Affinage

Showing RBCK1 — RBCK2 is a alias.

RBCK1

RanBP-type and C3HC4-type zinc finger-containing protein 1 · UniProt Q9BYM8

Length
510 aa
Mass
57.6 kDa
Annotated
2026-06-10
67 papers in source corpus 39 papers cited in narrative 37 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

RBCK1 (HOIL-1) is an RBR-family E3 ubiquitin ligase that functions both as a catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC) and as a stand-alone enzyme with an unusual chemistry, governing innate and adaptive immune signaling, cellular quality control, and glycogen metabolism (PMID:31209050, PMID:23104095, PMID:42062483). Its defining biochemical feature is the formation of atypical oxyester bonds between the ubiquitin C-terminus and serine/threonine residues — and even mono- and disaccharides — rather than the canonical lysine isopeptide linkage; this O-linked monoubiquitylation seeds de novo polyubiquitin chains on Myddosome components IRAK1, IRAK2, and MyD88 during TLR signaling (PMID:31209050, PMID:40169258). This activity depends on a unique C-terminal bi-nuclear Zn-cluster that replaces the second zinc finger of the canonical RING2 fold and on a catalytic histidine (His510) that acts as the catalytic base, enabling oxyester transfer while prohibiting discharge onto lysine; substrate engagement also requires binding of linear tetra-ubiquitin (PMID:36685275, PMID:40169258). Through LUBAC, HOIL-1 controls NF-κB activation downstream of IL-1β and antigen receptors, and patient loss-of-function mutations destabilize LUBAC and produce cell-type-specific dysregulation of NF-κB (PMID:23104095). A central negative-feedback axis is set by MALT1 paracaspase cleavage of HOIL-1 at antigen receptor signalosomes, which generates a C-terminal fragment with LUBAC-inhibitory and broader anti-inflammatory activity (including STAT1 engagement), dampening lymphocyte and myeloid inflammatory responses (PMID:26525107, PMID:26573773, PMID:27006117, PMID:41799187). HOIL-1 also drives MDA5-selective type I/III interferon induction during RNA virus infection (PMID:30209176). Beyond immunity, HOIL-1 is required for cytoprotective ribosome-associated quality control, ubiquitinating ribosomes to prevent nutrient-stress ribotoxicity, and regulates glycogen branch-length through its action on polyglucosan structures (PMID:42062483, PMID:35084461). In numerous cancer contexts RBCK1 additionally catalyzes K48-linked polyubiquitination and proteasomal degradation of regulatory substrates including p53, PTEN, and YAP (PMID:30874541, PMID:35174471, PMID:36280829).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 Medium

    Established that a single RBCK1 gene yields two splice products and that RBCK1 possesses intrinsic transcriptional activity requiring its RING and B-Box motifs, with the RING-IBR-lacking variant RBCK2 acting as an inhibitor — the first functional dissection of the locus.

    Evidence In vitro interaction and GAL4-chimeric transcription reporter assays with mutational analysis

    PMID:9642138 PMID:9755849

    Open questions at the time
    • Transcriptional mechanism not connected to a defined promoter or DNA-binding partner
    • No endogenous target genes identified at this stage
  2. 2005 High

    Defined how RBCK1 subcellular distribution is encoded, mapping an N-terminal NES and a C-terminal RING-IBR NLS and showing RBCK1 localizes to nuclear bodies with CBP/PML and that RBCK2 tethers it in the cytoplasm.

    Evidence Leptomycin B treatment, signal mutagenesis, co-IP, fractionation, and co-expression localization assays

    PMID:15833741 PMID:16083853

    Open questions at the time
    • Functional consequence of nuclear-body residence not linked to ubiquitin ligase activity
    • RBCK2 tethering shown in overexpression context only
  3. 2008 High

    Demonstrated RBCK1 has in vitro E3 ligase activity that is regulated by RBCK2 binding and by PKCβ phosphorylation, coupling its enzymatic output to a kinase input.

    Evidence In vitro ubiquitin ligase assay, co-IP, and PKCβ overexpression/inhibition

    PMID:18303026

    Open questions at the time
    • Phosphosites on RBCK1 not mapped
    • Physiological substrates of this E3 activity not yet defined
  4. 2008 Medium

    Positioned RBCK1 as a negative-feedback regulator of innate immune signaling by showing it targets TAB2/TAB3 and IRF3 for proteasomal degradation, restraining NF-κB and type I interferon responses.

    Evidence Co-IP, ubiquitination assays, overexpression/knockdown with NF-κB reporter and antiviral plaque readouts

    PMID:17449468 PMID:18711448

    Open questions at the time
    • No in vitro reconstitution with purified components
    • Ubiquitin linkage type not defined at this stage
  5. 2012 High

    Linked RBCK1/HOIL-1 to human disease and LUBAC biology, showing biallelic loss-of-function mutations destabilize LUBAC and cause cell-type-specific NF-κB dysregulation.

