BIRC6 (also known as BRUCE or Apollon) is a giant (~528 kDa) dual-function E2 ubiquitin-conjugating enzyme and E3 ubiquitin-protein ligase (EC 2.3.2.24) belonging to the inhibitor of apoptosis (IAP) protein family. It contains an N-terminal BIR (baculovirus IAP repeat) domain that mediates caspase binding and inhibition, and a C-terminal UBC (ubiquitin-conjugating enzyme) domain that confers chimeric E2/E3 ubiquitin ligase activity. BIRC6 functions as an antiparallel homodimer with a central substrate-binding cavity. Its primary molecular functions are (1) ubiquitination of pro-apoptotic factors (caspases-3, -7, -9, Smac/DIABLO, HtrA2) to inhibit apoptosis, (2) mono-ubiquitination of LC3 at K51 to suppress autophagy (in cooperation with E1 enzyme UBA6), and (3) regulation of cytokinesis by localizing to the midbody ring and coordinating vesicular targeting during abscission. BIRC6 exhibits cell cycle-dependent localization, concentrating at the trans-Golgi network and endosomes in interphase and relocating to spindle poles, the midzone, and the midbody during cell division. Smac/DIABLO antagonizes BIRC6 by competing for substrate binding sites. BIRC6 is itself regulated by RNF41/Nrdp1-mediated ubiquitination and proteasomal degradation, by deubiquitination via USP8, and by caspase-mediated cleavage. A nuclear pool forms a complex with USP8 and BRIT1/MCPH1 that supports the DNA double-strand-break response.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005802 trans-Golgi network | IBA GO_REF:0000033 | ACCEPT | Summary: BIRC6 localizes to the trans-Golgi network membrane in interphase cells, as demonstrated by immunofluorescence in PMID:18329369 and confirmed in the UniProt subcellular location annotation. This IBA annotation is consistent with both experimental and phylogenetic evidence. Reason: Trans-Golgi network localization is experimentally established for BIRC6 (PMID:18329369) and is a core aspect of its interphase localization. The IBA annotation is well-supported by the phylogenetic inference and direct experimental data. Supporting Evidence: UniProtKB:Q9NR09 In interphase cells, localizes to the trans-Golgi network membrane and endosomes. PMID:15200957 BRUCE, a conserved 528 kDa peripheral membrane protein of the trans-Golgi network |
| GO:0061631 ubiquitin conjugating enzyme activity | IBA GO_REF:0000033 | ACCEPT | Summary: BIRC6 contains a C-terminal UBC domain and functions as a chimeric E2/E3 ubiquitin ligase, confirmed by multiple structural and biochemical studies (PMID:15200957, PMID:36758104, PMID:36758105, PMID:36758106). The IBA annotation accurately captures the E2 conjugating enzyme activity component. Reason: Ubiquitin conjugating enzyme activity is a core molecular function of BIRC6, well established by the presence of the UBC domain and direct biochemical demonstration of E2 activity. The IBA annotation is at the correct level of specificity. Supporting Evidence: PMID:15200957 BRUCE has the distinctive property of functioning as a chimeric E2/E3 ubiquitin ligase with Smac being a substrate. |
| GO:0043066 negative regulation of apoptotic process | IBA GO_REF:0000033 | ACCEPT | Summary: BIRC6 is a member of the IAP family and inhibits apoptosis by ubiquitinating and promoting degradation of pro-apoptotic factors including caspases and Smac/DIABLO (PMID:15200957, PMID:10544019, PMID:14765125). This is a core evolved function. Reason: Anti-apoptotic activity is one of the two primary evolved functions of BIRC6. The IBA annotation is well-supported by extensive experimental evidence from multiple studies. Supporting Evidence: PMID:15200957 BRUCE inhibits caspase activity and apoptosis depending on its BIR domain. PMID:14765125 BRUCE normally inhibits apoptosis, and Nrdp1 can be important in the initiation of apoptosis by catalyzing ubiquitination and degradation of BRUCE. