Affinage

BIRC6

Dual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein ligase BIRC6 · UniProt Q9NR09

Length
4857 aa
Mass
530.3 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BIRC6 (BRUCE/Apollon) is a giant (~528 kDa) chimeric E2/E3 ubiquitin ligase and inhibitor of apoptosis protein that integrates apoptosis suppression, autophagy regulation, DNA damage repair, and cytokinesis through its multidomain architecture. Its BIR domain directly inhibits executioner caspases-3, -7, and -9, while its UBC domain catalyzes ubiquitination of substrates including Smac, caspases, LC3B, KRAS4A, and Axin exclusively via the non-canonical E1 UBA6, with which BIRC6 engages through a high-affinity bespoke thioester switch mechanism (PMID:15200957, PMID:36758105, PMID:31692446, PMID:39705142, PMID:41350950). Structurally, BIRC6 forms an antiparallel crescent-shaped dimer with a central cavity harboring client receptor sites, where SMAC binds with subnanomolar multisite affinity to competitively displace caspases and block ubiquitination of both apoptotic and autophagic substrates (PMID:36758105, PMID:38291026). Beyond apoptosis suppression, BIRC6 promotes autophagosome–lysosome fusion through non-catalytic interactions with GABARAP/GABARAPL1 and Syntaxin 17, scaffolds USP8-mediated deubiquitination of BRIT1 to enable homologous recombination repair, activates ATR signaling to maintain replication fork stability, and translocates to the midbody ring during cytokinesis to facilitate abscission (PMID:29426817, PMID:25733871, PMID:30693543, PMID:18329369).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2004 High

    Establishing BIRC6 as a bifunctional IAP and E2/E3 ubiquitin ligase resolved how a single protein could both inhibit caspases and target pro-apoptotic factors like Smac for ubiquitin-dependent degradation.

    Evidence In vitro ubiquitination assays, domain mutagenesis, caspase activity assays, and co-immunoprecipitation in mammalian cells

    PMID:15200957 PMID:15507451

    Open questions at the time
    • E1 enzyme specificity for BIRC6 was unknown
    • structural basis for dual BIR/UBC function unresolved
    • full substrate repertoire undefined
  2. 2004 High

    Identification of Nrdp1 as an E3 ligase promoting BIRC6 proteasomal degradation during apoptosis established that BIRC6 protein levels are actively regulated upstream, explaining how cells overcome its anti-apoptotic activity.

    Evidence Reconstituted in vitro ubiquitination with purified Nrdp1 plus RNAi validation in cells

    PMID:14765125

    Open questions at the time
    • Signals triggering Nrdp1-mediated BIRC6 degradation not fully defined
    • additional upstream E3 ligases not explored
  3. 2004 High

    Knockout mouse studies revealed that BIRC6 is essential for placental development and perinatal viability, demonstrating a critical in vivo developmental function beyond apoptosis suppression.

    Evidence Complete and partial knockout mice with histological and TUNEL analysis of placenta

    PMID:15485903 PMID:15887267

    Open questions at the time
    • Whether placental defect reflects apoptotic or proliferative role was debated across labs
    • downstream targets in trophoblast differentiation unknown
  4. 2005 High

    Conditional deletion of the BIRC6 UBC domain proved that its ubiquitin-conjugating activity is required to suppress a p53-dependent mitochondrial apoptosis cascade involving Bax, caspase-2, and caspase-9 in vivo.

    Evidence Conditional knockout mouse with p53 RNAi rescue, subcellular fractionation, and caspase activation assays

    PMID:15640352

    Open questions at the time
    • Direct ubiquitination substrates mediating p53 suppression not identified
    • whether BIRC6 ubiquitinates p53 directly was unresolved
  5. 2008 High

    Discovery that BIRC6 translocates from vesicular membranes to the midbody ring during cytokinesis and is required for abscission revealed an unexpected cell-division function independent of classical IAP activity.

    Evidence RNAi knockdown, live imaging, and immunofluorescence in dividing mammalian cells

    PMID:18329369

    Open questions at the time
    • Substrates ubiquitinated at the midbody ring not identified
    • mechanism of BIRC6 vesicular targeting to midbody unknown
  6. 2011 High

    Demonstration that Drosophila BRUCE ubiquitinates the IAP-antagonist Reaper via non-lysine residues established an unconventional ubiquitination mechanism for IAP-antagonist neutralization.

    Evidence In vivo ubiquitination assay with lysine-deficient Reaper mutants and genetic loss-of-function in Drosophila

    PMID:21886178

    Open questions at the time
    • Non-lysine acceptor site identity (Ser/Thr/Cys) unresolved
    • conservation of non-lysine ubiquitination for mammalian BIRC6 substrates not tested
  7. 2015 High

    Identification of BIRC6 as a scaffold bridging USP8 and BRIT1 to enable BRIT1 deubiquitination and recruitment to DNA damage sites established a direct role for BIRC6 in homologous recombination repair, with the UBC domain required for promoting USP8 activity.

    Evidence Reciprocal co-immunoprecipitation, in vivo ubiquitination assays, HR repair assays, and domain mutagenesis in BRUCE-mutant cells and mice

    PMID:25733871 PMID:26683461

    Open questions at the time
    • Whether BIRC6 UBC domain directly ubiquitinates a component of the repair complex or acts allosterically unclear
    • how BIRC6 is recruited to DSB sites unknown
  8. 2018 High

    Discovery that BIRC6 promotes autophagosome–lysosome fusion through non-catalytic binding of GABARAP/GABARAPL1 and Syntaxin 17 revealed a ubiquitin-independent membrane-tethering function, separating its autophagy-promoting role from its E2/E3 activity.

