Affinage

RBX1

E3 ubiquitin-protein ligase RBX1 · UniProt P62877

Length
108 aa
Mass
12.3 kDa
Annotated
2026-06-10
78 papers in source corpus 42 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RBX1 is an evolutionarily conserved RING-H2 finger protein that serves as the catalytic RING subunit of Cullin-RING E3 ubiquitin ligases (CRLs), directing the timely proteasomal degradation of specific substrates across diverse cellular processes (PMID:10213691, PMID:10213692). Structurally, RBX1 docks onto the globular domain of a Cullin through an intermolecular beta-sheet, forming a two-subunit catalytic core that recruits the E2 ubiquitin-conjugating enzyme, while the Cullin acts as a rigid scaffold positioning the substrate-recognition module >100 Å away (PMID:11961546). This architecture is shared across CRL families, with substrate-adaptor sequences (Cul2-box vs. Cul5-box) and Cullin interface hotspots dictating selective assembly of RBX1 with CUL1 (SCF), CUL2 (e.g. VHL–EloBC), CUL3, and CUL4 complexes (PMID:15601820, PMID:28591624, PMID:24989250). Beyond ubiquitin transfer, RBX1 functions as the E3 for conjugation of the ubiquitin-like protein NEDD8/Rub1 onto Cullins, an activity dependent on its atypical RING residue D97 and required to activate CRL ubiquitination (PMID:10579999, PMID:15966899). RBX1 RING-domain repositioning underlies the conformational logic of CRL catalysis: it is constrained or released in distinct neddylation, ubiquitination, and CSN-mediated deneddylation states (PMID:35982156), and its activity is competitively inhibited by direct binding of Glomulin (GLMN) to the E2-interacting RING surface (PMID:22748924, PMID:22405651). Through these CRL complexes RBX1 controls cell-cycle progression by driving degradation of p27, CDT1/ORC1, and EXO1 (PMID:19325126, PMID:21115485, PMID:31562368), Nrf2 antioxidant signaling via the Cul3–Keap1 axis (PMID:19279002, PMID:20452971), regulatory T-cell and thymus development via the UBE2M–RBX1 neddylation axis (PMID:35641500, PMID:40642056), cardiac morphogenesis (PMID:34363825), and mTORC1 activation through CUL3–KLHL9-mediated Rheb ubiquitination (PMID:39708321). RBX1 protein levels are themselves controlled by USP15-mediated deubiquitination (PMID:16005295) and caspase-dependent N-terminal cleavage under ER stress (PMID:22822056).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 High

    Established RBX1 as a shared catalytic component of both ubiquitin and NEDD8/Rub1 conjugation machineries, defining it as more than a passive structural subunit.

    Evidence Co-IP from rat liver and yeast genetics placing RBX1 in VHL-Cul2 and SCF complexes, plus in vitro reconstitution of cyclin and Rub1 conjugation with purified Rbx1/Cdc34/Ubc12

    PMID:10213691 PMID:10213692 PMID:10579999

    Open questions at the time
    • Did not resolve how RBX1 physically couples E2 recruitment to catalysis
    • Substrate range across Cullin families not yet defined
  2. 2002 High

    Defined the structural basis of RBX1 function: it binds the Cullin globular domain through an intermolecular beta-sheet to form an E2-recruiting catalytic core held rigidly apart from the substrate receptor.

    Evidence X-ray crystallography of the Cul1-Rbx1-Skp1-Skp2 SCF complex with scaffold-rigidity mutagenesis

    PMID:11961546

    Open questions at the time
    • Static structure did not capture catalytic conformational dynamics
    • How ubiquitin reaches the distant substrate left unexplained
  3. 2005 Medium

    Resolved how RBX1 catalytic specificity and stability differ across Cullins, identifying the atypical RING residue D97 as key for neddylation and revealing complex-specific stability and a deubiquitination control mechanism.

    Evidence Systematic D97 mutagenesis with in vitro neddylation/ubiquitination assays, and USP15 zinc-finger-dependent stabilization assays

    PMID:15966899 PMID:16005295

    Open questions at the time
    • USP15 stabilization from single lab without in vivo confirmation
    • Physiological triggers of RBX1 auto-ubiquitination not defined
  4. 2009 High

    Demonstrated that RBX1 loss has distinct consequences in proliferation control, linking it causally to substrate accumulation through genetic rescue.

    Evidence Gene-trap mouse knockout with p27 double-knockout rescue, and siRNA in cancer cells showing G2-M arrest/apoptosis/senescence

    PMID:19325126 PMID:19509229

    Open questions at the time
    • Mouse lethality at E7.5 limited analysis of later roles
    • Senescence pathway downstream of RBX1 loss remained p53/p16-independent and unexplained
  5. 2010 High

    Connected RBX1 to genome stability and antioxidant feedback by identifying CDT1/ORC1 as replication-licensing substrates and an Nrf2-driven autoregulatory loop on Cul3/Rbx1 transcription.

    Evidence siRNA in human cells with C. elegans RNAi epistasis (CDT-1), γH2AX readouts, and ARE promoter mutagenesis/reporter assays

    PMID:20452971 PMID:21115485

    Open questions at the time
    • Nrf2 feedback evidence from a single lab
    • Direct CRL adaptor for CDT1 in this context not specified
  6. 2012 High

    Identified Glomulin as a direct competitive inhibitor of the RBX1 RING domain and linked RBX1 to disease and to autophagy/ER-stress regulation.