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: A nuclear BIRC6/BRUCE pool supports DNA damage-response scaffolding. Reason: PMID:25733871 directly detects endogenous BRUCE in nuclear and chromatin-enriched fractions and a nuclear BRUCE-USP8-BRIT1 complex in human cells. This overturns the previous exclusion based on Golgi/cytoplasmic localization. The IBA from PTN000799330 is compatible with target-specific evidence, although the nuclear repair role is additional to the best-characterized apoptosis and cytokinesis functions. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000799330 · PTN000799330 SUPPORTS TRANSFER The IBD is compatible with direct human BRUCE nuclear fractionation and complex evidence (PMID:25733871); the UBE2Z seed is not evidence against transfer. Supporting Evidence: PMID:25733871 the presence of a preexisting BRUCE–USP8–BRIT1 complex in the cell nucleus under normal growth conditions. |
| GO:0000922 spindle pole | IEA GO_REF:0000044 | ACCEPT | Summary: BIRC6 moves partially to spindle poles in metaphase as part of its cell cycle-dependent localization pattern (PMID:18329369). This IEA annotation is consistent with direct experimental evidence. Reason: Spindle pole localization is experimentally established by immunofluorescence (PMID:18329369) and consistent with BIRC6's role in cytokinesis. Supporting Evidence: UniProtKB:Q9NR09 Concentrates in a pericentriolar compartment in interphase, moves partially to spindle poles in metaphase |
| GO:0004842 ubiquitin-protein transferase activity | IEA GO_REF:0000120 | MODIFY | Summary: BIRC6 has ubiquitin-protein transferase (E3 ligase) activity demonstrated biochemically with multiple substrates including Smac, caspases, and LC3 (PMID:15200957, PMID:36758104, PMID:36758105, PMID:36758106). This IEA annotation is well-supported by direct evidence. Reason: Ubiquitin-protein transferase activity is a core function of BIRC6, but it is a broad parent. The PN projection to GO:0061630 ubiquitin protein ligase activity is the more specific molecular-function term for the E3 component of BIRC6's dual E2/E3 activity. Proposed replacements: ubiquitin protein ligase activity Supporting Evidence: PMID:15200957 BRUCE has the distinctive property of functioning as a chimeric E2/E3 ubiquitin ligase with Smac being a substrate. |
| GO:0004869 cysteine-type endopeptidase inhibitor activity | IEA GO_REF:0000043 | ACCEPT | Summary: BIRC6 inhibits caspase activity through its BIR domain-mediated binding and through ubiquitination-dependent degradation of caspases (PMID:15200957). The inhibition of caspases-3, -6, -7, and -9 is well-established. This IEA annotation is consistent with experimental data. Reason: Caspase inhibition is a core function of BIRC6 as an IAP family member. The BIR domain directly binds and inhibits active caspases, and the UBC domain promotes their ubiquitination and degradation. Supporting Evidence: PMID:15200957 BRUCE inhibits caspase activity and apoptosis depending on its BIR domain. |
| GO:0005768 endosome | IEA GO_REF:0000044 | ACCEPT | Summary: BIRC6 localizes to endosomes in interphase cells (PMID:18329369). This IEA annotation is consistent with direct immunofluorescence evidence. Reason: Endosomal localization is part of the vesicular system localization of BIRC6 in interphase, as experimentally demonstrated. Supporting Evidence: UniProtKB:Q9NR09 In interphase cells, localizes to the trans-Golgi network membrane and endosomes. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | ACCEPT | Summary: BIRC6 localizes to the trans-Golgi network, which is part of the Golgi apparatus (PMID:18329369, PMID:15200957). This broader IEA annotation is consistent with experimental evidence, though trans-Golgi network (GO:0005802) is more specific. Reason: The Golgi apparatus annotation is correct as a broader term encompassing the more specific trans-Golgi network localization. Both the IEA and more specific IDA/IBA annotations coexist appropriately. Supporting Evidence: PMID:15200957 BRUCE, a conserved 528 kDa peripheral membrane protein of the trans-Golgi network |
