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.
|
KCTD10 (potassium channel tetramerization domain-containing 10; also BACURD3)
is, despite the "potassium channel tetramerization domain" name, not an ion
channel. It is the substrate-recognition subunit of a Cullin-3–RBX1 (CRL3 /
BCR) RING E3 ubiquitin ligase. Family: BACURD (BTB/POZ adapters for CUL3).
The GOA annotation GO:0160020 positive regulation of ferroptosis (IDA,
PMID:30404837) cites the CEP97/ciliogenesis paper, which contains no
ferroptosis/SLC7A11 content (verified abstract). The correct primary source is
PMID:38959043 (Gou et al., PNAS 2024), which UniProt cites for this exact
function. This is the same mechanically-valid-but-semantically-wrong citation
found in GO-CAM gomodel:69729a3800005900 (USP18/SLC7A11 activity), where
PMID:30404837 was inherited from the (correctly-cited) KCTD10 adaptor activity
onto the antagonist node. The ferroptosis biology is correct; only the
reference is wrong. Recorded in the GO:0160020 review with additional_reference_ids.
KCTD10's single core molecular function — CRL3 substrate-recognition adapter —
is deployed against several unrelated substrates (RHOB, CEP97, SLC7A11, TICAM1,
KCTD13, TCEA2), so its many biological-process annotations (Rho signaling,
ciliogenesis, ferroptosis, endothelial barrier, innate immunity) are
substrate-specific consequences of one ubiquitin-ligase-adapter activity rather
than independent core functions.
id: Q9H3F6
gene_symbol: KCTD10
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
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.
alternative_products:
- name: '1'
id: Q9H3F6-1
- name: '2'
id: Q9H3F6-2
sequence_note: VSP_019980
- name: '3'
id: Q9H3F6-3
sequence_note: VSP_019978, VSP_019979
existing_annotations:
- term:
id: GO:0043161
label: proteasome-mediated ubiquitin-dependent protein catabolic process
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Core process - KCTD10 targets substrates (CEP97, SLC7A11, RhoB) for proteasomal degradation as a CRL3 adapter.
action: ACCEPT
reason: Well supported by phylogenetic inference and direct experimental evidence (see the IDA annotation to the same term, PMID:30404837); central to KCTD10 function.
- term:
id: GO:0016567
label: protein ubiquitination
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Core process - KCTD10 mediates substrate ubiquitination within the CRL3 complex.
action: ACCEPT
reason: Directly supported; KCTD10's adapter activity delivers substrates for ubiquitination.
- term:
id: GO:0031463
label: Cul3-RING ubiquitin ligase complex
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: part_of
review:
summary: Core complex membership - KCTD10 is the BTB substrate-adapter subunit of a CUL3-RBX1 ligase.
action: ACCEPT
reason: Directly demonstrated by structural and biochemical data (5:5 KCTD10:CUL3 assembly, PMID:28963344; BCR(KCTD10) composition, PMID:29358211, PMID:30404837).
- term:
id: GO:0035024
label: negative regulation of Rho protein signal transduction
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Substrate-specific outcome - KCTD10 degrades RHOB, dampening Rho signaling.
action: KEEP_AS_NON_CORE
reason: A genuine but substrate-specific consequence of the core adapter activity (RHOB K63-ubiquitination/degradation, PMID:29358211), not an independent core function.
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: Nuclear localization, consistent with UniProt subcellular location.
action: ACCEPT
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).
- term:
id: GO:0006511
label: ubiquitin-dependent protein catabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: involved_in
review:
summary: Core process (general parent of proteasome-mediated catabolism).
action: ACCEPT
reason: Consistent with KCTD10's role in directing substrates for degradation; redundant with but not contradicted by the more specific GO:0043161.