    Evidence Crystal structure of GLMN-RBX1-CUL1 with ubiquitination inhibition assays and GVM disease mutations; DEPTOR-autophagy and caspase-cleavage functional studies

    PMID:22405651 PMID:22748924 PMID:22822056 PMID:22965024

    Open questions at the time
    • Regulatory cues controlling GLMN-RBX1 engagement in vivo unclear
    • Caspase-cleavage and DEPTOR findings from single labs
  7. 2017 High

    Captured RBX1 in a conformational trajectory within an intact pentameric CRL2 complex, advancing the dynamic model of catalysis beyond the static SCF structure.

    Evidence Crystal structure of full Cul2-Rbx1-EloBC-pVHL with ITC and selectivity-switch mutagenesis

    PMID:28591624

    Open questions at the time
    • Did not resolve fully neddylated active state
    • E2-bound catalytic intermediate not visualized
  8. 2018 High

    Expanded the RBX1 substrate and adaptor repertoire (RhoB via KCTD10, SESN2) and showed the RING domain is a target of small-molecule and metalloid inhibition.

    Evidence Co-IP, site-specific ubiquitination mapping, endothelial barrier assays, and arsenite RING-binding/ubiquitination assays

    PMID:29294217 PMID:29358211 PMID:29658272

    Open questions at the time
    • SESN2 link from single Tier 3 study
    • Selectivity of arsenite/RING engagement across CRLs unclear
  9. 2022 High

    Revealed that RBX1 RING orientation can be conformationally locked, explaining catalytically silent CRLs and the existence of CRL-CRL substrate-receptor partnerships, and defined the UBE2M-RBX1 neddylation axis as specifically required for Treg fitness.

    Evidence Cryo-EM of CRL7FBXW8 with in vitro activity assays; Treg-specific conditional knockout with genetic epistasis across neddylation enzymes

    PMID:35641500 PMID:35982156

    Open questions at the time
    • Substrates degraded by the CRL7-CUL1 partnership not enumerated
    • Tissue-specific substrates underlying Treg phenotype not identified
  10. 2024 High

    Placed RBX1 in nutrient-sensing signaling by defining a lysosomal CUL3-RBX1-KLHL9 complex that ubiquitinates Rheb to promote amino-acid-induced mTORC1 activation.

    Evidence Genetic knockout of CUL3/RBX1/KLHL9 with ubiquitination, fractionation, and mTORC1 activity assays; plus cryo-EM of closed SCFFBXO3

    PMID:39406020 PMID:39708321

    Open questions at the time
    • How amino acid signals trigger complex lysosomal translocation unclear
    • Rheb ubiquitin-chain topology not defined
  11. 2025 High

    Detailed the deneddylation cycle structurally—showing RBX1 RING repositioning during CSN-mediated NEDD8 removal—and extended RBX1 substrate control to ferroptosis and metabolic regulation across multiple disease tissues.

    Evidence Cryo-EM of CSN-CRL1 functional states (preprint); ubiquitination assays with in vivo models for NCOA4, TXNIP, and FoxO1 substrates

    PMID:40335979 PMID:40658786

    Open questions at the time
    • CSN-CRL structures are preprint, single lab
    • Tissue-specific substrate findings (NCOA4/TXNIP/FoxO1) each from single labs

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RBX1 substrate selection, neddylation timing, and inhibitor sensitivity are integrated to control specific physiological versus pathological outcomes across distinct Cullin complexes remains unresolved.
  • No unified model linking RBX1 conformational states to substrate choice in vivo
  • RBX1 vs. RBX2 functional partitioning across Cullins incompletely mapped
  • Disease-targeted modulation of specific RBX1-CRL pairs not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016874 ligase activity 4 GO:0031386 protein tag activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0005764 lysosome 2 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2 R-HSA-162582 Signal Transduction 1
Partners
CUL1CUL2CUL3GLMNKCTD10KLHL9USP15VHL
Complex memberships
CRL2 (CUL2-RBX1-EloBC-VHL)CRL3 (CUL3-RBX1)CRL4 (CUL4A-DDB1-RBX1)SCF (CUL1-RBX1)