| GO:0005813 centrosome | IEA GO_REF:0000044 | ACCEPT | Summary: BIRC6 concentrates in a pericentriolar compartment in interphase (PMID:18329369), which corresponds to centrosome localization. The IEA annotation is consistent with direct experimental evidence. Reason: Centrosomal/pericentriolar localization during interphase is experimentally established by immunofluorescence. Supporting Evidence: UniProtKB:Q9NR09 Concentrates in a pericentriolar compartment in interphase |
| GO:0006915 apoptotic process | IEA GO_REF:0000120 | ACCEPT | Summary: BIRC6 is involved in apoptotic process as an anti-apoptotic IAP protein. However, the more specific term 'negative regulation of apoptotic process' (GO:0043066) is already annotated and more accurately describes BIRC6's role. Reason: While the more specific annotation GO:0043066 (negative regulation of apoptotic process) better describes BIRC6's role, this broader IEA annotation is not incorrect. It is acceptable for IEA annotations to be broader than more specific experimental annotations. Supporting Evidence: PMID:15200957 BRUCE inhibits caspase activity and apoptosis depending on its BIR domain. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000117 | ACCEPT | Summary: BIRC6 catalyzes protein ubiquitination as a chimeric E2/E3 enzyme (PMID:15200957, PMID:36758104, PMID:36758105). Substrates include caspases, Smac/DIABLO, HtrA2, and LC3. This IEA annotation is well-supported. Reason: Protein ubiquitination is a core biochemical process catalyzed by BIRC6. The IEA annotation accurately captures this function. Supporting Evidence: PMID:15200957 BRUCE has the distinctive property of functioning as a chimeric E2/E3 ubiquitin ligase with Smac being a substrate. |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | ACCEPT | Summary: BIRC6 has transferase activity as a ubiquitin-conjugating/ligase enzyme. However, this is a very broad parent term; the more specific terms ubiquitin conjugating enzyme activity (GO:0061631) and ubiquitin-protein transferase activity (GO:0004842) are already annotated. Reason: This is a correct but very general IEA annotation. It is acceptable for automated IEA annotations to capture broader terms when more specific annotations already exist. Supporting Evidence: PMID:15200957 BRUCE has the distinctive property of functioning as a chimeric E2/E3 ubiquitin ligase |
| GO:0030414 peptidase inhibitor activity | IEA GO_REF:0000043 | ACCEPT | Summary: BIRC6 inhibits caspase (peptidase) activity through its BIR domain. The more specific term cysteine-type endopeptidase inhibitor activity (GO:0004869) is already annotated. This broader IEA term is not wrong. Reason: This broader IEA annotation is consistent with the more specific caspase inhibitor function. It is acceptable for IEA annotations to be broader. Supporting Evidence: PMID:15200957 BRUCE inhibits caspase activity and apoptosis depending on its BIR domain. |
| GO:0032465 regulation of cytokinesis | IEA GO_REF:0000002 | ACCEPT | Summary: BIRC6 is a major regulator of the final stages of cytokinesis, controlling abscission, midbody ring formation, and vesicular targeting (PMID:18329369). This IEA annotation is consistent with strong experimental evidence. Reason: Regulation of cytokinesis is a core function of BIRC6, well-established by the detailed mechanistic study in PMID:18329369. Supporting Evidence: PMID:18329369 we identify BRUCE, a 528 kDa multifunctional protein, which processes ubiquitin-conjugating activity, as a major regulator of abscission. |
| GO:0042127 regulation of cell population proliferation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: BIRC6 is involved in cell proliferation indirectly through its anti-apoptotic and cytokinesis regulatory functions. The review by Dubrez-Daloz et al. (PMID:18414036) discusses IAP roles in cell proliferation. However, this is a broad and somewhat indirect annotation for BIRC6. Reason: Regulation of cell proliferation is not a direct core function of BIRC6 but rather an indirect consequence of its anti-apoptotic and cytokinesis roles. It should be kept as non-core. Supporting Evidence: PMID:18414036 IAPs are also known as BIR-containing proteins (BIRCs). Most of them display anti-apoptotic properties when overexpressed. |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000117 | ACCEPT | Summary: Duplicate IEA annotation of negative regulation of apoptotic process. This is a core function of BIRC6 as an IAP family member, supported by multiple experimental studies. Reason: This IEA annotation duplicates the IBA and IMP annotations for the same term. The function is well-established as a core role of BIRC6. Supporting Evidence: PMID:15200957 BRUCE inhibits caspase activity and apoptosis depending on its BIR domain. