncology Medium 30832692
2019 RNF128 isoform 2 (Iso2) is a potent E3 ubiquitin ligase that degrades mutant p53; isoform 1 (Iso1) is heavily N-glycosylated with limited ligase activity, and it stabilizes mutant p53 (acting as a dominant negative-like form). In Barrett's esophagus progression to adenocarcinoma, Iso2 decreases while Iso1 increases. Iso2 is itself degraded via ATM/GSK3β-mediated phosphorylation and β-TrCP1-SCF ubiquitin ligase complex. Simvastatin degrades Iso1 and slows EAC xenograft growth. Co-immunoprecipitation, ubiquitination ligase assay, siRNA knockdown, isoform-specific expression constructs, xenograft mouse model, immunoblot for p53 and RNF128 Gastroenterology High 31715145
2019 RNF128 promotes invasion and metastasis of esophageal squamous cell carcinoma (ESCC) through activation of the EGFR/MAPK/MMP-2 pathway; RNF128 interacts with p53, and p53 interacts with EGFR to activate this cascade. Inhibition of EGFR, MEK/ERK, or MMP-2 reverses RNF128-enhanced ESCC progression. Co-immunoprecipitation, transwell invasion assays, xenograft mouse model, Western blot, pathway inhibitor experiments Cancers Medium 31216681
2020 RNF128 promotes HCC progression by activating the EGFR/MEK/ERK signaling pathway; RNF128 overexpression enhances hepatoma cell proliferation, migration, invasion, and apoptotic resistance in vitro and in vivo, which is partially reversed by the EGFR inhibitor gefitinib. Knockdown and overexpression assays, xenograft mouse model, Western blot for pathway activation, EGFR inhibitor treatment OncoTargets and therapy Low 33116595
2021 Grail interacts with sirtuin 1 (Sirt1) and promotes hepatic lipid accumulation in NAFLD; Grail ablation alleviates high-fat diet-induced hepatic fat accumulation, while Grail overexpression exacerbates it. Co-immunoprecipitation, Grail KO mice on high-fat diet, in vitro lipid accumulation assays, gene expression analysis Cell death & disease Medium 33771967
2021 RNF128 Iso2-UBCH5C (UBE2D3) complex is the p53-degrading E2-E3 pair in normal esophageal cells; during Barrett's progression, loss of UBE2D3 and rise of UBE2D1 (UBCH5A) paired with Iso1 forms an inactive E2-E3 complex that stabilizes mutant p53. Glycosylation of Iso1 at N48, N59, N101 blocks its ligase activity, and proline residues P54/P105 are required for p53 polyubiquitinating ability. Single-cell RNA sequencing, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis of Iso1 glycosylation and proline residues, clonogenic survival assays Cellular and molecular gastroenterology and hepatology High 34416429
2021 RNF128 regulates β-catenin ubiquitination and inhibits Wnt/β-catenin signaling in colorectal cancer cells, suppressing proliferation and metastasis. Co-immunoprecipitation, Western blot for β-catenin ubiquitination, RNF128 knockdown/overexpression functional assays American journal of translational research Low 35035697
2023 RNF128 binds myeloperoxidase (MPO) and reduces its levels and activity, inhibiting neutrophil activation; RNF128 also interacts with TLR4 in alveolar macrophages, targeting it for degradation and inhibiting NF-κB activation and pro-inflammatory cytokine production. RNF128 deficiency exacerbates LPS-induced acute lung injury, while AAV9-mediated RNF128 overexpression alleviates lung damage. Co-immunoprecipitation, RNF128-deficient mice, LPS-induced ALI model, AAV9 overexpression, MPO activity assay, NF-κB activation assays Cell death & disease Medium 37344492
2024 RNF128 interacts with IL-6 receptor α subunit (IL-6Rα) and gp130, mediating their lysosomal degradation through K48-linked polyubiquitination; specific ubiquitination sites are K398/K401 on IL-6Rα and K718/K816/K866 on gp130. This inhibits IL-6-STAT3 signaling and attenuates colitis and colorectal tumorigenesis. Co-immunoprecipitation, site-directed mutagenesis of ubiquitination sites, ubiquitination assay, RNF128-deficient mouse models (DSS colitis, AOM/DSS CRC), in vitro proliferation assays, STAT3 activation assays Journal of advanced research High 38964734