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Crystal structure of the Cul1-Rbx1-Skp1-F-box(Skp2) SCF complex reveals that Rbx1 binds the globular domain of Cul1 through an intermolecular beta-sheet, forming a two-subunit catalytic core that recruits the E2 ubiquitin-conjugating enzyme. Cul1 acts as a rigid scaffold holding Rbx1 and the substrate-recognition complex >100 Å apart. X-ray crystallography with functional validation via Cul1 scaffold rigidity mutations Nature High 11961546
1999 Rbx1 is a component of the endogenous VHL tumor suppressor complex (elongin B/C–Cul2–VHL) and SCF ubiquitin ligase complexes. It contains a RING-H2 finger motif, interacts with Cullins, and its yeast homolog is a subunit and potent activator of the SCFCdc4 ubiquitin ligase required for ubiquitination of Sic1 and G1-to-S transition. Co-immunoprecipitation from rat liver, yeast genetic and biochemical studies Science High 10213691
1999 Rbx1 promotes association of E2 Cdc34 with Cdc53 and stimulates Cdc34 auto-ubiquitination in the context of Cdc53 or SCF complexes. Phosphorylated G1 cyclin Cln1 ubiquitination was reconstituted in vitro with SCFGrr1, Rbx1, and Cdc34, directly demonstrating Rbx1's role in E3 catalytic activity. In vitro ubiquitination reconstitution assay with purified components Science High 10213692
1999 The Cdc53/Rbx1 and Cul2/Rbx1 modules activate conjugation of the ubiquitin-like protein Rub1 (NEDD8) to Cdc53 and Cul2 by the dedicated E2 Ubc12, identifying Rbx1 as a common component of both ubiquitin and Rub1 (neddylation) modification enzyme systems. In vitro neddylation assay with purified Cdc53/Rbx1 and Cul2/Rbx1 modules Genes & development High 10579999
2004 VHL specifically interacts with endogenous Cul2-Rbx1 in mammalian cells (not Cul5-Rbx2), whereas SOCS-box proteins associate with Cul5-Rbx2. Domain-swapping analyses showed that specificity for Cul2-Rbx1 vs. Cul5-Rbx2 is determined by the Cul2-box or Cul5-box sequences of substrate adaptors. RNAi-mediated knockdown of Cul2-Rbx1 inhibited VHL-mediated degradation of HIF-2α. Co-immunoprecipitation, domain-swap mutagenesis, RNAi knockdown Genes & development High 15601820
2005 USP15, a deubiquitinating enzyme associated with the COP9 signalosome, stabilizes Rbx1 by reversing its poly/auto-ubiquitination. The zinc finger of USP15 is essential for this rescue; a single cysteine mutation in the zinc finger abolishes USP15's ability to stabilize Rbx1. Co-transfection, pulldown, ubiquitination assay, site-directed mutagenesis Current Biology Medium 16005295
2005 Mutational analysis of Rbx1's RING finger residue D97 (the atypical 8th coordination residue) showed that aspartate is superior to cysteine for cullin neddylation activity. Different D97 mutants exhibit distinct activities across 6 Cullins, and specific mutants discriminate between neddylation activity and involvement in VBC-Cul2 ubiquitylation. Rbx1 mutants also destabilize VBC-Cul2 but not SCF, indicating complex-specific stability roles. Site-directed mutagenesis, in vitro neddylation and ubiquitination assays Genes to cells High 15966899
2009 RBX1/ROC1 silencing by siRNA in human cancer cells induces sequential G2-M arrest, apoptosis, and senescence. G2-M arrest is associated with accumulation of 14-3-3σ and loss of cyclin B1/Cdc2; apoptosis involves accumulation of Puma and reduction of Bcl-2/Mcl-1/survivin; senescence is coupled with DNA damage in p53/p21- and p16/pRb-independent manners. siRNA knockdown, cell cycle analysis, apoptosis assays, Western blot Cancer Research Medium 19509229
2009 Mouse Rbx1 gene-trap disruption causes embryonic lethality at E7.5 due to proliferation failure. p27 accumulates at high levels in Rbx1-null embryos. Simultaneous loss of p27 partially rescues lethality to E9.5, demonstrating that Rbx1-dependent p27 degradation is essential for early embryonic cell proliferation. Gene-trap mouse knockout, genetic epistasis (double knockout with p27), immunostaining PNAS High 19325126
2009 The INrf2/Cul3-Rbx1 complex is imported into the nucleus via prothymosin-alpha binding to the DGR region of INrf2. Inside the nucleus, the complex exchanges prothymosin-alpha for Nrf2, leading to Nrf2 ubiquitination and degradation. Cul3 and Rbx1 require INrf2 for nuclear import. Co-immunoprecipitation, subcellular fractionation, siRNA knockdown, co-transfection Journal of Biological Chemistry Medium 19279002
2010 RBX1 silencing in human cancer cells causes accumulation of DNA replication licensing proteins CDT1 and ORC1, leading to DNA double-strand breaks, DNA damage response (DDR), G2 arrest, and aneuploidy. CHK1 activation is responsible for G2 arrest. In C. elegans, RBX-1 silencing causes CDT-1 accumulation and DDR; simultaneous CDT-1 silencing largely abrogates this DDR. siRNA knockdown, RNAi in C. elegans, DNA damage markers (γH2AX), genetic epistasis Journal of Biological Chemistry High 21115485