    Evidence Patient-derived fibroblasts and monocytes with NF-κB signaling assays and genetic analysis

    PMID:23104095

    Open questions at the time
    • Molecular basis for opposite fibroblast vs monocyte responses not resolved
    • Direct LUBAC substrates affected not enumerated
  6. 2012 Medium

    Solved the HOIL-1 Ubl-domain structure, providing a structural rationale for proteasome recruitment via a conserved hydrophobic patch.

    Evidence NMR spectroscopy with structural comparison to parkin

    PMID:22517668

    Open questions at the time
    • S5a/proteasome interaction inferred from comparison, not confirmed by direct mutagenesis
    • Functional contribution of Ubl domain to substrate degradation untested here
  7. 2016 High

    Identified MALT1 paracaspase cleavage of HOIL-1 as a negative-feedback brake on antigen-receptor-driven NF-κB activation, with the cleavage fragments having distinct activities.

    Evidence TAILS N-terminal proteomics, co-IP, NF-κB reporter, and antigen receptor stimulation with cleavage-resistant mutants

    PMID:26525107 PMID:26573773 PMID:27006117

    Open questions at the time
    • Precise molecular activity of the inhibitory C-terminal fragment not yet defined
    • Kinetics relative to LUBAC assembly incompletely resolved
  8. 2018 High

    Revealed pathway selectivity in antiviral signaling, showing HOIL-1/LUBAC is required for MDA5-dependent but not RIG-I-dependent interferon induction.

    Evidence HOIL1-deficient mouse dendritic cells, IRF3 phosphorylation and IFN induction assays, in vivo norovirus infection

    PMID:30209176

    Open questions at the time
    • Direct molecular substrate in the MDA5 pathway not identified in this study
    • Catalytic requirement vs scaffolding role not separated
  9. 2019 High

    Established the unprecedented catalytic chemistry of HOIL-1, demonstrating it forms oxyester (Ser/Thr) bonds and acts as a monoubiquitylating initiator on Myddosome substrates in vivo.

    Evidence Hydroxylamine cleavage, catalytically inactive HOIL-1[C458S] knock-in mice, mass spectrometry, in vitro ubiquitination

    PMID:31209050

    Open questions at the time
    • Full repertoire of physiological oxyester substrates not defined
    • How hybrid chain elongation by HOIP is coordinated not fully resolved
  10. 2023 High

    Provided the structural and mechanistic basis for oxyester catalysis, identifying a bi-nuclear Zn-cluster RING2 and a catalytic histidine, and showing linear tetra-ubiquitin binding licenses substrate ubiquitylation.

    Evidence X-ray crystallography of IBR-RING2, catalytic-residue mutagenesis, in vitro ubiquitylation; extended by His510 biochemical characterization

    PMID:36685275 PMID:40169258

    Open questions at the time
    • Structural basis for substrate Ser/Thr selection not visualized with bound substrate
    • How linear-Ub binding allosterically activates the active site not detailed
  11. 2022 Medium

    Connected HOIL-1 to glycogen metabolism, showing its loss produces malin-like polyglucosans with abnormal branch length that are rescued by reducing glycogen synthase.

    Evidence RBCK1 knockout mice, glycogen structural analysis, genetic rescue by glycogen synthase downregulation

    PMID:35084461

    Open questions at the time
    • Direct enzymatic target linking RBCK1 to branch-length control not defined
    • Relationship to oxyester ubiquitylation of carbohydrate not established in this study
  12. 2025 High

    Defined a cytoprotective ribosome-associated quality-control role, with HOIL-1 ubiquitinating ribosomes to prevent nutrient-stress ribotoxicity and disulfidptosis, and linked truncating mutations to dilated cardiomyopathy.

    Evidence HOIL-1 loss-of-function mouse models, ribosome ubiquitination assays, ZAKα genetic epistasis, ATF4 readouts, in vivo cardiac model

    PMID:42062483

    Open questions at the time
    • Specific ribosomal residues/proteins ubiquitinated not enumerated
    • Whether ribosome ubiquitylation uses oxyester chemistry not stated
  13. 2026 Medium

    Resolved the function of the MALT1-generated C-terminal HOIL-1 fragment, showing it suppresses NF-κB and STAT1 signaling and limits M1 macrophage differentiation in vivo.

    Evidence Uncleavable HOIL-1 transgenic mice, engineered THP-1 cells, STAT1 co-IP, DSS colitis model

    PMID:41799187

    Open questions at the time
    • Mechanism of STAT1 inhibition not biochemically detailed
    • Single-lab findings without independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HOIL-1's single active site is partitioned between LUBAC-associated immune signaling, ribosome quality control, glycogen-branch regulation, and the many reported K48-degradative cancer substrates — and whether all use the same oxyester chemistry — remains unresolved.
  • Linkage chemistry (oxyester vs K48 isopeptide) not reconciled across the diverse reported substrates
  • Substrate-selection determinants in vivo unknown
  • Many cancer substrate findings rest on single-lab co-IP/ubiquitination assays without reconstitution