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: BIRC6 contains a BIR domain that coordinates zinc ions, as is characteristic of BIR domains across IAP family members. The cryo-EM structure (PMID:36758105) was solved in complex with zinc. This IEA annotation is consistent with the structural data. Reason: Metal (zinc) ion binding is a structural feature of the BIR domain. While not a core functional annotation per se, it is an accurate molecular property of the protein. Supporting Evidence: file:human/BIRC6/BIRC6-deep-research-falcon.md BIRC6 forms an anti-parallel U-shaped dimer with a central substrate-binding cavity that accommodates Smac/DIABLO, and includes multiple domains (including a ubiquitin-like domain, N-terminal WD40 beta-propeller, a small BIR domain, and a UBC domain). |
| GO:0051301 cell division | IEA GO_REF:0000043 | ACCEPT | Summary: BIRC6 is involved in cell division through its critical role in cytokinesis (PMID:18329369). The more specific term 'regulation of cytokinesis' (GO:0032465) is already annotated. Reason: Cell division is a broader term that encompasses cytokinesis. This IEA annotation is acceptable as a parent of the more specific cytokinesis annotation. Supporting Evidence: PMID:18329369 Depletion of BRUCE in cell cultures causes defective abscission and cytokinesis-associated apoptosis |
| GO:0061631 ubiquitin conjugating enzyme activity | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate IEA annotation of ubiquitin conjugating enzyme activity, also annotated by IBA. BIRC6 has a UBC domain and functions as a chimeric E2/E3 enzyme. Reason: This duplicates the IBA annotation for the same GO term. The E2 conjugating enzyme activity is a core function of BIRC6, well-established by structural and biochemical data. Supporting Evidence: PMID:15200957 BRUCE has the distinctive property of functioning as a chimeric E2/E3 ubiquitin ligase |
| GO:0090543 Flemming body | IEA GO_REF:0000044 | ACCEPT | Summary: BIRC6 localizes to the midbody ring (also called the Flemming body) during cytokinesis, as demonstrated by immunofluorescence (PMID:18329369). The UniProt subcellular location annotation explicitly mentions this. Reason: Flemming body (midbody ring) localization is experimentally established and is central to BIRC6's role in cytokinesis regulation. Supporting Evidence: UniProtKB:Q9NR09 On the midbody, localizes to the midbody ring, also called Flemming body. |
| GO:0005515 protein binding | IPI PMID:18329369 Final stages of cytokinesis and midbody ring formation are c... | REMOVE | Summary: BIRC6 interacts with multiple proteins during cytokinesis including KIF23/MKLP1, USP8/UBPY, survivin, MEK1, RAB8, RAB11, PLK1, SEC6, and SEC8 (PMID:18329369). However, 'protein binding' is uninformative as a molecular function term. Reason: The term 'protein binding' (GO:0005515) provides no specific information about BIRC6's actual molecular function. The interactions are biologically meaningful but better captured by process annotations (regulation of cytokinesis) and more specific molecular function terms. Supporting Evidence: PMID:18329369 BRUCE moves from the vesicular system to the midbody ring and serves as a platform for the membrane delivery machinery and mitotic regulators. |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | REMOVE | Summary: High-throughput interactome study. 'Protein binding' is uninformative. Reason: The term 'protein binding' (GO:0005515) is uninformative. High-throughput interaction data should be captured by more specific interaction types when possible. Supporting Evidence: PMID:26496610 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput interactome study. 