2010 Nrf2 controls its own degradation by transcriptionally inducing Cul3 and Rbx1 gene expression via antioxidant response elements (AREs) in their promoters. Increased Cul3-Rbx1 then ubiquitinates and degrades Nrf2, forming a feedback autoregulatory loop. Promoter mutagenesis, transfection, siRNA, ARE reporter assays Journal of Biological Chemistry Medium 20452971
2010 Molecular dynamics simulations demonstrate that the flexible linker of Rbx1 undergoes conformational changes that allow CRL neddylation and initiation of ubiquitination even before neddylation occurs, and that large NEDD8-induced CRL conformational changes are retained after deneddylation, enabling continued ubiquitin chain elongation post-deneddylation. Molecular dynamics simulation, mutational analysis of cullin acceptor lysine Biophysical Journal Low 20682250
2012 Crystal structure of a GLMN-RBX1-CUL1 fragment complex reveals that Glomulin (GLMN) adopts a HEAT-like repeat fold that tightly binds the E2-interacting surface of the RBX1 RING domain, competitively inhibiting E2 (CDC34) recruitment and CRL-mediated ubiquitin chain formation. Disease-associated GVM mutations disrupt the GLMN-RBX1 interface. X-ray crystallography, biochemical ubiquitination inhibition assay, mutagenesis Molecular Cell High 22748924
2012 Glomulin (Glmn) binds directly to the RING domain of Rbx1 and inhibits its E3 ubiquitin ligase activity. Loss of Glmn increases turnover of Fbw7 and consequently elevated levels of Cyclin E and c-Myc, all reversible by CRL or proteasome inhibition. Direct binding assay, genetic loss-of-function, Western blot, proteasome/CRL inhibitors Molecular Cell High 22405651
2012 Antioxidant-induced phosphorylation of INrf2 (Keap1) Tyr85 controls nuclear export of the INrf2-Cul3-Rbx1 complex. Mutation of Tyr85 blocks nuclear export of INrf2 and co-blocks Cul3-Rbx1 export, demonstrating that Cul3-Rbx1 exits the nucleus as a complex with INrf2. Newly synthesized INrf2-Cul3-Rbx1 re-imports to degrade nuclear Nrf2 post-induction. Site-directed mutagenesis, subcellular fractionation, siRNA, immunofluorescence Journal of Cell Science Medium 22448038
2012 RBX1 knockdown triggers autophagy through accumulation of DEPTOR, an mTOR-inhibitory CRL substrate, thereby activating the DEPTOR-mTOR axis. Blockage of autophagy upon RBX1 knockdown enhances apoptosis, showing that this autophagy is a protective/survival response. siRNA knockdown, Western blot for DEPTOR/mTOR substrates, autophagy assays Autophagy Medium 22965024
2012 ER stress induces caspase-dependent cleavage of RBX1 eight amino acids from the N-terminus during B-cell plasma cell differentiation. Yeast expressing the N-terminally cleaved human RBX1 (Δ8) are hypersensitive to ER stress and impaired in CRL-mediated ubiquitination and degradation, demonstrating that the N-terminal region is required for RBX1 function. Biochemical cleavage assay, yeast complementation, ubiquitination assay, ER stress induction Journal of Biological Chemistry Medium 22822056
2014 Cullin 2-RBX1 E3 ligase interacts with RhoB and promotes its ubiquitination and degradation in liver cancer cells; this requires NEDD8 conjugation (neddylation) for activation. Inhibition of the neddylation-CRL pathway causes RhoB accumulation and contributes to p21/p27 induction and apoptosis. Co-immunoprecipitation, iTRAQ quantitative proteomics, siRNA knockdown, ubiquitination assay Molecular & Cellular Proteomics Medium 25540389
2016 Rotavirus NSP1 hijacks the host Cullin-3-Rbx1 CRL complex to mediate strain-specific β-TrCP degradation. NSP1 localizes to the Golgi with the Cul3-Rbx1 complex, which targets β-TrCP and NSP1 for co-destruction at the proteasome. siRNA silencing or chemical inhibition of Cul3 or Rbx1 impairs this β-TrCP degradation. Tandem-affinity purification/MS, siRNA knockdown, chemical inhibition, co-localization imaging PLoS Pathogens Medium 27706223
2017 Crystal structure of the pentameric CRL2VHL complex (Cul2-Rbx1-EloBC-pVHL) reveals full-length Cul2 architecture and a new pose of Rbx1 in a trajectory from closed to open conformation. Hotspots at the Cul2-pVHL-EloBC interface were identified, and mutations defining selectivity switch for Cul2 vs. Cul5 recognition were characterized. X-ray crystallography, isothermal titration calorimetry, mutagenesis Structure High 28591624
2018 The Cullin-3-Rbx1-KCTD10 E3 ligase complex mediates K63-linked polyubiquitination of RhoB at lysines 162 and 181 in primary endothelial cells, targeting RhoB to lysosomes and regulating endothelial barrier integrity via RhoB-mediated cell contraction. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K162/K181), siRNA knockdown, endothelial permeability assay Journal of Cell Biology High 29358211