    Evidence RNAi screen, co-immunoprecipitation, domain deletion rescue in Bruce−/− cells, and autophagic flux assays

    PMID:29426817

    Open questions at the time
    • Structural basis for selectivity of GABARAP over LC3 subfamily binding unresolved
    • whether BIRC6 tethers autophagosomes to lysosomes directly or via intermediate complexes not determined
  9. 2019 High

    Genome-wide CRISPR screening identified UBA6 as the exclusive E1 for BIRC6-mediated monoubiquitination and proteasomal degradation of LC3B, establishing UBA6–BIRC6 as a negative regulator of autophagy that limits LC3B availability.

    Evidence Whole-genome CRISPR/Cas9 screen, LC3B ubiquitination assay, autophagic flux measurement, and α-synuclein aggregate quantification in neurons

    PMID:31692446

    Open questions at the time
    • Which LC3B lysine residues are ubiquitinated not fully mapped
    • whether other ATG8 family members are similarly targeted unknown
  10. 2019 High

    Demonstration that BIRC6 is required for ATR activation, CHK1 phosphorylation, and replication fork stability—with liver-specific knockout exacerbating hepatocarcinogenesis—established BIRC6 as a replication stress response factor distinct from its DSB repair role.

    Evidence IP-kinase assays, DNA fiber assays, conditional liver-specific KO mouse with DEN-induced HCC

    PMID:30693543

    Open questions at the time
    • Mechanism by which BIRC6 activates ATR (direct binding vs. scaffold) not established
    • relationship between ATR and BRIT1/USP8 repair functions unclear
  11. 2021 High

    Germline-specific knockout proved BIRC6 is essential for meiotic homologous recombination via ATM/ATR signaling at unsynapsed chromosomal regions, extending its DNA repair role to a specialized developmental context.

    Evidence Germline-specific conditional KO mouse with immunofluorescence for synaptonemal complex components and ATM/ATR markers

    PMID:32139899

    Open questions at the time
    • Direct interaction partners mediating BIRC6 recruitment to meiotic chromosomes unknown
    • whether BIRC6 ubiquitinates meiotic repair substrates not tested
  12. 2023 High

    Cryo-EM structures revealing the BIRC6 antiparallel dimer with a central substrate-binding cavity, combined with quantitative binding data showing SMAC's subnanomolar multisite engagement that displaces caspases and blocks ubiquitination, provided the first structural framework integrating BIRC6's IAP and E2/E3 functions.

    Evidence Cryo-EM structure determination, ITC binding measurements, in vitro caspase inhibition and ubiquitination assays across three concurrent studies

    PMID:36758104 PMID:36758105 PMID:36758106

    Open questions at the time
    • Conformational dynamics during ubiquitin transfer cycle unresolved
    • how dimer architecture accommodates diverse substrates of vastly different sizes not explained
  13. 2024 High

    Identification of KRAS4A as a splice-variant-specific BIRC6 substrate ubiquitinated at K128/K147 on the Golgi linked BIRC6's E3 activity to RAS signaling regulation, revealing a new oncogenic signaling axis.

    Evidence Proximity labeling interactome, co-immunoprecipitation, mass spectrometry ubiquitination site mapping, and GTP-loading assay

    PMID:39705142

    Open questions at the time
    • Whether KRAS4A ubiquitination promotes degradation or alters signaling competence not fully resolved
    • selectivity mechanism excluding KRAS4B not structurally explained
  14. 2025 High

    Cryo-EM structures of the BIRC6–UBA6 complex revealed a bespoke high-affinity engagement mechanism via the UBA6 ubiquitin fold domain and a thioester switch that ejects BIRC6 after ubiquitin loading, explaining how BIRC6 achieves priority E1 access over other UBA6-competent E2 enzymes.

    Evidence Cryo-EM structures of BIRC6–UBA6 in multiple states, biochemical E1–E2 specificity assays, and domain mutagenesis