2025 RNF128 directly binds scavenger receptor B1 (SRB1) in macrophages and catalyzes K63-linked polyubiquitination at lysine K478 on SRB1's cytoplasmic C-terminus, preventing lysosomal degradation of SRB1 and promoting its Rab11-assisted endosome recycling to the cell membrane; this enhances oxLDL-induced foam cell formation and inflammatory response, aggravating atherosclerosis. Co-immunoprecipitation, ubiquitination assay with K63-linkage specificity, site-directed mutagenesis of K478, macrophage-specific RNF128 ablation in ApoE/LDLR-deficient mice, single-cell RNA sequencing, Rab11 interaction studies Nature communications High 40038329
2007 GRAIL is expressed at ~10-fold higher mRNA levels in naturally occurring CD4+CD25+ T regulatory cells than in naive CD25- T cells; forced retroviral expression of GRAIL in a T cell line is sufficient to convert it to a regulatory phenotype in the absence of detectable Foxp3. Quantitative RT-PCR, flow cytometry, retroviral transduction with functional suppression assay The Journal of biological chemistry Medium 17259178

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity 239 12705856
2006 75 years of opioid research: the exciting but vain quest for the Holy Grail. British journal of pharmacology 231 16402099
2001 Markers for the lymphatic endothelium: in search of the holy grail? Microscopy research and technique 165 11596151
2016 E3 ubiquitin ligase RNF128 promotes innate antiviral immunity through K63-linked ubiquitination of TBK1. Nature immunology 163 27776110
2008 Targeting the leukemic stem cell: the Holy Grail of leukemia therapy. Leukemia 160 18800146
2016 Attacking hepatitis B virus cccDNA--The holy grail to hepatitis B cure. Journal of hepatology 152 27084036
2002 Opioid tolerance-in search of the holy grail. Cell 145 11893329
2019 Downregulation of RNF128 activates Wnt/β-catenin signaling to induce cellular EMT and stemness via CD44 and CTTN ubiquitination in melanoma. Journal of hematology & oncology 144 30832692
1996 T-cell responses to autoantigens in IDDM. The search for the Holy Grail. Diabetes 141 8772714
2003 Two isoforms of otubain 1 regulate T cell anergy via GRAIL. Nature immunology 135 14661020
2010 The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation. Immunity 125 20493730
1993 Pharmacological approaches to the prevention of restenosis following angioplasty. The search for the Holy Grail? (Part I). Drugs 124 7691506
2005 Single-molecule fluorescence detection in microfluidic channels--the Holy Grail in muTAS? Analytical and bioanalytical chemistry 111 16075229
2021 Akkermansia muciniphila: is it the Holy Grail for ameliorating metabolic diseases? Gut microbes 108 34674606
1993 THE HOLY GRAIL OF THE PERFECT CHARACTER: THE CLADISTIC TREATMENT OF MORPHOMETRIC DATA. Cladistics : the international journal of the Willi Hennig Society 104 34929957
2017 The Holy Grail of Orthopedic Surgery: Mesenchymal Stem Cells-Their Current Uses and Potential Applications. Stem cells international 92 28698718
2006 Animal models of osteoarthritis: lessons learned while seeking the "Holy Grail". Current opinion in rheumatology 90 16896297
2012 Laboratory diagnosis of acute pancreatitis: in search of the Holy Grail. Critical reviews in clinical laboratory sciences 89 22339380
2012 Anxioselective anxiolytics: on a quest for the Holy Grail. Trends in pharmacological sciences 84 22981367
2004 Chronic inflammation in peritoneal dialysis: the search for the holy grail? Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis 80 15335146