2018 Arsenite binds directly to the RING finger domain of Rbx1 in vitro and in cells, suppressing Cul3-Rbx1 E3 ubiquitin ligase activity, thereby impairing Nrf2 ubiquitination and activating the Nrf2 antioxidant signaling pathway. In vitro and cellular RING-domain binding assay, ubiquitination assay Chemical Research in Toxicology Medium 29658272
2018 RBX1 is a novel E3 ligase for SESN2 (Sestrin 2), mediating its K48-linked ubiquitination upon prolonged mitochondrial damage in SH-SY5Y cells. Downregulation of RBX1 stabilizes SESN2 and reduces cell death, identifying a direct RBX1-SESN2 interaction. Co-immunoprecipitation, ubiquitination assay (K48-linkage), siRNA knockdown, overexpression Molecular and Cellular Biochemistry Medium 29294217
2019 RBX1 expression is elevated in G1 phase cells and promotes neddylation of Cullin1, thereby driving G1 phase-specific ubiquitination and degradation of EXO1, which limits homologous recombination (HR) DNA repair in G1. Knockdown of RBX1 in G1-phase cells increases EXO1 levels, DSB end resection, and HR activity. DNA-PKcs autophosphorylation at S2056 is responsible for elevated RBX1 in G1; its inhibition decreases RBX1 and increases EXO1. siRNA knockdown, Western blot, immunofluorescence (RPA32/BrdU/RAD51 foci), HR reporter assay, DNA-PKcs inhibition Cell Death & Differentiation Medium 31562368
2020 Gossypol inhibits cullin neddylation by directly binding to the SAG-CUL5 or RBX1-CUL1 complex, blocking neddylation of both CUL5 and CUL1. CUL5-H572 plays a key role for gossypol binding. Cellular treatment with gossypol selectively causes accumulation of NOXA and MCL1, substrates of CUL5 and CUL1, respectively. AlphaScreen HTS assay, direct binding biochemistry, site-directed mutagenesis (H572), cellular substrate accumulation assay Neoplasia Medium 32145688
2021 Purified recombinant CUL2-RBX1 complex expressed from E. coli assembles with substrate receptor modules (e.g., VHL-EloBC) and is enzymatically active in transferring ubiquitin and ubiquitin-like proteins to substrates in vitro, validating the reconstituted complex as functional. Recombinant protein expression and purification, in vitro ubiquitination assay Scientific Reports Medium 34045610
2022 Cryo-EM structure of CRL7FBXW8 reveals that the RBX1 RING domain is constrained in an orientation incompatible with binding E2~NEDD8 or E2~ubiquitin intermediates, explaining why purified CRL7FBXW8 lacks auto-neddylation and ubiquitination activities. Instead, CRL7 acts as a substrate receptor linked via SKP1-FBXW8 to a neddylated CUL1-RBX1 catalytic module for ubiquitination. Cryo-EM structure determination, in vitro neddylation and ubiquitination assays Nature Structural & Molecular Biology High 35982156
2022 Treg cell-specific deletion of Rbx1 in mice causes early-onset fatal inflammatory disorder with disrupted Treg homeostasis and suppressive functions. Rbx1 is required for maintenance of effector Treg subpopulation and regulates inflammatory pathways. Similar but less severe phenotypes occur with Ube2m deletion; deletion of Rbx2/Sag or Ube2f yields no obvious phenotype, establishing the Ube2m-Rbx1 axis as specifically required for Treg fitness. Conditional knockout mouse model, flow cytometry, transcriptomics, genetic epistasis Nature Communications High 35641500
2023 RBX1 interacts with and ubiquitinates p27 (phospho-Thr187), promoting its degradation in multiple myeloma cells. RBX1 overexpression induces G1-S cell cycle entry; RBX1 knockdown causes p27 accumulation and growth arrest. RBX1 knockdown inhibited myeloma development in SCID-Hu and xenotransplant mouse models. Co-immunoprecipitation, ubiquitination assay, cell cycle analysis, in vivo xenograft Cancer Biology & Therapy Medium 37639640
2023 RBX1 promotes PKM alternative splicing toward PKM2 in anaplastic thyroid carcinoma by ubiquitinating and degrading the SMAR1 transcription factor via the proteasome pathway. This destroys the SMAR1/HDAC6 complex, facilitating PKM2-mediated Warburg effect and ATC metastasis. Ubiquitination assay, co-immunoprecipitation, siRNA knockdown, splicing analysis Cell & Bioscience Medium 36810109
2024 The CUL3-RBX1-KLHL9 E3 ligase complex translocates to the lysosome in response to amino acid stimulation and ubiquitinates Rheb there, enhancing its interaction with mTORC1 for activation. KLHL9 is the essential adaptor bridging CUL3-RBX1 to Rheb. Deletion of CUL3, RBX1, or KLHL9 diminishes Rheb ubiquitination and reduces amino acid-induced mTORC1 activation without affecting lysosomal mTORC1 localization. Genetic knockout, co-immunoprecipitation, ubiquitination assay, subcellular fractionation, mTORC1 activity assay Cell Reports High 39708321
2024 Cryo-EM structure of SCFFBXO3 (CUL1-RBX1-SKP1-FBXO3) at 3.70 Å resolution shows that unmodified SCFFBXO3 adopts a closed conformation where the RBX1 globular region is near the FBXO3 ApaG domain, suggesting CUL1 neddylation is required to achieve high E3 activity. Cryo-EM structure determination Biochemical and Biophysical Research Communications Medium 39406020