    PMID:41350950

    Open questions at the time
    • Whether the thioester switch is regulated by post-translational modifications in vivo unknown
    • structural basis for how UBA6 selectivity excludes UBE1 completely not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The integration of BIRC6's multiple functions—apoptosis suppression, autophagy regulation, DNA repair, cytokinesis, and KRAS signaling—into a unified regulatory model remains unresolved, particularly how substrate selection is spatiotemporally controlled within the dimer cavity.
  • No full-length structure with bound substrates other than SMAC
  • spatial and temporal regulation of BIRC6 dimer across different cellular compartments and cell cycle phases unknown
  • whether post-translational modifications (e.g., Lyn-mediated phosphorylation) switch BIRC6 between functions not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0098772 molecular function regulator activity 5
Localization
GO:0005694 chromosome 3 GO:0005794 Golgi apparatus 3 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-73894 DNA Repair 4 R-HSA-9612973 Autophagy 4 R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 1
Partners
BRIT1GABARAPGABARAPL1NRDP1SMACSTX17UBA6USP8
Complex memberships
BIRC6 antiparallel homodimerBIRC6-USP8-BRIT1 complexUBA6-BIRC6 E1-E2 complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 BRUCE functions as a chimeric E2/E3 ubiquitin ligase and inhibitor of apoptosis (IAP) protein localized to the trans-Golgi network. Its BIR domain is required for caspase inhibition and anti-apoptotic activity. BRUCE is antagonized by Smac binding, HtrA2 protease cleavage, and caspase-mediated cleavage. BRUCE ubiquitinates Smac as a substrate. Wild-type and mutant protein overexpression, in vitro ubiquitination assay, co-immunoprecipitation, caspase activity assay, apoptosis induction assays Molecular cell High 15200957
2004 Nrdp1/FLRF, a RING finger E3 ubiquitin ligase, associates with BRUCE and promotes its ubiquitination and proteasomal degradation. Purified Nrdp1 catalyzes BRUCE ubiquitination in vitro in the presence of E2 UbcH5c. Apoptotic stimuli induce proteasomal degradation of BRUCE, and reducing Nrdp1 by RNAi attenuates BRUCE loss and reduces apoptosis. Co-immunoprecipitation, in vitro ubiquitination assay with purified proteins, RNAi knockdown, proteasome inhibitor experiments The EMBO journal High 14765125
2004 BRUCE/Apollon associates with precursor and mature forms of Smac, HtrA2, and caspase-9 through regions beyond the IAP-binding motif. BRUCE promotes degradation of Smac and inhibits caspase-9 activity but not caspase-3 activity. Upon apoptotic stimuli, BRUCE is degraded by proteasomes or cleaved by caspases and HtrA2 in a stimulus- and cell type-dependent manner. Co-immunoprecipitation, caspase activity assays, proteasome inhibitor and caspase inhibitor experiments, in vitro binding assays The Journal of biological chemistry High 15507451
2004 BRUCE is a 528 kDa peripheral membrane protein of the trans-Golgi network required for normal placental development in mice. Complete inactivation causes perinatal lethality due to impaired maturation of the labyrinth layer and reduced spongiotrophoblast in the placenta, without elevated apoptosis in embryonic tissues. Knockout mouse generation and characterization, histological analysis, TUNEL assay Molecular and cellular biology High 15485903
2005 Deletion of the C-terminal half of BRUCE (including the UBC domain) in mice causes caspase activation and apoptosis in placenta and yolk sac, leading to embryonic lethality. This apoptosis involves p53 upregulation and nuclear localization, Bax/Bak upregulation, mitochondrial translocation of Bax and caspase-2, cytochrome c and AIF release, and caspase-9/-3 activation. RNAi of p53 rescues cell viability in Bruce-ablated cells by reducing Bax, Bak, Pidd expression and preventing caspase-2/-9/-3 activation. Conditional knockout mouse, RNAi, caspase activity assays, subcellular fractionation, western blot for apoptosis markers Proceedings of the National Academy of Sciences of the United States of America High 15640352
2005 Bruce mutant mice (gene trap) show progressive loss of the spongiotrophoblast layer between embryonic days 11.5 and 14.5, resulting in embryonic lethality due to lack of spongiotrophoblast cell proliferation rather than elevated apoptosis. Gene trap mutagenesis, histological analysis, proliferation assays Genesis (New York, N.Y. : 2000) Medium 15887267
2008 During cytokinesis, BRUCE translocates from the vesicular system to the midbody ring and serves as a platform for membrane delivery machinery and mitotic regulators. BRUCE depletion causes defective abscission and cytokinesis-associated apoptosis, blocks vesicular targeting, and disrupts midbody and midbody ring formation. Ubiquitin relocalizes from midbody microtubules to the midbody ring during cytokinesis, and BRUCE depletion disrupts this process. RNAi knockdown in cell culture, live imaging, immunofluorescence, subcellular fractionation Cell High 18329369
2008 In Drosophila oogenesis, the effector caspase Dcp-1 and IAP protein Bruce function together to regulate both starvation-induced autophagy and cell death at germarium and mid-oogenesis checkpoints. Drosophila genetics (mutant analysis), systematic RNAi screen in cultured cells, DNA fragmentation assays The Journal of cell biology Medium 18794330