2001 "Other" breast cancer susceptibility genes: searching for more holy grail. Human molecular genetics 72 11257104
2011 In search of the Holy Grail: Folate-targeted nanoparticles for cancer therapy. Biochemical pharmacology 71 21300030
2009 Th2 cell hyporesponsiveness during chronic murine schistosomiasis is cell intrinsic and linked to GRAIL expression. The Journal of clinical investigation 71 19258704
2009 E3 ubiquitin ligase GRAIL controls primary T cell activation and oral tolerance. Proceedings of the National Academy of Sciences of the United States of America 69 19805371
2005 Are plant DNA barcodes a search for the Holy Grail? Trends in ecology & evolution 66 16701459
2014 Epigenetics, the holy grail in the pathogenesis of systemic sclerosis. Rheumatology (Oxford, England) 64 24740406
2008 The single subunit transmembrane E3 ligase gene related to anergy in lymphocytes (GRAIL) captures and then ubiquitinates transmembrane proteins across the cell membrane. The Journal of biological chemistry 60 18713730
2007 GRAIL is up-regulated in CD4+ CD25+ T regulatory cells and is sufficient for conversion of T cells to a regulatory phenotype. The Journal of biological chemistry 59 17259178
1993 Pharmacological approaches to the prevention of restenosis following angioplasty. The search for the Holy Grail? (Part II). Drugs 58 7691514
2007 Chemical modification of therapeutic drugs or drug vector systems to achieve targeted therapy: looking for the grail. Medicinal research reviews 56 17022028
2019 Pharmacomicrobiomics: The Holy Grail to Variability in Drug Response? Clinical pharmacology and therapeutics 55 30937887
2010 GRAIL: a unique mediator of CD4 T-lymphocyte unresponsiveness. The FEBS journal 54 21078124
2004 After the holy grail: establishing a molecular basis for Mammalian olfaction. Cell 53 14744441
2022 Imaging Synaptic Density: The Next Holy Grail of Neuroscience? Frontiers in neuroscience 52 35401097
1994 Recognizing exons in genomic sequence using GRAIL II. Genetic engineering 51 7765200
2010 Is interleukin-6 receptor blockade the Holy Grail for inflammatory diseases? Clinical pharmacology and therapeutics 49 20305672
2014 Grail controls Th2 cell development by targeting STAT6 for degradation. Nature communications 48 25145352
2013 RNA-dependent DNA endonuclease Cas9 of the CRISPR system: Holy Grail of genome editing? Trends in microbiology 48 24095303
2008 Cutting edge: The transmembrane E3 ligase GRAIL ubiquitinates the costimulatory molecule CD40 ligand during the induction of T cell anergy. Journal of immunology (Baltimore, Md. : 1950) 48 18641297
2000 Treatment of acute (Adult) respiratory distress syndrome. The holy grail of surfactant therapy. Biology of the neonate 41 10828579
2019 RNF128 Promotes Invasion and Metastasis Via the EGFR/MAPK/MMP-2 Pathway in Esophageal Squamous Cell Carcinoma. Cancers 39 31216681
2009 Naive CD4 t cell proliferation is controlled by mammalian target of rapamycin regulation of GRAIL expression. Journal of immunology (Baltimore, Md. : 1950) 39 19414743
2013 Grail as a molecular determinant for the functions of the tumor suppressor p53 in tumorigenesis. Cell death and differentiation 37 23370271
2009 The transmembrane E3 ligase GRAIL ubiquitinates and degrades CD83 on CD4 T cells. Journal of immunology (Baltimore, Md. : 1950) 37 19542455
2015 Mannose-Capped Lipoarabinomannan from Mycobacterium tuberculosis Induces CD4+ T Cell Anergy via GRAIL. Journal of immunology (Baltimore, Md. : 1950) 34 26667170
2023 RNF128 regulates neutrophil infiltration and myeloperoxidase functions to prevent acute lung injury. Cell death & disease 33 37344492
2018 Combinatorial Screening of Nanoclay-Reinforced Hydrogels: A Glimpse of the "Holy Grail" in Orthopedic Stem Cell Therapy? ACS applied materials & interfaces 33 30226363