2025 RBX1 loss in thymus causes shrinkage, delayed T cell development, increased γδ T cells, and altered γδ T1/T17 balance. Mechanistically, Rbx1 loss alters Akt, NF-κB, and metabolic pathways in progenitor γδ T/DN3a cells. Some phenotypes are partially rescued by simultaneous Bim deletion. Rbx2/Sag deletion has no obvious thymic phenotype, establishing Rbx1 specificity. Conditional knockout mouse model, flow cytometry, genetic epistasis (Bim co-deletion), transcriptomic pathway analysis Research Medium 40642056
2025 Cryo-EM structures of CSN-CRL1 (SCF) complexes in multiple functional states reveal that during the catalytic intermediate of deneddylation, the RBX1 RING domain is repositioned along with the CSN5 Ins-1 loop and neddylated Cullin WHB domain for isopeptide bond cleavage. Four dissociation intermediates reveal stepwise CSN release, with RBX1 RING playing a central role in stabilizing key interactions throughout the deneddylation cycle. Cryo-EM structure determination of multiple states bioRxivpreprint High
2025 RBX1 ubiquitinates NCOA4, modulating its expression and thereby inhibiting NCOA4-mediated ferritinophagy (selective autophagy for ferritin degradation) in nucleus pulposus stem cells. Inhibition of RBX1 promotes ferroptosis through enhanced NCOA4-mediated ferritinophagy. RBX1 overexpression in vivo ameliorates ferroptosis and intervertebral disc degeneration. Ubiquitination assay, siRNA knockdown, overexpression, in vivo animal model Journal of Translational Medicine Medium 40335979
2025 RBX1 mediates ubiquitination and degradation of TXNIP; METTL3 enhances RBX1 mRNA stability through m6A modification, increasing RBX1 protein levels, which then ubiquitinates TXNIP and reduces its expression, initiating ferroptosis that ameliorates liver fibrosis. Western blot, siRNA/overexpression, ubiquitination assay, in vivo liver fibrosis models (CCl4 and bile duct ligation) Hepatology Communications Medium 40658786
2025 RBX1 promotes ubiquitination and proteasomal degradation of FoxO1 transcription factor, thereby suppressing FoxO1-driven c-Myc expression and c-Myc-mediated glutamine metabolism. Reduced RBX1 in cardiac hypertrophy models correlates with increased FoxO1 protein and enhanced glutamine metabolism; RBX1 overexpression reverses cardiomyocyte hypertrophy. Co-immunoprecipitation, ubiquitination assay, Western blot, siRNA/overexpression International Immunopharmacology Low 41999689
2003 In C. elegans, RBX1 depletion by RNAi causes defects in meiotic division, mitotic chromosomal condensation/segregation, cytokinesis, and reduced histone H3 phosphorylation at Ser10/Ser28. The histone H3 phosphorylation defect is rescued by simultaneous depletion of protein phosphatase 1 (GLC7α/β), linking RBX1 to chromosome metabolism via H3 phosphorylation regulation. RNAi knockdown in C. elegans, epistasis with PP1 RNAi, immunofluorescence Genes to Cells Medium 14622138
2021 In zebrafish, Rbx1 loss-of-function mutants exhibit cardiomyocyte multi-layering (excess trabeculation). Endothelial-specific (but not myocardial-specific) rbx1 overexpression normalizes cardiac wall morphogenesis, indicating endocardial Rbx1 activity is required for this process. The phenotype requires blood flow/cardiac contractility and is Notch-pathway associated; pharmacological Hedgehog activation ameliorates the phenotype. Zebrafish genetic mutant, tissue-specific transgenic overexpression, Hedgehog pharmacological activation, Notch reporter assay Developmental Biology Medium 34363825
2015 Cancer-testis antigen MAGE-C2 binds directly to the RING domain of Rbx1 and participates in the SCF complex, inhibiting its E3 ubiquitin ligase activity. MAGE-C2 ablation decreases cyclin E levels by accelerating ubiquitin-mediated proteasome degradation; overexpression of MAGE-C2 increases cyclin E and promotes G1-S transition. Co-immunoprecipitation, in vitro binding, ubiquitination assay, siRNA/overexpression Oncotarget Medium 26540345
2014 The CUL4A-DDB1-Rbx1 E3 ligase complex (CRL4A) mediates ubiquitin-dependent proteasomal degradation of dysfunctional PEX7 (the PTS2 peroxisome import receptor, including RCDP patient mutants), serving as a quality control E3 for Pex7p. Degradation of dysfunctional Pex7p is essential for maintaining normal PTS2 import. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor, siRNA knockdown, PTS2 import assay Biochemical Journal Medium 24989250
2015 Both Rbx1 and Rbx2 can activate Cul5-Vif E3 ubiquitin ligase to promote APOBEC3G (A3G) ubiquitination in vitro. However, in cells, only reduction of endogenous Rbx2 (not Rbx1) impairs Vif-induced A3G degradation. Rbx2 dose-dependently inhibits the interaction of Rbx1 with Cul5, suggesting competitive assembly. In vitro ubiquitination assay, Co-immunoprecipitation in cells, siRNA knockdown Biochemical and Biophysical Research Communications Medium 25912140