'Protein binding' is uninformative. Reason: The term 'protein binding' (GO:0005515) is uninformative. These high-throughput data do not provide functional insight beyond what is captured by more specific annotations. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0001890 placenta development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This annotation is transferred from mouse ortholog data. BIRC6-knockout mice show placental defects (labyrinthine layer development issues), which could be a consequence of the general anti-apoptotic and cytokinesis functions of BIRC6 rather than a placenta-specific function. Reason: Placenta development is likely a pleiotropic consequence of BIRC6's core anti-apoptotic and cytokinesis functions rather than a specific evolved function for placental biology. The annotation should be kept but marked as non-core. Supporting Evidence: file:human/BIRC6/BIRC6-deep-research-falcon.md BIRC6 is a giant dual-function E2/E3 ubiquitin enzyme with a BIR domain that binds caspase regulators and a UBC domain enabling ubiquitin transfer. |
| GO:0016020 membrane | IEA GO_REF:0000107 | ACCEPT | Summary: BIRC6 is described as a peripheral membrane protein of the trans-Golgi network (PMID:15200957). The 'membrane' annotation is very broad but not incorrect. Reason: BIRC6 is a peripheral membrane protein associated with the trans-Golgi network membrane. This broad IEA annotation is acceptable alongside the more specific trans-Golgi network annotation. Supporting Evidence: PMID:15200957 BRUCE, a conserved 528 kDa peripheral membrane protein of the trans-Golgi network |
| GO:0005794 Golgi apparatus | IDA GO_REF:0000052 | ACCEPT | Summary: BIRC6 localizes to the Golgi apparatus (specifically the trans-Golgi network) based on immunofluorescence data (GO_REF:0000052). Consistent with PMID:18329369 and PMID:15200957. Reason: Golgi apparatus localization is experimentally established by immunofluorescence and consistent with the more specific trans-Golgi network localization. Supporting Evidence: PMID:15200957 BRUCE, a conserved 528 kDa peripheral membrane protein of the trans-Golgi network |
| GO:0072686 mitotic spindle | IDA GO_REF:0000052 | ACCEPT | Summary: BIRC6 localizes to the spindle midzone during telophase as part of its cell cycle-dependent localization (PMID:18329369). Immunofluorescence data supports mitotic spindle localization. Reason: Mitotic spindle localization is experimentally established and is part of BIRC6's dynamic cell cycle-dependent localization pattern relevant to its cytokinesis function. Supporting Evidence: UniProtKB:Q9NR09 moves partially to spindle poles in metaphase, and finally localizes to the spindle midzone and the midbody in telophase |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9700131 | ACCEPT | Summary: The Reactome pathway R-HSA-9700131 (ALK mutants bind type I TKIs) seems unrelated to BIRC6's primary biology. However, BIRC6 is a cytoplasmic/cytosolic protein that functions in the cytoplasm. Cytosol localization is reasonable given the protein's known distribution. Reason: While the Reactome reference seems tangential, cytosolic localization of BIRC6 is consistent with its known function as a cytoplasmic protein that associates with membranes and cytoskeletal structures. Supporting Evidence: file:human/BIRC6/BIRC6-deep-research-falcon.md BIRC6 and Axin are reported to colocalize in the cytoplasm |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: BIRC6 was identified in the membrane proteome of NK cells by high-throughput mass spectrometry (PMID:19946888). This is consistent with BIRC6 being a peripheral membrane protein of the trans-Golgi network. Reason: Membrane association is consistent with BIRC6's established localization at the trans-Golgi network membrane. The HDA evidence supports the known biology. Supporting Evidence: PMID:15200957 BRUCE, a conserved 528 kDa peripheral membrane protein of the trans-Golgi network |