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-1430728 Metabolism 1 R-HSA-8953854 Metabolism of RNA 1
Partners
MALT1PKCBRBCK2RNF31SHARPINSOCS6TAB2TAB3
Complex memberships
LUBAC

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 HOIL-1 (RBCK1) is an atypical E3 ligase that forms oxyester bonds between the C terminus of ubiquitin and serine/threonine residues in substrates. Using hydroxylamine cleavage of oxyester bonds and knock-in mice expressing E3 ligase-inactive HOIL-1[C458S], IRAK1, IRAK2, and MyD88 (Myddosome components) were identified as physiological substrates during Toll-like receptor signaling. HOIL-1 acts as a monoubiquitylating E3 that initiates de novo polyubiquitin chain synthesis on these proteins, and also catalyzes its own monoubiquitylation and likely that of Sharpin via oxyester linkages. Hydroxylamine cleavage assay, knock-in mice expressing catalytically inactive HOIL-1[C458S], mass spectrometry, in vitro ubiquitination assay Proceedings of the National Academy of Sciences of the United States of America High 31209050
2023 Crystal structure of the C-terminal tandem IBR-RING2 domain of HOIL-1 reveals a unique bi-nuclear Zn-cluster substituting the second zinc finger of the canonical RING2 fold. The C-terminal histidine of this Zn-cluster was identified as the catalytic base required for HOIL-1 ubiquitylation activity. HOIL-1 activity also requires binding of linear tetra-ubiquitin, which enables mono-ubiquitylation of linear Ub chains and polysaccharides. X-ray crystallography, mutagenesis of catalytic residues, in vitro ubiquitylation assay Frontiers in molecular biosciences High 36685275
2025 HOIL-1 ubiquitinates serine residues and diverse mono- and disaccharides via O-linked ubiquitination but cannot ubiquitinate lysine. A critical catalytic histidine residue, His510, in the flexible catalytic site of HOIL-1 enables O-linked ubiquitination and prohibits ubiquitin discharge onto lysine sidechains. In vitro ubiquitination assays with model substrates, mutagenesis of His510, biochemical characterization Life science alliance High 40169258
2008 RBCK1 E3 ubiquitin ligase activity was demonstrated in vitro. This E3 activity is inhibited by interaction with its splice variant RBCK2 (which lacks the RING-IBR domain). Additionally, phosphorylation of RBCK1 by PKCbeta abolishes self-ubiquitination activity in vitro, and PKCbeta overexpression increases intracellular RBCK1 levels by suppressing its proteasomal degradation. In vitro ubiquitin ligase assay, co-immunoprecipitation, PKCbeta overexpression/inhibition The Journal of biological chemistry High 18303026
2005 RBCK1 shuttles between cytoplasm and nucleus via defined nuclear export and localization signals: an N-terminal region containing Leu-142/Leu-145 serves as the nuclear export signal, and the C-terminal RING-IBR domain serves as the nuclear localization signal. RBCK1 localizes to nuclear bodies and interacts with CBP and PML. CBP co-expression enhances RBCK1 transcriptional activity, while PML represses CBP-enhanced activity. Leptomycin B treatment, mutational analysis, co-immunoprecipitation, live-cell imaging/fractionation, transcriptional reporter assay The Journal of biological chemistry High 15833741
2005 RBCK2, the splice variant of RBCK1 lacking the RING-IBR domain, is cytoplasmic and contains Leu-rich nuclear export signals. RBCK2 acts as a cytoplasmic tethering protein for RBCK1 by forming a hetero-oligomeric complex, causing nuclear RBCK1 to relocalize to the cytoplasm when RBCK2 is co-expressed. Co-expression of NES-disrupted RBCK1 with RBCK2, immunofluorescence/localization assay Biochemical and biophysical research communications Medium 16083853
1998 RBCK1 and RBCK2 are generated from a single gene by alternative splicing. RBCK1 protein interacts with both RBCK1 and RBCK2 in vitro, but RBCK2 does not self-interact. RBCK2 inhibits the transcriptional activity of RBCK1, likely through complex formation. Both RING-finger and B-Box motifs of RBCK1 are indispensable for its transcriptional activity. In vitro interaction assay, GAL4-chimeric transcription assay, mutational analysis FEBS letters / Biochemical and biophysical research communications Medium 9642138 9755849
2008 RBCK1 (E3 ubiquitin ligase) catalyzes K48-linked ubiquitination and proteasomal degradation of IRF3, acting as a negative feedback regulator of virus-triggered type I interferon induction. Viral infection induces RBCK1 expression, leading to subsequent IRF3 degradation. Overexpression of RBCK1 reduces antiviral IFN responses; knockdown has the opposite effect. Overexpression/knockdown, ubiquitination assay, plaque assay, immunoblot Cell research Medium 18711448
