KCTD10 (potassium channel tetramerization domain-containing 10; also known as BACURD3) is, despite its name, not an ion channel but the substrate-recognition subunit of a Cullin-3-RBX1 (CRL3 / BCR) RING E3 ubiquitin ligase. Through its N-terminal BTB/POZ domain it binds Cullin-3 directly and oligomerizes (forming a homopentamer and a 5:5 assembly with CUL3), while its C-terminal region selects substrates for ubiquitination. KCTD10 directs both degradative and non-degradative ubiquitination of multiple, functionally unrelated substrates: K63-linked polyubiquitination and lysosomal degradation of the small GTPase RHOB (maintaining endothelial barrier integrity), proteasomal degradation of CEP97 (removing the CEP97-CP110 cap from the mother centriole to license primary cilium formation), destabilization of the cystine/glutamate antiporter SLC7A11 (lowering cystine uptake and glutathione synthesis and thereby promoting ferroptosis), and K27-linked ubiquitination of TICAM1/TRIF (promoting TLR3/4 innate immune signaling). It localizes to both the cytoplasm and the nucleus and belongs to the BACURD family of CUL3 adapters. Its single core molecular activity - CRL3 substrate-recognition adapter - thus links the ubiquitin-proteasome system to Rho/cytoskeletal signaling, ciliogenesis, redox/ferroptosis control, and innate immunity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Core process - KCTD10 targets substrates (CEP97, SLC7A11, RhoB) for proteasomal degradation as a CRL3 adapter. Reason: Well supported by phylogenetic inference and direct experimental evidence (see the IDA annotation to the same term, PMID:30404837); central to KCTD10 function. |
| GO:0016567 protein ubiquitination | IBA GO_REF:0000033 | ACCEPT | Summary: Core process - KCTD10 mediates substrate ubiquitination within the CRL3 complex. Reason: Directly supported; KCTD10's adapter activity delivers substrates for ubiquitination. |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Core complex membership - KCTD10 is the BTB substrate-adapter subunit of a CUL3-RBX1 ligase. Reason: Directly demonstrated by structural and biochemical data (5:5 KCTD10:CUL3 assembly, PMID:28963344; BCR(KCTD10) composition, PMID:29358211, PMID:30404837). |
| GO:0035024 negative regulation of Rho protein signal transduction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Substrate-specific outcome - KCTD10 degrades RHOB, dampening Rho signaling. Reason: A genuine but substrate-specific consequence of the core adapter activity (RHOB K63-ubiquitination/degradation, PMID:29358211), not an independent core function. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization, consistent with UniProt subcellular location. Reason: UniProt records Nucleus as a subcellular location (PMID:19125419); corroborated by the nucleoplasm IDA (GO_REF:0000052) and roles at the replication fork (PCNA/POLD2 interactions). |
| GO:0006511 ubiquitin-dependent protein catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: Core process (general parent of proteasome-mediated catabolism). Reason: Consistent with KCTD10's role in directing substrates for degradation; redundant with but not contradicted by the more specific GO:0043161. |
| GO:0051260 protein homooligomerization | IEA GO_REF:0000002 | ACCEPT | Summary: KCTD10 self-associates via its BTB/POZ domain into a homopentamer. Reason: Supported by structural data showing a two-fold symmetric oligomer and a 5:5 KCTD10:CUL3 assembly (PMID:28963344); corroborated by the identical-protein-binding IPI. |
| GO:0005515 protein binding | IPI PMID:19615732 Defining the human deubiquitinating enzyme interaction lands... | KEEP AS NON CORE | Summary: Generic binding annotation from a deubiquitinase interaction screen. Reason: 'Protein binding' is uninformative; the informative molecular function is the substrate-adapter activity (GO:1990756). Retained as interaction evidence, not elevated to a core function. |
| GO:0005515 protein binding | IPI PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by... | KEEP AS NON CORE | Summary: Generic binding from a cullin-RING ligase network proteomics study. Reason: Supports CRL3 network membership but is uninformative as an MF; the specific CUL3 interaction underlies the adapter activity (GO:1990756). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Generic binding from a binary interactome map. Reason: High-throughput interaction evidence; uninformative as a molecular function. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Generic binding from a cell-specific interactome study. Reason: High-throughput interaction evidence; uninformative as a molecular function. |
| GO:0005515 protein binding | IPI PMID:34591642 A protein network map of head and neck cancer reveals PIK3CA... | KEEP AS NON CORE | Summary: Generic binding from a head-and-neck-cancer protein network. Reason: High-throughput interaction evidence; uninformative as a molecular function. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Generic binding from a multimodal cell-map interactome. Reason: High-throughput interaction evidence; uninformative as a molecular function. |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Self-association, consistent with BTB-mediated homo-oligomerization. Reason: Corroborates the homopentameric BTB assembly (PMID:28963344) underlying CUL3 binding, captured by GO:0051260; retained as supporting evidence rather than a core function. |
| GO:0036038 MKS complex | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Dubious electronic assignment to the ciliary MKS transition-zone complex. Reason: KCTD10's effect on ciliogenesis is mechanistic (CEP97 degradation), not structural membership in the MKS/transition-zone complex (whose components are MKS1, TMEM67, B9D1/2, CC2D2A, etc.). This is an automated Ensembl Compara ortholog transfer with no experimental support for KCTD10 being a structural MKS subunit; likely an over-propagation. |