2008 Prostaglandin F2alpha (PGF2alpha) increases BRUCE expression through an NFAT2-dependent pathway, reducing muscle cell death during myogenesis. BRUCE overexpression is sufficient to promote muscle cell survival and myotube growth, establishing a PGF2alpha-NFAT2-BRUCE signaling axis. In vitro myogenesis assay, siRNA knockdown, overexpression constructs, in vivo mouse experiments Cell death and differentiation Medium 18566603
2011 Drosophila BRUCE (dBruce) ubiquitinates the IAP-antagonist Reaper through an unconventional mechanism involving non-lysine ubiquitin acceptor sites. dBruce physically interacts with Reaper dependent on Reaper's IAP-binding (IBM) and GH3 motifs. dBruce loss elevates Reaper protein levels. Co-immunoprecipitation, in vivo ubiquitination assay with lysine-deficient Reaper mutants, genetic loss-of-function analysis Cell death and differentiation High 21886178
2013 EBV-encoded miRNA miR-BART15-3p directly targets the 3' UTR of BRUCE mRNA at a specific seed-matched site, suppressing BRUCE protein translation and promoting apoptosis in EBV-negative and EBV-infected cells. Luciferase reporter assay with 3'UTR constructs, mutation analysis of seed-match sites, western blot, miRNA inhibitor experiments Journal of virology Medium 23678170
2014 BIRC6 interacts with p53 and facilitates its degradation, promoting hepatocellular carcinogenesis. BIRC6 knockdown activates p53, causes G1/S arrest, and sensitizes hepatoma cells to sorafenib-induced apoptosis, with these effects partially reversed by p53 RNAi. Co-immunoprecipitation, lentiviral shRNA knockdown, flow cytometry, RNAi epistasis, xenograft tumor model International journal of cancer Medium 25196217
2015 BRUCE acts as a scaffold bridging USP8 and BRIT1 in a complex. BRIT1 is K63-ubiquitinated in unstressed cells, and BRUCE promotes USP8-catalyzed deubiquitination of BRIT1, which is prerequisite for BRIT1 recruitment to DSB sites via γ-H2AX binding. Loss of BRUCE impairs BRIT1 deubiquitination, BRIT1 DNA damage foci formation, chromatin relaxation, and homologous recombination repair. Co-immunoprecipitation, in vivo ubiquitination assay, chromatin immunoprecipitation, HR repair assay, BRUCE-mutant mouse analysis Proceedings of the National Academy of Sciences of the United States of America High 25733871
2015 The UBC domain of BRUCE (but not the BIR domain) is required for promoting USP8-mediated deubiquitination of BRIT1 and its recruitment to DSBs. UBC domain mutation or deletion does not disrupt the BRUCE-USP8-BRIT1 complex but impairs BRIT1 deubiquitination, chromatin relaxation, accumulation of MDC1, NBS1, pATM, and RAD51 at DSBs, and homologous recombination repair. Domain deletion/mutation analysis, in vivo ubiquitination assay, co-immunoprecipitation, immunofluorescence, HR repair assay PloS one High 26683461
2017 BIRC6 protein stability is regulated by the Src family kinase Lyn in imatinib-resistant CML cells. Lyn inhibition or knockdown reduces BIRC6 protein stability, promotes formation of an N-terminal BIRC6 fragment, and reduces BIRC6 phosphopeptide levels (phosphorylated at S480, S482, S486), suggesting Lyn regulates BIRC6 phosphorylation and stability. BIRC6 mediates imatinib resistance independently of Mcl-1. Phosphoproteomic analysis, lentiviral shRNA knockdown, kinase inhibitor treatment, caspase activation assays PloS one Medium 28520795
2018 BRUCE promotes autophagosome-lysosome fusion by selectively interacting with ATG8 family members GABARAP and GABARAPL1 and with Syntaxin 17, and colocalizes with LAMP2. BRUCE depletion leads to defective autolysosome formation. A non-catalytic N-terminal BRUCE fragment sufficient to bind GABARAP/GABARAPL1 and Syntaxin 17 rescues autolysosome formation, indicating this function is independent of ubiquitin-conjugating activity. RNAi screen, co-immunoprecipitation, immunofluorescence colocalization, domain deletion rescue experiments in Bruce-/- cells, autophagic flux assays Nature communications High 29426817
2019 UBA6 and BIRC6 cooperate to monoubiquitinate LC3B, targeting it for proteasomal degradation. Knockout of UBA6 or BIRC6 increases autophagic flux under nutrient deprivation and decreases aggresome-like structures and α-synuclein aggregates, demonstrating that UBA6-BIRC6 negatively regulate autophagy by limiting LC3B availability. Whole-genome CRISPR/Cas9 knockout screen, LC3B ubiquitination assay, autophagic flux assays, α-synuclein aggregate quantification in neurons eLife High 31692446
2019 BRUCE together with the proteasome activator PA28γ causes proteasomal degradation of LC3-I, inhibiting autophagy. SIP/CacyBP inhibits BRUCE-mediated degradation of LC3-I under normal conditions by blocking Nrdp1 binding to BRUCE. Upon starvation, SIP enhances BRUCE translocation into the recycling endosome and promotes autophagic destruction of BRUCE via optineurin-mediated autophagy. Co-immunoprecipitation, LC3-I degradation assays, RNAi knockdown, subcellular fractionation, autophagic flux assays Proceedings of the National Academy of Sciences of the United States of America High 31213539
2019 BRUCE depletion promotes autophagy induction by lowering cellular energy levels (elevated AMP/ATP ratio) and activating AMPK (pThr-172), which then activates ULK1 (pSer-555) to initiate autophagy. This is distinct from starvation-induced autophagy, as BRUCE depletion alone does not block autophagosome-lysosome fusion. BRUCE depletion-induced autophagy is coupled to enhanced cisplatin resistance in ovarian cancer cells. AMP/ATP ratio measurement, AMPK and ULK1 phosphorylation assays, autophagy flux assays, ATG16L puncta quantification, lysosomal enzyme activity measurement PloS one Medium 31091257