2021 Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm. Diagnostics (Basel, Switzerland) 32 34943407
1998 Glycobiology and proteomics: is mass spectrometry the Holy Grail? Electrophoresis 31 9740047
2013 Biomarkers in TAA-the Holy Grail. Progress in cardiovascular diseases 30 23993244
2014 Upregulation of GRAIL is associated with impaired CD4 T cell proliferation in sepsis. Journal of immunology (Baltimore, Md. : 1950) 29 24477910
2022 Fenofibrate for COVID-19 and related complications as an approach to improve treatment outcomes: the missed key for Holy Grail. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 28 35941297
2021 E3 ubiquitin ligase Grail promotes hepatic steatosis through Sirt1 inhibition. Cell death & disease 28 33771967
2017 Absence of Grail promotes CD8+ T cell anti-tumour activity. Nature communications 27 28798332
2022 In Search of the Holy Grail: Toward a Unified Hypothesis on Mitochondrial Dysfunction in Age-Related Diseases. Cells 26 35741033
2022 Dipyridamole and adenosinergic pathway in Covid-19: a juice or holy grail. The Egyptian journal of medical human genetics 25 37521831
2015 Reaching for the Holy Grail: insights from infection/cure models on the prospects for vaccines for Trypanosoma cruzi infection. Memorias do Instituto Oswaldo Cruz 25 25946159
2002 The pH of the Plasmodium falciparum digestive vacuole: holy grail or dead-end trail? Trends in parasitology 25 12377594
2020 In Search of Reward Deficiency Syndrome (RDS)-free Controls: The "Holy Grail" in Genetic Addiction Risk Testing. Current psychopharmacology 24 32432025
2017 GRAIL and Otubain-1 are Related to T Cell Hyporesponsiveness during Trypanosoma cruzi Infection. PLoS neglected tropical diseases 24 28114324
2023 The role of anti-diabetic drugs in NAFLD. Have we found the Holy Grail? A narrative review. European journal of clinical pharmacology 23 37938366
2018 Cancer-associated thrombosis: The search for the holy grail continues. Research and practice in thrombosis and haemostasis 23 30349879
2018 Three-Dimensional Organoids in Cancer Research: The Search for the Holy Grail of Preclinical Cancer Modeling. Omics : a journal of integrative biology 23 30571609
2025 Insights into the results of Resmetirom trials: Can a thyroid hormone receptor agonist be the holy grail of MASH therapy? Pharmacology & therapeutics 22 39938598
2020 RNF128 Promotes Malignant Behaviors via EGFR/MEK/ERK Pathway in Hepatocellular Carcinoma. OncoTargets and therapy 22 33116595
2019 Platelets: the holy grail in cancer blood biomarker research? Angiogenesis 22 30341541
2019 Isoforms of RNF128 Regulate the Stability of Mutant P53 in Barrett's Esophageal Cells. Gastroenterology 22 31715145
1994 Raf: the holy grail of Ras biology? Trends in cell biology 22 14731620
2007 T cell immunomodulation--the Holy Grail of therapeutic tolerance. Current opinion in pharmacology 21 17611158
2022 Multi Cancer Early Detection by Using Circulating Tumor DNA-The Galleri Test. Reply to Klein et al. The Promise of Multicancer Early Detection. Comment on "Pons-Belda et al. Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm. Diagnostics 2021, 11, 2171". Diagnostics (Basel, Switzerland) 20 35626399
2011 GRAIL (gene related to anergy in lymphocytes) regulates cytoskeletal reorganization through ubiquitination and degradation of Arp2/3 subunit 5 and coronin 1A. The Journal of biological chemistry 19 22016387
2006 h-Goliath, paralog of GRAIL, is a new E3 ligase protein, expressed in human leukocytes. Gene 19 16549277
2023 The quest for the holy grail: overcoming challenges in expanding human hematopoietic stem cells for clinical use. Stem cell investigation 18 37457748
2021 Gene Editing and Modulation: the Holy Grail for the Genetic Epilepsies? Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 17 34235638