2007 RBCK1 physically interacts with TAB2 and TAB3 adapter proteins and facilitates their proteasome-dependent degradation, thereby negatively regulating TNF- and IL-1-induced NF-κB activation. Overexpression of RBCK1 inhibits TAB2/3-mediated NF-κB activation; knockdown potentiates it. Co-immunoprecipitation, overexpression/RNAi, NF-κB reporter assay, proteasome inhibitor treatment The Journal of biological chemistry Medium 17449468
2012 HOIL-1 (RBCK1) deficiency in patients carrying biallelic loss-of-function HOIL1 mutations impairs LUBAC stability and compromises NF-κB activation in response to IL-1β in fibroblasts, while monocytes from the same patients are hyper-responsive to IL-1β, demonstrating cell-type-specific regulation of NF-κB by HOIL-1/LUBAC. Patient-derived cells (fibroblasts and monocytes), NF-κB signaling assays, genetic analysis of loss-of-function mutations Nature immunology High 23104095
2015 MALT1 paracaspase cleaves HOIL-1 late in the NF-κB activation cycle during antigen receptor signaling. Cleavage generates an N-terminal fragment that retains support for HOIP-induced NF-κB signaling and a C-terminal fragment with LUBAC inhibitory properties, providing negative feedback regulation of NF-κB. This cleavage transiently reduces linear ubiquitination of NEMO and RIP1. 10-plex TMT TAILS N-terminal peptide proteomics, co-immunoprecipitation, NF-κB reporter assay, B-cell receptor signaling assays Nature communications / The FEBS journal High 26525107 26573773
2016 MALT1-mediated cleavage of HOIL1 occurs following antigen receptor engagement in T and B lymphocytes. Overexpression of MALT1-insensitive HOIL1 mitigates TCR-mediated NF-κB activation and cytokine production, establishing HOIL1 as a negative regulator of lymphocyte activation that is removed by MALT1 cleavage. Antigen receptor stimulation assays, overexpression of cleavage-resistant HOIL1, NF-κB reporter assay, cytokine measurement Journal of cell science Medium 27006117
2021 Non-cleavable HOIL-1 (MALT1-resistant) expressed in primary HOIL-1-deficient patient fibroblasts results in enhanced NF-κB signaling and a hyperinflammatory cytokine profile compared to wild-type HOIL-1, demonstrating that MALT1-dependent HOIL-1 cleavage is physiologically required to dampen inflammatory responses. Stable transduction of patient fibroblasts, NF-κB assays, transcriptomics, multiplexed cytokine assays Frontiers in immunology Medium 34721419
2006 HOIL-1 (RBCK1) interacts with SOCS6, requiring HOIL-1's Ubl domain and SOCS6's SH2 and Socs-box domains. HOIL-1 expression stabilizes SOCS6 itself but induces the ubiquitination and proteasomal degradation of proteins associated with SOCS6. Co-immunoprecipitation, domain mapping, ubiquitination assay, proteasome inhibitor treatment FEBS letters Medium 16643902
2012 RBCK1 interacts with hPXR (pregnane X receptor) via all RBCK1 domains (identified by yeast two-hybrid and confirmed by co-IP), ubiquitinates hPXR, and targets it for proteasomal degradation. Overexpression of RBCK1 decreased endogenous PXR in HepG2 cells and primary hepatocytes; RBCK1 silencing increased PXR levels and enhanced induction of PXR target genes. Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor (MG-132) treatment, siRNA knockdown in primary hepatocytes Drug metabolism and disposition Medium 23160820
2019 RBCK1 facilitates poly-ubiquitination and proteasomal degradation of p53 via direct interaction, promoting renal cell carcinoma proliferation. Knockdown of RBCK1 in p53 wild-type RCC cells reduces proliferation; this effect is rescued by p53 knockdown. Co-immunoprecipitation, ubiquitination assay, knockdown/rescue experiments, in vivo xenograft Cell death & disease Medium 30874541
2022 RBCK1 interacts with PTEN and promotes K48-linked polyubiquitination and proteasomal degradation of PTEN in ovarian cancer cells, facilitating tumor progression. Co-immunoprecipitation, ubiquitination assay with K48-linkage specificity, knockdown/overexpression Human cell Medium 35174471
2024 RBCK1 interacts with and polyubiquitylates mitofusin 2 (MFN2) to facilitate its proteasomal degradation under ferroptotic stress, leading to decreased mitochondrial ROS production and lipid peroxidation, thereby conferring ferroptosis resistance in pancreatic cancer cells. Co-immunoprecipitation, ubiquitination assay, RBCK1 depletion/overexpression, in vivo xenograft, measurement of mitochondrial ROS and lipid peroxidation Free radical biology & medicine Medium 38763208