2019 BRUCE is recruited to induced DNA damage sites and is required for ATR activation during replication stress. BRUCE depletion inhibits ATR auto-activation, phosphorylation of CHK1 and RPA, and monoubiquitination of FANCD2. BRUCE deficiency results in stalled DNA replication forks and increased firing of new replication origins. Liver-specific BRUCE knockout in mice impairs ATR activation and exacerbates inflammation, fibrosis, and hepatocellular carcinoma. Immunoprecipitation, in vitro kinase assays, DNA fiber assays, conditional liver-specific KO mouse model with DEN-induced HCC Hepatology (Baltimore, Md.) High 30693543
2021 BIRC6 stability is increased by EGF-JNK signaling, which prevents ubiquitination and degradation of BIRC6 mediated by the E3 ubiquitin ligase HECTD1. BIRC6 in turn decreases SMAC expression by inducing the ubiquitin-proteasome pathway, antagonizing apoptosis. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, western blot, xenograft tumor model Molecular therapy. Nucleic acids Medium 34729249
2021 BRUCE interacts with Syntaxin 17 (STX17) as shown by co-immunoprecipitation and colocalization. miR-204 targets BRUCE, and knockdown of STX17 or BRUCE inhibits autophagosome-lysosome fusion and impairs axon growth, contributing to axonal dystrophy in an Alzheimer's disease cell model. Co-immunoprecipitation, dual luciferase reporter assay, immunofluorescence, RNAi knockdown Translational psychiatry Medium 34354038
2021 BRUCE deficiency in male germline leads to impaired spermatogonia maintenance, persistent meiotic DNA breaks, impaired homologous synapsis, chromosomal fragmentation and translocations. Bruce-deficient pachytene spermatocytes show unsynapsed regions devoid of ATM and ATR signaling, indicating BRUCE is required for ATM- and ATR-dependent meiotic homologous recombination. Germline-specific conditional KO mouse, FISH, immunofluorescence for synaptonemal complex components, ATM/ATR signaling markers Cell death and differentiation High 32139899
2021 BRUCE deficiency combined with PKA activates β-catenin through PKA-dependent phosphorylation at Ser-675 (pSer-675-β-catenin) and promotes nuclear β-catenin accumulation. BRUCE and PKA colocalize in hepatocyte cytoplasm, and BRUCE suppresses PKA activity. BRUCE deficiency elevates PKA activity and activates β-catenin signaling during liver disease progression. Co-localization by immunofluorescence, PKA activity assay, western blot for phospho-β-catenin, liver-specific KO mouse model World journal of hepatology Medium 33815677
2023 Cryo-EM structures show BIRC6 forms a megadalton crescent-shaped antiparallel dimer with a spacious central cavity containing client protein receptor sites. BIRC6 directly restricts executioner caspase-3 and -7 and ubiquitinates caspase-3, -7, and -9 exclusively via non-canonical E1 UBA6. SMAC binds BIRC6 with multisite, subnanomolar affinity, competitively displacing caspases and obstructing ubiquitination of both apoptotic and autophagy substrates. Cryo-electron microscopy structure determination, in vitro caspase inhibition assays, in vitro ubiquitination assay, ITC binding measurements Science (New York, N.Y.) High 36758104 36758105 36758106
2024 BIRC6 forms an antiparallel U-shaped dimer with multiple previously unannotated domains including a ubiquitin-like domain. SMAC/DIABLO binds BIRC6 in the central cavity and outcompetes effector caspase-3 and HtrA2 but not procaspase-9 for BIRC6 binding in cells. BIRC6 also binds LC3 through its LC3-interacting region (LIR). Induction of autophagy promotes autophagic degradation of BIRC6 and caspase-9 but not other effector caspases. Cryo-EM structure, co-immunoprecipitation competition assay, LC3-pull down, LC3 ubiquitylation site mutagenesis, autophagic flux assays Nature communications High 38291026
2024 BIRC6 acts as a ubiquitin ligase for KRAS4A, interacting with it on the Golgi apparatus and promoting mono- and di-ubiquitination of KRAS4A at lysines 128 and 147. This interaction is specific to KRAS4A over KRAS4B. Silencing BIRC6 diminishes GTP loading of KRAS4A and suppresses KRAS4A-driven growth stimulation. Proximity labeling interactome mapping, co-immunoprecipitation, ubiquitination site mapping by mass spectrometry, GTP-loading assay, RNAi knockdown Cell reports High 39705142
2024 BIRC6 modulates Axin protein stability by interacting with Axin and promoting its ubiquitination and degradation, thereby activating β-catenin signaling in renal cell carcinoma cells. Co-immunoprecipitation, ubiquitination assay, protein turnover assay, siRNA knockdown, xenograft tumor model ACS omega Medium 38405482
2025 BIRC6 gains priority access to UBA6 over all other UBA6-competent E2s through an exceptionally high-affinity interaction mediated by BIRC6 engagement with the UBA6 ubiquitin fold domain, modulated by the UBA6 Cys-Cap loop. BIRC6 disengages from UBA6 upon receiving ubiquitin via a bespoke thioester switch mechanism to prevent inhibition of UBA6. Cryo-EM structures of BIRC6-UBA6 complexes in different states, biochemical E1-E2 specificity assays, domain mutagenesis Nature structural & molecular biology High 41350950