| GO:2001237 negative regulation of extrinsic apoptotic signaling pathway | IMP PMID:14765125 Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a ... | ACCEPT | Summary: Qiu et al. (PMID:14765125) showed that decreasing BRUCE content by RNAi promotes apoptosis, and that Nrdp1-mediated degradation of BRUCE triggers apoptosis. This demonstrates that BIRC6 negatively regulates the extrinsic apoptotic signaling pathway. Reason: The IMP evidence from PMID:14765125 directly demonstrates that BIRC6 loss promotes apoptosis, consistent with its role as an IAP. This annotation captures the specific pathway (extrinsic apoptotic signaling) that BIRC6 negatively regulates. Supporting Evidence: PMID:14765125 decreasing BRUCE content by RNA interference or overexpression of Nrdp1 promotes apoptosis. Thus, BRUCE normally inhibits apoptosis |
| GO:0000922 spindle pole | IDA PMID:18329369 Final stages of cytokinesis and midbody ring formation are c... | ACCEPT | Summary: BIRC6 moves to spindle poles in metaphase as demonstrated by immunofluorescence (PMID:18329369). Direct experimental evidence for this localization. Reason: Spindle pole localization is directly demonstrated by immunofluorescence in PMID:18329369 as part of BIRC6's cell cycle-dependent localization. Supporting Evidence: UniProtKB:Q9NR09 moves partially to spindle poles in metaphase |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:15200957 Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2... | MODIFY | Summary: Bartke et al. (PMID:15200957) directly demonstrated that BIRC6 functions as a chimeric E2/E3 ubiquitin ligase with Smac as a substrate. This is core experimental evidence for ubiquitin-protein transferase activity, but the more specific term is GO:0061630 ubiquitin protein ligase activity. Reason: Direct biochemical demonstration of E2/E3 ubiquitin ligase activity supports a core molecular function of BIRC6. The broad parent term should be replaced by the PN-supported specific term GO:0061630. Proposed replacements: ubiquitin protein ligase activity Supporting Evidence: PMID:15200957 BRUCE has the distinctive property of functioning as a chimeric E2/E3 ubiquitin ligase with Smac being a substrate. |
| GO:0004869 cysteine-type endopeptidase inhibitor activity | IMP PMID:15200957 Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2... | ACCEPT | Summary: Bartke et al. (PMID:15200957) showed that BIRC6 inhibits caspase activity in a BIR domain-dependent manner. BIRC6 strongly inhibits caspase-9 and more weakly inhibits caspase-3 activity. Reason: Caspase inhibition is a core function of BIRC6 as an IAP. The IMP evidence from PMID:15200957 directly demonstrates this activity. Supporting Evidence: PMID:15200957 BRUCE inhibits caspase activity and apoptosis depending on its BIR domain. |
| GO:0005515 protein binding | IPI PMID:15200957 Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2... | REMOVE | Summary: BIRC6 interacts with Smac, HtrA2, caspases-3, -6, -7, and -9 (PMID:15200957). However, 'protein binding' is uninformative. These interactions are better captured by the caspase inhibitor activity and ubiquitin ligase annotations. Reason: The term 'protein binding' is uninformative. The specific interactions with Smac and caspases are better represented by the cysteine-type endopeptidase inhibitor activity (GO:0004869) and ubiquitin-protein transferase activity (GO:0004842) annotations. Supporting Evidence: PMID:15200957 BRUCE inhibits caspase activity and apoptosis depending on its BIR domain. Upon apoptosis induction, BRUCE is antagonized by three mechanisms: first, through binding to Smac |
| GO:0005768 endosome | IDA PMID:18329369 Final stages of cytokinesis and midbody ring formation are c... | ACCEPT | Summary: BIRC6 localizes to endosomes in interphase cells (PMID:18329369). Direct immunofluorescence evidence. Reason: Endosomal localization is experimentally established by immunofluorescence and is part of BIRC6's vesicular system localization pattern. Supporting Evidence: UniProtKB:Q9NR09 In interphase cells, localizes to the trans-Golgi network membrane and endosomes. |