| GO:0045724 positive regulation of cilium assembly | IDA PMID:29358211 The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrie... | KEEP AS NON CORE | Summary: Substrate-specific outcome - KCTD10 promotes ciliogenesis via CEP97 degradation. CITATION IS WRONG. Reason: The ciliogenesis role is genuine (via CEP97 degradation) but the cited reference PMID:29358211 is the RHOB/endothelial-barrier paper, whose full text contains zero mentions of cilium/cilia/ciliogenesis (verified). This is a SECOND mis-citation from the same PMID:30404837-vs-PMID:29358211 confusion seen on the ferroptosis annotation: the correct source for KCTD10's cilium role is PMID:30404837 (CEP97 degradation). Substrate-specific consequence of the core adapter activity, hence non-core; flagged for re-citation. |
| GO:0005737 cytoplasm | IDA PMID:30404837 Cullin-3-KCTD10-mediated CEP97 degradation promotes primary ... | ACCEPT | Summary: Core cytoplasmic localization where KCTD10 assembles with CUL3. Reason: Directly observed (PMID:30404837); the CRL3(KCTD10) complex acts in the cytoplasm/centriolar region. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:30404837 Cullin-3-KCTD10-mediated CEP97 degradation promotes primary ... | ACCEPT | Summary: THE core molecular function - substrate-recognition adapter of the CRL3 ligase. Reason: Directly demonstrated (PMID:30404837); KCTD10 bridges CUL3 and substrates (CEP97, SLC7A11, RHOB) for ubiquitination. This is the unifying core activity. |
| GO:0060271 cilium assembly | IDA PMID:30404837 Cullin-3-KCTD10-mediated CEP97 degradation promotes primary ... | KEEP AS NON CORE | Summary: Substrate-specific outcome - CEP97 degradation licenses primary cilium formation. Reason: Directly supported (PMID:30404837) but a substrate-specific consequence of the core adapter activity, not an independent core function. |
| GO:0061028 establishment of endothelial barrier | IDA PMID:29358211 The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrie... | KEEP AS NON CORE | Summary: Substrate-specific outcome - RHOB degradation preserves endothelial barrier integrity. Reason: Directly supported (PMID:29358211) but a downstream, tissue-specific consequence of the core adapter activity. |
| GO:1902523 positive regulation of protein K63-linked ubiquitination | IDA PMID:29358211 The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrie... | KEEP AS NON CORE | Summary: Mechanistic detail - KCTD10 directs K63-linked polyubiquitination of RHOB. Reason: Accurately captures the linkage type used on RHOB (PMID:29358211); a substrate-specific mechanistic feature of the core adapter activity. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | ACCEPT | Summary: Core process (electronic, UniPathway-derived). Reason: Consistent with the experimentally supported ubiquitination role; redundant with the IBA/ISS annotations to the same term. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:30404837 Cullin-3-KCTD10-mediated CEP97 degradation promotes primary ... | ACCEPT | Summary: Core process, experimentally demonstrated (CEP97 proteasomal degradation). Reason: Directly supported (PMID:30404837); KCTD10 drives proteasomal degradation of its substrates. |
| GO:0160020 positive regulation of ferroptosis | IDA PMID:30404837 Cullin-3-KCTD10-mediated CEP97 degradation promotes primary ... | KEEP AS NON CORE | Summary: Substrate-specific outcome - KCTD10 destabilizes SLC7A11, promoting ferroptosis. CITATION IS WRONG. Reason: The biology is correct - KCTD10 (CRL3) destabilizes SLC7A11, lowering cystine/GSH and promoting ferroptosis - but the cited reference PMID:30404837 is the CEP97/ciliogenesis paper, whose abstract contains no mention of SLC7A11 or ferroptosis (verified). The correct primary source is PMID:38959043 (Gou et al., PNAS 2024), which UniProt cites for this function. The wrong reference appears to have been carried over from KCTD10's (correctly cited) adapter activity. A substrate-specific outcome, hence non-core; flagged for re-citation. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Nuclear localization observed by immunofluorescence (HPA). Reason: Corroborates the nucleus annotation and KCTD10's nuclear roles (e.g. PCNA/POLD2 association, transcription-replication conflict resolution). |
| GO:0005112 Notch binding | IPI PMID:25401743 KCTD10 is involved in the cardiovascular system and Notch si... | ACCEPT | Summary: Specific interaction with Notch1, in a cardiovascular/Notch developmental context. Reason: A specific, informative binding (PMID:25401743) consistent with KCTD10 acting on Notch1 during early development; retained but not a core catalytic function. Supporting Evidence: PMID:25401743 KCTD10 negatively regulated Notch signaling by mediating Notch1 proteolytic degradation. |
| GO:0006511 ubiquitin-dependent protein catabolic process | IDA PMID:25401743 KCTD10 is involved in the cardiovascular system and Notch si... | ACCEPT | Summary: Core process in the Notch/cardiovascular developmental context (Notch1 proteolytic degradation). Reason: Directly supported (PMID:25401743); consistent with KCTD10's substrate-degradation activity. Supporting Evidence: PMID:25401743 KCTD10 negatively regulated Notch signaling by mediating Notch1 proteolytic degradation. |
| GO:0016567 protein ubiquitination | ISS GO_REF:0000024 | ACCEPT | Summary: Core process (sequence-similarity transfer from orthologs). Reason: Consistent with experimental evidence; redundant with the IBA/IEA annotations to the same term. |
| GO:0031463 Cul3-RING ubiquitin ligase complex | ISS GO_REF:0000024 | ACCEPT | Summary: Core complex membership (sequence-similarity transfer). Reason: Consistent with directly demonstrated CUL3-RBX1-KCTD10 complex formation; redundant with the IBA annotation. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Core process (sequence-similarity transfer). Reason: Consistent with the IDA/IBA evidence for the same term. |
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