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture. Cancer research 529 10606224
1995 Camptothecin and taxol: discovery to clinic--thirteenth Bruce F. Cain Memorial Award Lecture. Cancer research 280 7850785
2004 Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase. Molecular cell 181 15200957
2008 Effector caspase Dcp-1 and IAP protein Bruce regulate starvation-induced autophagy during Drosophila melanogaster oogenesis. The Journal of cell biology 155 18794330
2008 Final stages of cytokinesis and midbody ring formation are controlled by BRUCE. Cell 149 18329369
2005 The Birc6 (Bruce) gene regulates p53 and the mitochondrial pathway of apoptosis and is essential for mouse embryonic development. Proceedings of the National Academy of Sciences of the United States of America 126 15640352
2004 Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a novel pathway for triggering apoptosis. The EMBO journal 120 14765125
1996 Beyond DNA cross-linking: history and prospects of DNA-targeted cancer treatment--fifteenth Bruce F. Cain Memorial Award Lecture. Cancer research 98 8971150
2013 Epstein-Barr virus-encoded microRNA BART15-3p promotes cell apoptosis partially by targeting BRUCE. Journal of virology 94 23678170
2020 Anti-apoptotic proteins in the autophagic world: an update on functions of XIAP, Survivin, and BRUCE. Journal of biomedical science 85 32019552
2019 Negative regulation of autophagy by UBA6-BIRC6-mediated ubiquitination of LC3. eLife 82 31692446
2018 The IAP family member BRUCE regulates autophagosome-lysosome fusion. Nature communications 81 29426817
2011 Comparative proteomics of colon cancer stem cells and differentiated tumor cells identifies BIRC6 as a potential therapeutic target. Molecular & cellular proteomics : MCP 77 21788403
2004 The membrane-associated inhibitor of apoptosis protein, BRUCE/Apollon, antagonizes both the precursor and mature forms of Smac and caspase-9. The Journal of biological chemistry 76 15507451
2002 Drosophila Bruce can potently suppress Rpr- and Grim-dependent but not Hid-dependent cell death. Current biology : CB 70 12121627
2009 Die hard: are cancer stem cells the Bruce Willises of tumor biology? Cytometry. Part A : the journal of the International Society for Analytical Cytology 69 19051297
2004 BRUCE, a giant E2/E3 ubiquitin ligase and inhibitor of apoptosis protein of the trans-Golgi network, is required for normal placenta development and mouse survival. Molecular and cellular biology 60 15485903
2007 Inactivation of the oxytocin and the vasopressin (Avp) 1b receptor genes, but not the Avp 1a receptor gene, differentially impairs the Bruce effect in laboratory mice (Mus musculus). Endocrinology 56 17947352
2019 circ-BIRC6, a circular RNA, promotes hepatocellular carcinoma progression by targeting the miR-3918/Bcl2 axis. Cell cycle (Georgetown, Tex.) 54 30931701
2023 Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex. Science (New York, N.Y.) 49 36758105
2019 SIP/CacyBP promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation. Proceedings of the National Academy of Sciences of the United States of America 49 31213539
2020 CircRNA BIRC6 promotes non-small cell lung cancer cell progression by sponging microRNA-145. Cellular oncology (Dordrecht, Netherlands) 44 32297303
2013 Elevated expression of BIRC6 protein in non-small-cell lung cancers is associated with cancer recurrence and chemoresistance. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 42 23287853
2020 MALAT1 knockdown inhibits prostate cancer progression by regulating miR-140/BIRC6 axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 41 31935634
1995 Initiatives with platinum- and quinazoline-based antitumor molecules--Fourteenth Bruce F. Cain Memorial Award Lecture. Cancer research 41 7796401
2015 BRUCE regulates DNA double-strand break response by promoting USP8 deubiquitination of BRIT1. Proceedings of the National Academy of Sciences of the United States of America 39 25733871
2014 BIRC6 promotes hepatocellular carcinogenesis: interaction of BIRC6 with p53 facilitating p53 degradation. International journal of cancer 38 25196217
1998 Translational research: walking the bridge between idea and cure--seventeenth Bruce F. Cain Memorial Award lecture. Cancer research 36 9766639
2022 Circular RNA BIRC6 depletion promotes osteogenic differentiation of periodontal ligament stem cells via the miR-543/PTEN/PI3K/AKT/mTOR signaling pathway in the inflammatory microenvironment. Stem cell research & therapy 35 35964136
2013 BIRC6 protein, an inhibitor of apoptosis: role in survival of human prostate cancer cells. PloS one 34 23409057
2023 Structural basis for SMAC-mediated antagonism of caspase inhibition by the giant ubiquitin ligase BIRC6. Science (New York, N.Y.) 33 36758106
2023 Structures of BIRC6-client complexes provide a mechanism of SMAC-mediated release of caspases. Science (New York, N.Y.) 32 36758104
2016 miR-30e Blocks Autophagy and Acts Synergistically with Proanthocyanidin for Inhibition of AVEN and BIRC6 to Increase Apoptosis in Glioblastoma Stem Cells and Glioblastoma SNB19 Cells. PloS one 30 27388765
2014 The BIRC6 gene as a novel target for therapy of prostate cancer: dual targeting of inhibitors of apoptosis. Oncotarget 30 25071009