| GO:0005802 trans-Golgi network | IDA PMID:18329369 Final stages of cytokinesis and midbody ring formation are c... | ACCEPT | Summary: BIRC6 localizes to the trans-Golgi network membrane in interphase cells (PMID:18329369). Direct experimental evidence by immunofluorescence. Reason: Trans-Golgi network localization is a core localization of BIRC6, established by multiple studies. Supporting Evidence: UniProtKB:Q9NR09 In interphase cells, localizes to the trans-Golgi network membrane and endosomes. |
| GO:0005815 microtubule organizing center | IDA PMID:18329369 Final stages of cytokinesis and midbody ring formation are c... | ACCEPT | Summary: BIRC6 concentrates in a pericentriolar compartment (microtubule organizing center) in interphase (PMID:18329369). Direct immunofluorescence evidence. Reason: Microtubule organizing center (pericentriolar) localization during interphase is experimentally demonstrated and consistent with BIRC6's dynamic cell cycle-dependent localization. Supporting Evidence: UniProtKB:Q9NR09 Concentrates in a pericentriolar compartment in interphase |
| GO:0006468 protein phosphorylation | TAS PMID:18329369 Final stages of cytokinesis and midbody ring formation are c... | UNDECIDED | Summary: The phosphorylation-process attribution requires inspection of the original full text. Reason: BIRC6 is an E2/E3 ubiquitin enzyme, and being phosphorylated would not itself establish participation in protein phosphorylation. However, the cached PMID:18329369 is abstract-only, and the absence of a phosphorylation mechanism there cannot establish that the source annotation was erroneous. A kinase-scaffolding or other direct contribution must be checked before a confident removal. Supporting Evidence: PMID:18329369 we identify BRUCE, a 528 kDa multifunctional protein, which processes ubiquitin-conjugating activity, as a major regulator of abscission. |
| GO:0016567 protein ubiquitination | TAS PMID:18329369 Final stages of cytokinesis and midbody ring formation are c... | ACCEPT | Summary: BIRC6 catalyzes protein ubiquitination during cytokinesis, and ubiquitin relocalizes from midbody microtubules to the midbody ring in a BRUCE-dependent manner (PMID:18329369). TAS evidence from a well-characterized study. Reason: Protein ubiquitination is a core biochemical activity of BIRC6, directly supported by PMID:18329369 and multiple other studies. Supporting Evidence: PMID:18329369 ubiquitin relocalizes from midbody microtubules to the midbody ring during cytokinesis, and depletion of BRUCE disrupts this process. |
| GO:0030496 midbody | IDA PMID:18329369 Final stages of cytokinesis and midbody ring formation are c... | ACCEPT | Summary: BIRC6 localizes to the midbody during telophase and cytokinesis, specifically to the midbody ring (PMID:18329369). Direct immunofluorescence evidence. Reason: Midbody localization is experimentally established and central to BIRC6's role in cytokinesis. Supporting Evidence: UniProtKB:Q9NR09 finally localizes to the spindle midzone and the midbody in telophase and during cytokinesis. |
| GO:0032465 regulation of cytokinesis | IMP PMID:18329369 Final stages of cytokinesis and midbody ring formation are c... | ACCEPT | Summary: Pohl and Jentsch (PMID:18329369) demonstrated that BIRC6 depletion causes defective abscission and cytokinesis-associated apoptosis. BIRC6 coordinates vesicular targeting to the abscission site and midbody ring formation. Reason: Regulation of cytokinesis is a core function of BIRC6, demonstrated by IMP evidence showing that BIRC6 depletion causes cytokinesis defects. Supporting Evidence: PMID:18329369 Depletion of BRUCE in cell cultures causes defective abscission and cytokinesis-associated apoptosis, accompanied by a block of vesicular targeting and defective formation of the midbody and the midbody ring. |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:15200957 Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2... | ACCEPT | Summary: Bartke et al. (PMID:15200957) showed that BIRC6 inhibits caspase activity and apoptosis through its BIR domain. Wild-type and mutant forms were used to demonstrate BIR domain-dependent anti-apoptotic activity. Reason: IMP evidence from PMID:15200957 directly demonstrates that BIRC6 negatively regulates apoptosis. This is a core function of BIRC6. Supporting Evidence: PMID:15200957 BRUCE inhibits caspase activity and apoptosis depending on its BIR domain. |