2019 Is the pre-antral ovarian follicle the 'holy grail'for female fertility preservation? Animal reproduction science 17 31208845
2018 Grail is involved in adipocyte differentiation and diet-induced obesity. Cell death & disease 17 29743578
2014 Template CoMFA: the 3D-QSAR Grail? Journal of chemical information and modeling 17 24437630
2022 circPHF16 suppresses prostate cancer metastasis via modulating miR-581/RNF128/Wnt/β-catenin pathway. Cellular signalling 15 36503162
2008 Plasmodium falciparum serine/threonine phoshoprotein phosphatases (PPP): from housekeeper to the 'holy grail'. Current drug targets 15 18991611
2019 Transparent to Black Electrochromism-The "Holy Grail" of Organic Optoelectronics. Polymers 14 30960257
2018 Biased agonism: the quest for the analgesic holy grail. Pain reports 14 29922742
2016 Is Transforming Stem Cells to Pancreatic Beta Cells Still the Holy Grail for Type 2 Diabetes? Current diabetes reports 14 27313072
2007 The quest for the Holy Grail: a disease-modifying osteoarthritis drug. Arthritis research & therapy 14 18096086
2023 Biomarkers in sepsis-looking for the Holy Grail or chasing a mirage! World journal of critical care medicine 13 37745257
2022 Lipid droplets, the Holy Grail of hepatic stellate cells: In health and hepatic fibrosis. Anatomical record (Hoboken, N.J. : 2007) 13 36516055
2020 Differentiating keratoacanthoma from squamous cell carcinoma-In quest of the holy grail. Journal of cutaneous pathology 13 31893469
2016 Klotho, the Holy Grail of the kidney: from salt sensitivity to chronic kidney disease. International urology and nephrology 13 27215557
2012 Searching for the Holy Grail; protein-protein interaction analysis and modulation. EMBO reports 13 22986552
2011 VIZ-GRAIL: visualizing functional connections across disease loci. Bioinformatics (Oxford, England) 13 21505031
2009 A Holy Grail of clinical pharmacology: prediction of drug pharmacokinetics and pharmacodynamics in the individual patient. Clinical pharmacology and therapeutics 13 19621007
2008 Upregulation of GRAIL is associated with remission of ulcerative colitis. American journal of physiology. Gastrointestinal and liver physiology 13 18467499
2025 E3 ubiquitin ligase RNF128 promotes Lys63-linked polyubiquitination on SRB1 in macrophages and aggravates atherosclerosis. Nature communications 12 40038329
2022 The Promise of Multicancer Early Detection. Comment on Pons-Belda et al. Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm. Diagnostics 2021, 11, 2171. Diagnostics (Basel, Switzerland) 12 35626398
2021 RNF128 suppresses the malignancy of colorectal cancer cells via inhibition of Wnt/β-catenin signaling. American journal of translational research 12 35035697
2018 GRAIL: GRids of phArmacophore Interaction fieLds. Journal of chemical theory and computation 12 30075621
2010 A novel GRAIL E3 ubiquitin ligase promotes environmental salinity tolerance in euryhaline tilapia. Biochimica et biophysica acta 12 21126558
2024 Quantification of healthspan in aging mice: introducing FAMY and GRAIL. GeroScience 11 38755467
2021 UBCH5 Family Members Differentially Impact Stabilization of Mutant p53 via RNF128 Iso1 During Barrett's Progression to Esophageal Adenocarcinoma. Cellular and molecular gastroenterology and hepatology 11 34416429
2017 Introduction: Biomarkers of embryo viability: the search for the "holy grail" of embryo selection. Fertility and sterility 11 29101996
2024 E3 ubiquitin ligase RNF128 attenuates colitis and colorectal tumorigenesis by triggering the degradation of IL-6 receptors. Journal of advanced research 10 38964734

Missed literature

Know a paper Affinage missed for RNF128? Flag it for the maintainers and the community.

No submissions yet.