2020 MTSS1 interacts with RBCK1 to facilitate RBCK1-mediated K48-linked polyubiquitination and degradation of NF-κB p65, suppressing NF-κB signaling and tumor-initiating cell properties in breast cancer. ACTBL2 competes with RBCK1 for MTSS1 binding, leading to p65 stabilization. Co-immunoprecipitation, ubiquitination assay, Mtss1 knockout mouse models, tumorsphere assay, xenograft Nature cancer Medium 35122005
2013 RBCK1 was identified as an FKBPL-interacting protein that regulates FKBPL stability via ubiquitination. Both RBCK1 and FKBPL are upregulated by 17-β-estradiol and interact within HSP90 chaperone complexes together with ERα. RBCK1 and FKBPL associate with ERα at the pS2 promoter and regulate pS2 expression. Co-immunoprecipitation, ubiquitination assay, chromatin immunoprecipitation, stable overexpression clones Oncogene Medium 23912458
2010 RBCK1 supports cell cycle progression in ERα-positive breast cancer cells by driving transcription of ERα and cyclin B1. Chromatin immunoprecipitation showed RBCK1 is recruited to the ERα promoter. RBCK1-depleted cells accumulate in G2-M phase (independent of ERα, associated with cyclin B1 reduction) and show decreased proliferation. siRNA knockdown, chromatin immunoprecipitation, cell cycle analysis, proliferation assay Cancer research Medium 20103625
2010 Rbck1 (zebrafish ortholog) interacts with Eya1 protein (confirmed by GST pulldown and co-immunoprecipitation). Sipl1 and Rbck1 enhance the function of Eya proteins as coactivators for Six transcription factors. Morpholino-mediated knockdown of a Rbck1 ortholog in zebrafish produces a BOR syndrome-like phenotype with ear and branchial arch defects. GST pulldown, co-immunoprecipitation, morpholino knockdown in zebrafish, in situ hybridization, transcriptional coactivation assay Molecular and cellular biology Medium 20956555
2006 RBCK1 physically interacts with PKCbetaI and is a key regulator of PKCbetaI function in cardiac myocytes. Acute phenylephrine treatment transiently increases RBCK1-PKCbetaI association. RBCK1 overexpression increases cardiac cell size (hypertrophy) in a PKCbeta-dependent manner; RNAi of RBCK1 inhibits phenylephrine-induced hypertrophy. Co-immunoprecipitation, adenovirus-based overexpression, RNAi knockdown, PKCbeta selective antagonist treatment, cell size measurement The Journal of biological chemistry Medium 17121852
2018 HOIL1 is essential for induction of type I and type III interferons and IRF3 phosphorylation during MDA5-dependent RNA virus (murine norovirus, Theiler's virus, poly(I:C)) infection in dendritic cells, but not for RIG-I-dependent virus (Sendai virus, VSV) responses, demonstrating that LUBAC selectively promotes MDA5 signaling. HOIL1-deficient mouse dendritic cells, IFN induction assay, IRF3 phosphorylation assay, in vivo norovirus infection model Journal of virology High 30209176
2024 HOIL1 E3 ligase activity is critical for MDA5-dependent IFN induction. HOIL1 interacts with and ubiquitinates LGP2 (a positive regulator of MDA5 oligomerization), and HOIL1 E3 ligase activity promotes MDA5 oligomerization, translocation to mitochondrial-associated membranes, and formation of MAVS aggregates. HOIP E3 ligase activity plays only a modest role in IFN induction. Co-immunoprecipitation, ubiquitination assay, E3 ligase-dead mutants, MDA5 oligomerization assay, MAVS aggregate formation assay (preprint) bioRxivpreprint Medium 38617308
2012 Solution structure of the HOIL-1 Ubl domain was solved by NMR spectroscopy, revealing a β-grasp Ubl-fold. Structural comparison with parkin indicates HOIL-1 likely uses a conserved hydrophobic patch (W58, V102, Y127, Y129) and a C-terminal basic residue (R134) to recruit the S5a subunit of the 26S proteasome. NMR spectroscopy, structural comparison with parkin Ubl domain Protein science Medium 22517668
2016 HOXA1 physically interacts with RBCK1/HOIL-1 (confirmed by proteome-wide screening and functional assays). HOXA1-mediated activation of NF-κB is non-transcriptional and requires RBCK1 and TRAF2. Genetic epistasis shows that RBCK1 and TRAF2 influences on NF-κB are epistatic to HOXA1 (RBCK1 acts downstream of HOXA1 in NF-κB activation). An 11 His repeat and the homeodomain of HOXA1 are required for RBCK1 interaction. Proteome-wide interaction screening, co-immunoprecipitation, NF-κB reporter assay, domain mapping, epistasis analysis Nucleic acids research Medium 27382069
2022 RBCK1 binds to YAP protein and promotes K48-linked poly-ubiquitination of YAP at lysine residues K76, K204, and K321, leading to YAP protein degradation and suppression of Hippo/YAP signaling in triple-negative breast cancer cells. RBCK1 overexpression inhibits TNBC cell progression in vitro and in vivo. Co-immunoprecipitation, ubiquitin-based immunoprecipitation, K48-specific ubiquitination assay, protein stability assay, RNA sequencing, in vivo xenograft Cell communication and signaling Medium 36280829