2016 BIRC6 Targeting as Potential Therapy for Advanced, Enzalutamide-Resistant Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 29 27663589
2002 BRUCE: a program for the detection of transfer-messenger RNA genes in nucleotide sequences. Nucleic acids research 28 12140330
2008 Prostaglandin F2alpha promotes muscle cell survival and growth through upregulation of the inhibitor of apoptosis protein BRUCE. Cell death and differentiation 27 18566603
2020 Paclitaxel Suppresses Hepatocellular Carcinoma Tumorigenesis Through Regulating Circ-BIRC6/miR-877-5p/YWHAZ Axis. OncoTargets and therapy 26 33061425
2019 The BRUCE-ATR Signaling Axis Is Required for Accurate DNA Replication and Suppression of Liver Cancer Development. Hepatology (Baltimore, Md.) 26 30693543
2012 Identification of BIRC6 as a novel intervention target for neuroblastoma therapy. BMC cancer 25 22788920
2011 Drosophila BRUCE inhibits apoptosis through non-lysine ubiquitination of the IAP-antagonist REAPER. Cell death and differentiation 25 21886178
2005 Progressive loss of the spongiotrophoblast layer of Birc6/Bruce mutants results in embryonic lethality. Genesis (New York, N.Y. : 2000) 25 15887267
2018 The anti-apoptotic ubiquitin conjugating enzyme BIRC6/BRUCE regulates autophagosome-lysosome fusion. Autophagy 22 29929453
2017 10H-3,6-Diazaphenothiazine induces G2/M phase cell cycle arrest and caspase-dependent apoptosis and inhibits cell invasion of A2780 ovarian carcinoma cells through the regulation of NF-κB and (BIRC6-XIAP) complexes. Drug design, development and therapy 22 29123378
2014 Expression and clinical significance of BIRC6 in human epithelial ovarian cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 22 24453032
2017 Exocrine Gland-Secreting Peptide 1 Is a Key Chemosensory Signal Responsible for the Bruce Effect in Mice. Current biology : CB 21 29033330
2010 Depletion of BIRC6 leads to retarded bovine early embryonic development and blastocyst formation in vitro. Reproduction, fertility, and development 20 20188030
2006 The contribution of Bruce Glick to the definition of the role played by the bursa of Fabricius in the development of the B cell lineage. Clinical and experimental immunology 20 16792666
2019 Loss of BRUCE reduces cellular energy level and induces autophagy by driving activation of the AMPK-ULK1 autophagic initiating axis. PloS one 19 31091257
2024 Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy. Nature communications 18 38291026
2011 Oestradiol treatment restores the capacity of castrated males to induce both the Vandenbergh and the Bruce effects in mice (Mus musculus). Reproduction (Cambridge, England) 18 22016382
2017 BIRC6 mediates imatinib resistance independently of Mcl-1. PloS one 17 28520795
2009 Dexamethasone regulates expression of BRUCE/Apollon and the proliferation of neural progenitor cells. FEBS letters 17 19527720
2022 Cellular and immunometabolic mechanisms of inflammation in depression: Preliminary findings from single cell RNA sequencing and a tribute to Bruce McEwen. Neurobiology of stress 16 35655933
2019 Analysis of the expression of BAX, BCL2, BIRC6, CASP3, CASP9 apoptosis genes during the first episode of schizophrenia. Psychiatria polska 16 32017818
2018 MiR-204 acts as a potential therapeutic target in acute myeloid leukemia by increasing BIRC6-mediated apoptosis. BMB reports 16 29764561
2022 Impact of stress on inhibitory neuronal circuits, our tribute to Bruce McEwen. Neurobiology of stress 15 35734023
2020 Long Non-Coding RNA DLEU1 Up-Regulates BIRC6 Expression by Competitively Sponging miR-381-3p to Promote Cisplatin Resistance in Nasopharyngeal Carcinoma. OncoTargets and therapy 15 32214823
2021 Overexpression of BIRC6 driven by EGF-JNK-HECTD1 signaling is a potential therapeutic target for triple-negative breast cancer. Molecular therapy. Nucleic acids 14 34729249
2020 Depletion of circ-BIRC6, a circular RNA, suppresses non-small cell lung cancer progression by targeting miR-4491. Bioscience trends 13 33177288
2021 BRUCE silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in Alzheimer's disease. Translational psychiatry 12 34354038
2021 Silencing circ‑BIRC6 inhibits the proliferation, invasion, migration and epithelial‑mesenchymal transition of bladder cancer cells by targeting the miR‑495‑3p/XBP1 signaling axis. Molecular medicine reports 12 34542161
2020 Bioactivity and cytotoxicity profiling of vincosamide and strictosamide, anthelmintic epimers from Sarcocephalus latifolius (Smith) Bruce leaf. Journal of ethnopharmacology 12 32697959
2014 Association of a polymorphism in the BIRC6 gene with pseudoexfoliative glaucoma. PloS one 12 25118708
2013 Redescription and genetic characterization of Hysterothylacium thalassini Bruce, 1990 (Nematoda: Anisakidae) from marine fishes in the South China Sea. The Journal of parasitology 12 23343397
2005 Bruce/apollon promotes hippocampal neuron survival and is downregulated by kainic acid. Biochemical and biophysical research communications 12 16236253
2016 Asymmetric hybridization between non-native winter moth, Operophtera brumata (Lepidoptera: Geometridae), and native Bruce spanworm, Operophtera bruceata, in the Northeastern United States, assessed with novel microsatellites and SNPs. Bulletin of entomological research 11 27876095