| GO:0042127 regulation of cell population proliferation | TAS PMID:18414036 IAPs: more than just inhibitors of apoptosis proteins. | KEEP AS NON CORE | Summary: Dubrez-Daloz et al. (PMID:18414036) is a review discussing IAP family roles in cell proliferation, differentiation, and signaling. This is an indirect and broad annotation. Reason: Regulation of cell proliferation is a secondary/indirect consequence of BIRC6's anti-apoptotic and cytokinesis functions, not a direct core function. The review reference discusses IAPs generally, not BIRC6 specifically. Supporting Evidence: PMID:18414036 research of protein partners have revealed the importance of IAPs in adaptive response to cellular stress, in cell proliferation, differentiation, signaling, motility and in immune response. |
| GO:0005515 protein binding | IPI PMID:14765125 Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a ... | REMOVE | Summary: BIRC6 interacts with RNF41/Nrdp1, which mediates BIRC6 ubiquitination and degradation (PMID:14765125). However, 'protein binding' is uninformative. Reason: The term 'protein binding' (GO:0005515) is uninformative. The interaction with RNF41 is a regulatory mechanism (BIRC6 being a substrate of RNF41 E3 ligase) and does not describe BIRC6's molecular function. Supporting Evidence: PMID:14765125 Nrdp1 associates with BRUCE/apollon, a 530 kDa membrane-associated IAP |
| GO:0043066 negative regulation of apoptotic process | TAS PMID:10544019 A human IAP-family gene, apollon, expressed in human brain c... | ACCEPT | Summary: Chen et al. (PMID:10544019) identified BIRC6/Apollon as a human IAP family member and showed that antisense knockdown sensitizes cells to apoptosis, indicating an anti-apoptotic function. This is the original identification paper. Reason: The original identification paper demonstrates that BIRC6/Apollon protects cells from apoptosis. TAS evidence from the foundational paper for this gene. Supporting Evidence: PMID:10544019 Treating SNB-78 cells with antisense oligonucleotide against Apollon reduced the expression of Apollon protein, and significantly sensitized the cells to apoptosis induced by cisplatin and camptothecin. |
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Download this section (compressed HTML)Q: What are the specific substrates ubiquitinated by BIRC6 during cytokinesis at the midbody ring? While BIRC6 is known to ubiquitinate apoptotic regulators (caspases, Smac) and autophagy proteins (LC3), the cytokinesis-relevant substrates at the midbody remain poorly defined.
Q: Is the Wnt/beta-catenin signaling axis (through Axin ubiquitination) a conserved normal function of BIRC6 or a cancer-specific gain of function? Current evidence is limited to renal cell carcinoma models.
Q: What determines the substrate selectivity between BIRC6's apoptotic (caspases, Smac), autophagy (LC3), and cytokinesis substrates? Is this regulated by localization, post-translational modifications, or interaction partners?
Experiment: Proximity labeling (BioID/TurboID) with BIRC6 at the midbody during cytokinesis to identify the specific ubiquitination substrates and interaction partners that mediate its cytokinesis function, as distinct from its apoptotic substrates.
Hypothesis: BIRC6 has a set of cytokinesis-specific substrates at the midbody ring that are distinct from its known apoptotic substrates.
Experiment: Systematic comparison of BIRC6-mediated LC3 K51 ubiquitination across cell types and stress conditions to determine whether this autophagy-regulatory function is constitutive or context-dependent.
Hypothesis: BIRC6's autophagy-suppressive function through LC3 ubiquitination is dynamically regulated by cellular stress status and BIRC6's own turnover state.
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