2022 RBCK1 promotes hepatocellular carcinoma metastasis and growth by stabilizing its LUBAC partner RNF31 (HOIP): RBCK1 interacts with RNF31 and represses its ubiquitination and proteasomal degradation. Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression functional assays Cell death discovery Medium 35869046
2023 HOIL-1 interacts with Numb via its A64/Q65 residues binding K78 of Numb, impairing Numb-mediated Notch1 lysosomal degradation and thereby activating Notch1 signaling to promote HCC stemness and sorafenib resistance, independently of HOIL-1 ubiquitin ligase activity. Mass spectrometry, co-immunoprecipitation, western blot, immunofluorescence, in vivo HCC models Hepatology Medium 37820061
2022 In RBCK1-deficient mice, glycogen accumulates as polyglucosans with overlong branches and hyperphosphorylation limited to precipitated polyglucosans (similar to malin-deficient Lafora disease). Downregulating glycogen synthase (the enzyme that elongates glycogen branches) rescues RBCK1 deficiency amylopectinosis, linking RBCK1 function to glycogen branch-length regulation. RBCK1 knockout mouse model, glycogen structural analysis, genetic rescue by glycogen synthase downregulation, behavioral testing, neuroinflammation assessment Brain : a journal of neurology Medium 35084461
2021 In HOIL1-deficient mice, loss of HOIL1 in radiation-resistant cells (not intestinal epithelial cells) leads to type 2 intestinal inflammation with tuft cell and goblet cell hyperplasia and elevated IL-13, IL-5, IL-25, including expansion of KLRG1hi CD90lo group 2 innate lymphoid cells. This inflammation is partly dependent on commensal microbiota. HOIL1-deficient mouse model, bone marrow chimeras, cell-type-specific knockouts, IL-4Rα signaling disruption, antibiotic treatment, immune profiling Mucosal immunology Medium 35534698
2023 HIF-1α upregulates RBCK1, which then interacts with and ubiquitinates PICK1, facilitating its proteasomal degradation in nasopharyngeal carcinoma cells under hypoxia. RBCK1 knockdown inhibited NPC proliferation, an effect rescued by double knockdown of RBCK1/PICK1. Co-immunoprecipitation, immunofluorescence, ubiquitination assay, siRNA knockdown, rescue assay, in vivo xenograft Life sciences Medium 36934971
2022 RBCK1 promotes PPARγ ubiquitination and degradation, leading to activation of WNT/β-catenin/GLUT1 pathway and enhanced aerobic glycolysis in hepatocellular carcinoma cells. RBCK1-induced HCC cell migration and aerobic glycolysis depend on destruction of the PPARγ/PGC1α complex. Co-immunoprecipitation, ubiquitination assay, WNT/β-catenin activity assay, metabolic (GLUT1/glycolysis) assays, migration assay American journal of cancer research Low 35411229
2025 HOIL-1 is required for cytoprotective ribosome-associated quality control. HOIL-1 promotes ribosome ubiquitination and its loss causes glucose starvation to become ribotoxic, leading to ZAKα (MAP3K)-dependent ATF4 activation and disulfidptosis driven by the cystine-glutamate antiporter xCT. Truncating HOIL-1 mutations associated with dilated cardiomyopathy exacerbate cardiac dysfunction in mice. HOIL-1 loss-of-function mouse models, ribosome ubiquitination assay, ZAKα genetic epistasis, ATF4 activation assay, nutrient stress experiments Nature cell biology High 42062483
2026 The C-terminal fragment of HOIL-1 generated by MALT1 cleavage (C-HOIL-1) has novel biological functions: it inhibits NF-κB signaling, interacts with STAT1 to downregulate STAT1-mediated inflammatory signaling, and upregulates ARG1 expression, collectively suppressing inflammatory responses in monocytes/macrophages and impeding M1 macrophage differentiation. Mice with uncleavable HOIL-1 (lacking C-HOIL-1) develop more severe DSS-induced colitis with elevated monocyte/macrophage/neutrophil infiltration. Transgenic uncleavable HOIL-1 mice (global and myeloid-specific), genetically engineered THP-1 cells expressing C-HOIL-1, co-immunoprecipitation (STAT1 interaction), DSS-induced colitis model, lentiviral C-HOIL-1 delivery Theranostics Medium 41799187
2007 HOIL-1 and IRP2 interact via the IRP2 73-amino acid domain in HEK293 cells (confirmed by co-immunoprecipitation), but this interaction is NOT iron-dependent, and HOIL-1 does NOT enhance the rate of IRP2 degradation by iron. Stable HOIL-1 expression does not alter iron-dependent degradation of endogenous IRP2; HOIL-1 siRNA knockdown has no effect on iron-mediated IRP2 degradation. Co-immunoprecipitation, stable expression, siRNA knockdown, iron treatment, IRP2 degradation assay Biochimica et biophysica acta Medium 17822790