2015 Knockdown of the Inhibitor of Apoptosis BRUCE Sensitizes Resistant Breast Cancer Cells to Chemotherapeutic Agents. Journal of cancer science & therapy 11 26191375
2015 The UBC Domain Is Required for BRUCE to Promote BRIT1/MCPH1 Function in DSB Signaling and Repair Post Formation of BRUCE-USP8-BRIT1 Complex. PloS one 11 26683461
2019 Circ_MDM2_000139, Circ_ATF2_001418, Circ_CDC25C_002079, and Circ_BIRC6_001271 Are Involved in the Functions of XAV939 in Non-Small Cell Lung Cancer. Canadian respiratory journal 9 31885751
2012 RNA interference-mediated validation of survivin and Apollon/BRUCE as new therapeutic targets for cancer therapy. Current topics in medicinal chemistry 9 22196277
2022 A new circular RNA-encoded protein BIRC6-236aa inhibits transmissible gastroenteritis virus (TGEV)-induced mitochondrial dysfunction. The Journal of biological chemistry 8 35863430
2020 BRUCE preserves genomic stability in the male germline of mice. Cell death and differentiation 8 32139899
2020 Reflections on Bruce S. McEwen's contributions to stress neurobiology and so much more. Stress (Amsterdam, Netherlands) 8 32851903
2012 BIRC6 (APOLLON) is down-regulated in acute myeloid leukemia and its knockdown attenuates neutrophil differentiation. Experimental hematology & oncology 8 23211188
2023 Evaluation of BIRC6 Expression in Oral Squamous Cell Carcinoma, Epithelial Dysplasia, Lichen Planus with and without Dysplasia, and Hyperkeratosis. Diagnostics (Basel, Switzerland) 7 38066801
2020 BIRC6 Is Associated with Vulnerability of Carotid Atherosclerotic Plaque. International journal of molecular sciences 7 33317170
2017 BRUCE Protein, New Marker for Targeted Therapy of Gastric Carcinoma. Journal of gastrointestinal cancer 7 27614745
2022 BIRC6 modifies risk of invasive bacterial infection in Kenyan children. eLife 6 35866869
2024 BIRC6 Modulates the Protein Stability of Axin to Regulate the Growth, Stemness, and Resistance of Renal Cancer Cells via the β-Catenin Pathway. ACS omega 5 38405482
2022 Oral Squamous Cell Carcinoma: The Role of BIRC6 Serum Level. BioMed research international 5 36033570
2016 Expression analysis of BRUCE protein in esophageal squamous cell carcinoma. Annals of diagnostic pathology 5 27649954
2020 Bruce Nathan Ames - Paradigm shifts inside the cancer research revolution. Mutation research. Reviews in mutation research 4 34083041
2019 A personally guided tour on some of our data with the Ames assay-A tribute to Professor Bruce Ames. Mutation research. Genetic toxicology and environmental mutagenesis 4 31585631
2019 Nrdp1 increases neuron apoptosis via downregulation of Bruce following intracerebral haemorrhage. Journal of inflammation (London, England) 4 31827407
2014 Apollon/Bruce is upregulated by Humanin. Molecular and cellular biochemistry 4 25138702
2008 Regulation of apoptosis and cytokinesis by the anti-apoptotic E2/E3 ubiquitin-ligase BRUCE. Ernst Schering Foundation symposium proceedings 4 19198067
2025 UBA6 specificity for ubiquitin E2 conjugating enzymes reveals a priority mechanism of BIRC6. Nature structural & molecular biology 3 41350950
2022 Exploring the Role of the Inhibitor of Apoptosis BIRC6 in Breast Cancer: A Database Analysis. JCO clinical cancer informatics 3 36455174
2021 BIR repeat-containing ubiquitin conjugating enzyme (BRUCE) regulation of β-catenin signaling in the progression of drug-induced hepatic fibrosis and carcinogenesis. World journal of hepatology 3 33815677
2018 Using the SSU, ITS, and Ribosomal DNA Operon Arrangement to Characterize Two Microsporidia Infecting Bruce Spanworm, Operophtera bruceata (Lepidoptera: Geometridae). The Journal of eukaryotic microbiology 3 30136341
2016 Nrdp1-mediated degradation of BRUCE decreases cell viability and induces apoptosis in human 786-O renal cell carcinoma cells. Experimental and therapeutic medicine 3 27446249
1988 The male-induced implantation failure (the Bruce effect) in laboratory mice: investigations on luteal failure in pregnancy-blocked females. Experimental and clinical endocrinology 3 3229446
1980 Evidence for the involvement of serotoninergic system in the male-induced ovo-implantation failure (Bruce effect) in mice. Annales d'endocrinologie 3 7235620
2024 The differential interactomes of the KRAS splice variants identify BIRC6 as a ubiquitin ligase for KRAS4A. Cell reports 2 39705142
2023 The Media Coverage of Bruce Willis Reveals Unfamiliarity With Frontotemporal Degeneration. Innovation in aging 2 38046892
2020 [Effect of small interfering RNA-mediated BIRC6 silencing on apoptosis and autophagy of renal cancer 786-O cells]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 2 33243730
2020 A Wide Frequency Scanning Printed Bruce Array Antenna with Bowtie and Semi-Circular Elements. Sensors (Basel, Switzerland) 2 33261220
2010 Improved synthesis of (3E,6Z,9Z)-1,3,6,9-nonadecatetraene, attraction inhibitor of bruce spanworm, Operophtera bruceata, to pheromone traps for monitoring winter moth, Operophtera brumata. Journal of agricultural and food chemistry 2 20041659
1998 Volume 8, Number 2 (1997): Kyung-Eui Ro, Carl S. Keener, and Bruce A. McPheron, "Molecular Phylogenetic Study of the Ranunculaceae: Utility of the Nuclear 26S Ribosomal DNA in Inferring Intrafamilial Relationships," pp. 117-127: Molecular phylogenetics and evolution 2 9527909