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature 1246 11961546
1999 Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science (New York, N.Y.) 669 10213691
2004 VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases. Genes & development 411 15601820
1999 Reconstitution of G1 cyclin ubiquitination with complexes containing SCFGrr1 and Rbx1. Science (New York, N.Y.) 350 10213692
1999 The Rbx1 subunit of SCF and VHL E3 ubiquitin ligase activates Rub1 modification of cullins Cdc53 and Cul2. Genes & development 238 10579999
2008 Characterization of Cullin-box sequences that direct recruitment of Cul2-Rbx1 and Cul5-Rbx2 modules to Elongin BC-based ubiquitin ligases. The Journal of biological chemistry 168 18187417
2001 Muf1, a novel Elongin BC-interacting leucine-rich repeat protein that can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase. The Journal of biological chemistry 138 11384984
2001 The pVHL-associated SCF ubiquitin ligase complex: molecular genetic analysis of elongin B and C, Rbx1 and HIF-1alpha in renal cell carcinoma. Oncogene 128 11526493
2005 The zinc finger of the CSN-associated deubiquitinating enzyme USP15 is essential to rescue the E3 ligase Rbx1. Current biology : CB 126 16005295
2017 Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex. Structure (London, England : 1993) 122 28591624
2009 ROC1/RBX1 E3 ubiquitin ligase silencing suppresses tumor cell growth via sequential induction of G2-M arrest, apoptosis, and senescence. Cancer research 114 19509229
2010 Small RING Finger Proteins RBX1 and RBX2 of SCF E3 Ubiquitin Ligases: The Role in Cancer and as Cancer Targets. Genes & cancer 83 21103004
2002 Mammalian mediator subunit mMED8 is an Elongin BC-interacting protein that can assemble with Cul2 and Rbx1 to reconstitute a ubiquitin ligase. Proceedings of the National Academy of Sciences of the United States of America 75 12149480
2012 Structure of a glomulin-RBX1-CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface. Molecular cell 70 22748924
2004 ASB2 is an Elongin BC-interacting protein that can assemble with Cullin 5 and Rbx1 to reconstitute an E3 ubiquitin ligase complex. The Journal of biological chemistry 69 15590664
2009 RBX1/ROC1 disruption results in early embryonic lethality due to proliferation failure, partially rescued by simultaneous loss of p27. Proceedings of the National Academy of Sciences of the United States of America 66 19325126
2016 Comparative Proteomics Reveals Strain-Specific β-TrCP Degradation via Rotavirus NSP1 Hijacking a Host Cullin-3-Rbx1 Complex. PLoS pathogens 60 27706223
2010 An autoregulatory loop between Nrf2 and Cul3-Rbx1 controls their cellular abundance. The Journal of biological chemistry 59 20452971
2018 MiR-378 and MiR-1827 Regulate Tumor Invasion, Migration and Angiogenesis in Human Lung Adenocarcinoma by Targeting RBX1 and CRKL, Respectively. Journal of Cancer 56 29344280
2009 Prothymosin-alpha mediates nuclear import of the INrf2/Cul3 Rbx1 complex to degrade nuclear Nrf2. The Journal of biological chemistry 55 19279002
2012 The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7. Molecular cell 54 22405651
2013 Frequent concerted genetic mechanisms disrupt multiple components of the NRF2 inhibitor KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex in thyroid cancer. Molecular cancer 53 24138990
2010 RBX1 (RING box protein 1) E3 ubiquitin ligase is required for genomic integrity by modulating DNA replication licensing proteins. The Journal of biological chemistry 52 21115485
2018 The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB. The Journal of cell biology 49 29358211
2014 miR-194 targets RBX1 gene to modulate proliferation and migration of gastric cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 47 25412959
2014 The neddylation-cullin 2-RBX1 E3 ligase axis targets tumor suppressor RhoB for degradation in liver cancer. Molecular & cellular proteomics : MCP 46 25540389
2022 The Ube2m-Rbx1 neddylation-Cullin-RING-Ligase proteins are essential for the maintenance of Regulatory T cell fitness. Nature communications 41 35641500
2012 A genome-wide association study on a southern European population identifies a new Crohn's disease susceptibility locus at RBX1-EP300. Gut 38 22936669
2012 Antioxidant-induced INrf2 (Keap1) tyrosine 85 phosphorylation controls the nuclear export and degradation of the INrf2-Cul3-Rbx1 complex to allow normal Nrf2 activation and repression. Journal of cell science 36 22448038
2019 RBX1 prompts degradation of EXO1 to limit the homologous recombination pathway of DNA double-strand break repair in G1 phase. Cell death and differentiation 35 31562368
2009 RBX1/ROC1-SCF E3 ubiquitin ligase is required for mouse embryogenesis and cancer cell survival. Cell division 31 19660140
2003 Caenorhabditis elegans RBX1 is essential for meiosis, mitotic chromosomal condensation and segregation, and cytokinesis. Genes to cells : devoted to molecular & cellular mechanisms 31 14622138
2020 Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes. Neoplasia (New York, N.Y.) 30 32145688
2021 A polydopamine nanomedicine used in photothermal therapy for liver cancer knocks down the anti-cancer target NEDD8-E3 ligase ROC1 (RBX1). Journal of nanobiotechnology 29 34654435
2014 Unique pattern of component gene disruption in the NRF2 inhibitor KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex in serous ovarian cancer. BioMed research international 27 25114896
2012 Protective autophagy induced by RBX1/ROC1 knockdown or CRL inactivation via modulating the DEPTOR-MTOR axis. Autophagy 26 22965024
2015 Cancer-testis antigen MAGE-C2 binds Rbx1 and inhibits ubiquitin ligase-mediated turnover of cyclin E. Oncotarget 25 26540345
2022 Structure of CRL7FBXW8 reveals coupling with CUL1-RBX1/ROC1 for multi-cullin-RING E3-catalyzed ubiquitin ligation. Nature structural & molecular biology 24 35982156
2020 A20 and RBX1 Regulate Brentuximab Vedotin Sensitivity in Hodgkin Lymphoma Models. Clinical cancer research : an official journal of the American Association for Cancer Research 24 32299816