Source papers

Stage 0 corpus · 67 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nature immunology 359 23104095
2008 Negative feedback regulation of cellular antiviral signaling by RBCK1-mediated degradation of IRF3. Cell research 129 18711448
2015 The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling. Nature communications 128 26525107
2019 The E3 ligase HOIL-1 catalyses ester bond formation between ubiquitin and components of the Myddosome in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 118 31209050
2013 Whole-genome DNA/RNA sequencing identifies truncating mutations in RBCK1 in a novel Mendelian disease with neuromuscular and cardiac involvement. Genome medicine 73 23889995
2007 RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-triggered NF-kappaB activation by targeting TAB2/3 for degradation. The Journal of biological chemistry 66 17449468
2016 HOXA1 binds RBCK1/HOIL-1 and TRAF2 and modulates the TNF/NF-κB pathway in a transcription-independent manner. Nucleic acids research 62 27382069
2019 RBCK1 contributes to chemoresistance and stemness in colorectal cancer (CRC). Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 57 31545242
2015 The multifaceted role of the E3 ubiquitin ligase HOIL-1: beyond linear ubiquitination. Immunological reviews 56 26085217
2015 MALT1 cleaves the E3 ubiquitin ligase HOIL-1 in activated T cells, generating a dominant negative inhibitor of LUBAC-induced NF-κB signaling. The FEBS journal 55 26573773
2010 RBCK1 drives breast cancer cell proliferation by promoting transcription of estrogen receptor alpha and cyclin B1. Cancer research 49 20103625
2016 The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling. Journal of cell science 47 27006117
2017 Mutations outside the N-terminal part of RBCK1 may cause polyglucosan body myopathy with immunological dysfunction: expanding the genotype-phenotype spectrum. Journal of neurology 46 29260357
2019 RBCK1 promotes p53 degradation via ubiquitination in renal cell carcinoma. Cell death & disease 44 30874541
2018 HOIL1 Is Essential for the Induction of Type I and III Interferons by MDA5 and Regulates Persistent Murine Norovirus Infection. Journal of virology 42 30209176
2010 Sipl1 and Rbck1 are novel Eya1-binding proteins with a role in craniofacial development. Molecular and cellular biology 39 20956555
2024 Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1. Nature communications 34 38580662
2013 Identification of RBCK1 as a novel regulator of FKBPL: implications for tumor growth and response to tamoxifen. Oncogene 33 23912458
2006 The E3 ubiquitin ligase HOIL-1 induces the polyubiquitination and degradation of SOCS6 associated proteins. FEBS letters 31 16643902
2012 RBCK1, an E3 ubiquitin ligase, interacts with and ubiquinates the human pregnane X receptor. Drug metabolism and disposition: the biological fate of chemicals 29 23160820
2008 Identification of ubiquitin ligase activity of RBCK1 and its inhibition by splice variant RBCK2 and protein kinase Cbeta. The Journal of biological chemistry 27 18303026
1998 Transcriptional activity of RBCK1 protein (RBCC protein interacting with PKC 1): requirement of RING-finger and B-Box motifs and regulation by protein kinases. Biochemical and biophysical research communications 26 9642138
2020 MTSS1 suppresses mammary tumor-initiating cells by enhancing RBCK1-mediated p65 ubiquitination. Nature cancer 24 35122005
2022 Glycogen synthase downregulation rescues the amylopectinosis of murine RBCK1 deficiency. Brain : a journal of neurology 23 35084461
2005 Nuclear-cytoplasmic shuttling of a RING-IBR protein RBCK1 and its functional interaction with nuclear body proteins. The Journal of biological chemistry 22 15833741
2021 Comprehensive Multi-Omics Identification of Interferon-γ Response Characteristics Reveals That RBCK1 Regulates the Immunosuppressive Microenvironment of Renal Cell Carcinoma. Frontiers in immunology 20 34795663
2006 RBCK1, a protein kinase CbetaI (PKCbetaI)-interacting protein, regulates PKCbeta-dependent function. The Journal of biological chemistry 18 17121852
2023 Noncanonical regulation of HOIL-1 on cancer stemness and sorafenib resistance identifies pixantrone as a novel therapeutic agent for HCC. Hepatology (Baltimore, Md.) 16 37820061
2022 Regulation of PTEN and ovarian cancer progression by an E3 ubiquitin ligase RBCK1. Human cell 16 35174471
2021 Proteomic characterisation of polyglucosan bodies in skeletal muscle in RBCK1 deficiency. Neuropathology and applied neurobiology 16 34405429
2024 E3 ubiquitin ligase RBCK1 confers ferroptosis resistance in pancreatic cancer by facilitating MFN2 degradation. Free radical biology & medicine 15 38763208
2022 RBCK1 is an endogenous inhibitor for triple negative breast cancer via hippo/YAP axis. Cell communication and signaling : CCS 15 36280829
2019 HOIL-1, an atypical E3 ligase that controls MyD88 signalling by forming ester bonds between ubiquitin and components of the Myddosome. Advances in biological regulation 15 31615747
2022 RBCK1 promotes hepatocellular carcinoma metastasis and growth by stabilizing RNF31. Cell death discovery 14 35869046
2021 MALT1-Dependent Cleavage of HOIL1 Modulates Canonical NF-κB Signaling and Inflammatory Responsiveness. Frontiers in immunology 14 34721419
1998 Molecular cloning and characterization of RBCK2, a splicing variant of a RBCC family protein, RBCK1. FEBS letters 13 9755849
2022 The E3 ubiquitin ligase RBCK1 promotes the invasion and metastasis of hepatocellular carcinoma by destroying the PPARγ/PGC1α complex. American journal of cancer research 12 35411229
2007 HOIL-1 is not required for iron-mediated IRP2 degradation in HEK293 cells. Biochimica et biophysica acta 12 17822790
2023 The E3 ligase RBCK1 reduces the sensitivity of ccRCC to sunitinib through the ANKRD35-MITD1-ANXA1 axis. Oncogene 11 36732658
2023 Structural basis for ubiquitylation by HOIL-1. Frontiers in molecular biosciences 9 36685275
2021 Regulation of ERα Stability and Estrogen Signaling in Breast Cancer by HOIL-1. Frontiers in oncology 9 34094957
2022 RBCK1 regulates the progression of ER-positive breast cancer through the HIF1α signaling. Cell death & disease 8 36473847
2022 A novel variant of RBCK1 gene causes mild polyglucosan myopathy. Neurosciences (Riyadh, Saudi Arabia) 6 35017290
2022 Normal lymphocyte homeostasis and function in MALT1 protease-resistant HOIL-1 knock-in mice. The FEBS journal 6 36479846
2012 Solution structure of the E3 ligase HOIL-1 Ubl domain. Protein science : a publication of the Protein Society 6 22517668
2025 The RBR E3 ubiquitin ligase HOIL-1 can ubiquitinate diverse non-protein substrates in vitro. Life science alliance 5 40169258
2024 A novel likely pathogenic homozygous RBCK1 variant in dilated cardiomyopathy with muscle weakness. ESC heart failure 5 38329383
2024 A case of polyglucosan body myopathy caused by an RBCK1 gene variant and literature review. Molecular genetics & genomic medicine 5 38588043
2023 Hypoxia-induced degradation of PICK1 by RBCK1 promotes the proliferation of nasopharyngeal carcinoma cells. Life sciences 5 36934971
2005 Cytoplasmic tethering of a RING protein RBCK1 by its splice variant lacking the RING domain. Biochemical and biophysical research communications 5 16083853
2005 Identification, expression, and assay of an oxidation-specific ubiquitin ligase, HOIL-1. Methods in enzymology 5 16275334
2023 RBCK1 Overexpression Attenuates Inflammation and Mobility of Derp1-Induced Nasal Mucosal Cells by Downregulating NLRP3. International archives of allergy and immunology 4 36702106
2023 A synonymous codon variant altering splicing of RBCK1 expands the phenotype and genotype spectra of polyglucosan body myopathy 1. Clinical genetics 4 37102570
2023 Expanding the phenotype of RBCK1-associated polyglucosan body myopathy type 1. Molecular genetics and metabolism reports 4 38077957
2024 HOIL1 mediates MDA5 activation through ubiquitination of LGP2. bioRxiv : the preprint server for biology 3 38617308
2022 HOIL1 regulates group 2 innate lymphoid cell numbers and type 2 inflammation in the small intestine. Mucosal immunology 3 35534698
2021 RBCK1-TRIB3 decelerated the progression of acute promyelocytic leukemia. Hematological oncology 3 34310740
2021 Ester-linked ubiquitination by HOIL-1 controls immune signalling by shaping the linear ubiquitin landscape. The FEBS journal 3 34322999
2023 HOIL1 Regulates Group 3 Innate Lymphoid Cells in the Colon and Protects against Systemic Dissemination, Colonic Ulceration, and Lethality from Citrobacter rodentium Infection. Journal of immunology (Baltimore, Md. : 1950) 2 37902285
2023 The E3 ubiquitin ligase RBCK1: Implications in the tumor immune microenvironment and antiangiogenic therapy of glioma. Computational and structural biotechnology journal 2 37928949
2025 Identification of a novel RBCK1 splice site donor variant in Basset Hounds with glycogen storage disease myopathy. Molecular genetics and metabolism 1 40939526
2025 The LUBAC subunit HOIL-1 promotes the progression of HBV-associated hepatocellular carcinoma independently of linear ubiquitination. Experimental & molecular medicine 1 41053347
2024 Phenotypic and genotyping spectrum of two Iranian cases with RBCK1-associated polyglucosan body myopathy. Neuropathology : official journal of the Japanese Society of Neuropathology 1 38922716
2026 An Alu mediated intergenic inversion in RBCK1 causing Polyglucosan body myopathy type 1. Human molecular genetics 0 41729854
2026 C-terminal Fragment Generated by HOIL-1 Cleavage Suppresses Inflammatory Responses of Myeloid Cells to Alleviate Colitis. Theranostics 0 41799187
2026 The atypical E3 ligase HOIL-1 safeguards the ribosome during cellular stress. Nature cell biology 0 42062483
2025 RBCK1 enhances antiviral response through promoting K63-linked polyubiquitination of IRF7 in Carassius auratus var. Pengze. Fish & shellfish immunology 0 40588086

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