2020 Reduced RBX1 expression induces chromosome instability and promotes cellular transformation in high-grade serous ovarian cancer precursor cells. Cancer letters 24 33290867
2018 Arsenite Targets the RING Finger Domain of Rbx1 E3 Ubiquitin Ligase to Inhibit Proteasome-Mediated Degradation of Nrf2. Chemical research in toxicology 23 29658272
2010 Rbx1 flexible linker facilitates cullin-RING ligase function before neddylation and after deneddylation. Biophysical journal 23 20682250
2018 RBX1-mediated ubiquitination of SESN2 promotes cell death upon prolonged mitochondrial damage in SH-SY5Y neuroblastoma cells. Molecular and cellular biochemistry 19 29294217
2020 ELF1-mediated LUCAT1 promotes choroidal melanoma by modulating RBX1 expression. Cancer medicine 18 31968402
2021 Long non-coding RNA DDX11-AS1 promotes esophageal carcinoma cell proliferation and migration through regulating the miR-514b-3p/RBX1 axis. Bioengineered 16 34281459
2021 Long noncoding RNA DARS-AS1 regulates TP53 ubiquitination and affects ovarian cancer progression by modulation miR-194-5p/RBX1 axis. Journal of biochemical and molecular toxicology 16 34328246
2005 Multiple roles of Rbx1 in the VBC-Cul2 ubiquitin ligase complex. Genes to cells : devoted to molecular & cellular mechanisms 16 15966899
2002 A homolog of the E3 ubiquitin ligase Rbx1 is induced during hyperosmotic stress of salmon. American journal of physiology. Regulatory, integrative and comparative physiology 16 12010746
2023 RBX1 regulates PKM alternative splicing to facilitate anaplastic thyroid carcinoma metastasis and aerobic glycolysis by destroying the SMAR1/HDAC6 complex. Cell & bioscience 15 36810109
2020 MiR-135b-5p inhibits the progression of malignant melanoma cells by targeting RBX1. European review for medical and pharmacological sciences 14 32096167
2015 Both Rbx1 and Rbx2 exhibit a functional role in the HIV-1 Vif-Cullin5 E3 ligase complex in vitro. Biochemical and biophysical research communications 13 25912140
2014 CUL4A-DDB1-Rbx1 E3 ligase controls the quality of the PTS2 receptor Pex7p. The Biochemical journal 12 24989250
2021 Expression and purification of functional recombinant CUL2•RBX1 from E. coli. Scientific reports 11 34045610
2022 E3 ubiquitin ligase RBX1 drives the metastasis of triple negative breast cancer through a FBXO45-TWIST1-dependent degradation mechanism. Aging 10 35802537
2012 Fbxw5 suppresses nuclear c-Myb activity via DDB1-Cul4-Rbx1 ligase-mediated sumoylation. Biochemical and biophysical research communications 10 22910413
2025 The KEAP1-Cullin3-RBX1-Nrf2 Axis in Redox Homeostasis: Molecular Mechanisms, Pathophysiological Roles, and Precision Therapeutic Opportunities. Molecular neurobiology 9 41206404
2025 RBX1 mitigates ferroptosis by inhibiting NCOA4-mediated ferritinophagy and contributes to the attenuation of intervertebral disc degeneration. Journal of translational medicine 8 40335979
2021 The E3 ubiquitin-protein ligase Rbx1 regulates cardiac wall morphogenesis in zebrafish. Developmental biology 8 34363825
1999 Genomic organization and expression of the ubiquitin-proteasome complex-associated protein Rbx1/ROC1/Hrt1. Cellular and molecular biology (Noisy-le-Grand, France) 8 10643962
2023 RING box protein-1(RBX1), a key component of SCF E3 ligase, induced multiple myeloma cell drug-resistance though suppressing p27. Cancer biology & therapy 6 37639640
2021 Cullin 2-RBX1 E3 ligase and USP2 regulate antithrombin ubiquitination and stability. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 6 34324733
2024 Structure of the CUL1-RBX1-SKP1-FBXO4 SCF ubiquitin ligase complex. Biochemical and biophysical research communications 5 39406020
2012 Endoplasmic reticulum stress induces a caspase-dependent N-terminal cleavage of RBX1 protein in B cells. The Journal of biological chemistry 4 22822056
2010 Identification and functional characterization of an Rbx1 in an invertebrate Haliotis diversicolor supertexta. Developmental and comparative immunology 4 20801156
2025 METTL3 inhibits liver fibrosis via RBX1 stability and TXNIP-mediated ferroptosis. Hepatology communications 3 40658786
2024 Proapoptotic effect of WS-299 induced by NOXA accumulation and NRF2-counterbalanced oxidative stress damage through targeting RBX1-UBE2M interaction in gastric cancers. Bioorganic chemistry 3 38280358
2024 The Cullin3-Rbx1-KLHL9 E3 ubiquitin ligase complex ubiquitinates Rheb and supports amino acid-induced mTORC1 activation. Cell reports 3 39708321
2025 Structural Insight Into the SKP1-CUL1-FBXO3-RBX1 Complex. Proteins 2 39921442
2025 Expression and purification of functional recombinant Cullin1-Rbx1/2 in E. coli. Protein expression and purification 1 40447239
2025 E3 Ligase Rbx1 Orchestrates Thymus Development and Fate Determination of αβ-γδ T Cells. Research (Washington, D.C.) 1 40642056
2026 Identification of RBX1 as a regulator of LIPT1 transcription and its role in copper-induced cell death in GBM cells. Scientific reports 0 41620535
2026 Z226407860 attenuates HDM-induced airway epithelial injury and ROS accumulation via RBX1 inhibition. Bioorganic chemistry 0 41707388
2026 RBX1+ CAFs Drives Pancreatic Ductal Adenocarcinoma Progression Through Tenascin C Overexpression. Cancers 0 41899625
2026 E3 ubiquitin ligase RBX1 inhibits glutamine metabolism and attenuates cardiomyocyte hypertrophy. International immunopharmacology 0 41999689
2026 Drug-Induced Cuproptosis Defines the Therapeutic Window of Celecoxib in Intervertebral Disc Degeneration via the HSP90-RBX1 Axis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 42080393
2026 RBX1 loss sensitizes tubo-ovarian, high-grade serous ovarian cells to CDK2 inhibition by SNS-032. Frontiers in cell and developmental biology 0 42131106
2025 Activation of the aryl hydrocarbon receptor relieves acute pancreatitis via the RBX1/HSF1 pathway. Journal of inflammation (London, England) 0 41275289
2025 The Characteristics and Expression of RBX1 Gene Involved in Ovarian Development of Scylla paramamosain. International journal of molecular sciences 0 41516238

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