- term:
id: GO:0051260
label: protein homooligomerization
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: KCTD10 self-associates via its BTB/POZ domain into a homopentamer.
action: ACCEPT
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.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19615732
qualifier: enables
review:
summary: Generic binding annotation from a deubiquitinase interaction screen.
action: KEEP_AS_NON_CORE
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."
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21145461
qualifier: enables
review:
summary: Generic binding from a cullin-RING ligase network proteomics study.
action: KEEP_AS_NON_CORE
reason: Supports CRL3 network membership but is uninformative as an MF; the specific CUL3 interaction underlies the adapter activity (GO:1990756).
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
qualifier: enables
review:
summary: Generic binding from a binary interactome map.
action: KEEP_AS_NON_CORE
reason: High-throughput interaction evidence; uninformative as a molecular function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
qualifier: enables
review:
summary: Generic binding from a cell-specific interactome study.
action: KEEP_AS_NON_CORE
reason: High-throughput interaction evidence; uninformative as a molecular function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:34591642
qualifier: enables
review:
summary: Generic binding from a head-and-neck-cancer protein network.
action: KEEP_AS_NON_CORE
reason: High-throughput interaction evidence; uninformative as a molecular function.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:40205054
qualifier: enables
review:
summary: Generic binding from a multimodal cell-map interactome.
action: KEEP_AS_NON_CORE
reason: High-throughput interaction evidence; uninformative as a molecular function.
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
qualifier: enables
review:
summary: Self-association, consistent with BTB-mediated homo-oligomerization.
action: KEEP_AS_NON_CORE
reason: Corroborates the homopentameric BTB assembly (PMID:28963344) underlying CUL3 binding, captured by GO:0051260; retained as supporting evidence rather than a core function.
- term:
id: GO:0036038
label: MKS complex
evidence_type: IEA
original_reference_id: GO_REF:0000107
qualifier: part_of
review:
summary: Dubious electronic assignment to the ciliary MKS transition-zone complex.
action: MARK_AS_OVER_ANNOTATED
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.
- term:
id: GO:0045724
label: positive regulation of cilium assembly
evidence_type: IDA
original_reference_id: PMID:29358211
qualifier: involved_in
review:
summary: Substrate-specific outcome - KCTD10 promotes ciliogenesis via CEP97 degradation. CITATION IS WRONG.
action: KEEP_AS_NON_CORE
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.
additional_reference_ids:
- PMID:30404837
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:30404837
qualifier: is_active_in
review:
summary: Core cytoplasmic localization where KCTD10 assembles with CUL3.
action: ACCEPT
reason: Directly observed (PMID:30404837); the CRL3(KCTD10) complex acts in the cytoplasm/centriolar region.
- term:
id: GO:1990756
label: ubiquitin-like ligase-substrate adaptor activity
evidence_type: IDA
original_reference_id: PMID:30404837
qualifier: enables
review:
summary: THE core molecular function - substrate-recognition adapter of the CRL3 ligase.
action: ACCEPT
reason: Directly demonstrated (PMID:30404837); KCTD10 bridges CUL3 and substrates (CEP97, SLC7A11, RHOB) for ubiquitination. This is the unifying core activity.
- term:
id: GO:0060271
label: cilium assembly
evidence_type: IDA
original_reference_id: PMID:30404837
qualifier: involved_in
review:
summary: Substrate-specific outcome - CEP97 degradation licenses primary cilium formation.
action: KEEP_AS_NON_CORE
reason: Directly supported (PMID:30404837) but a substrate-specific consequence of the core adapter activity, not an independent core function.
- term:
id: GO:0061028
label: establishment of endothelial barrier
evidence_type: IDA
original_reference_id: PMID:29358211
qualifier: involved_in
review:
summary: Substrate-specific outcome - RHOB degradation preserves endothelial barrier integrity.
action: KEEP_AS_NON_CORE
reason: Directly supported (PMID:29358211) but a downstream, tissue-specific consequence of the core adapter activity.
- term:
id: GO:1902523
label: positive regulation of protein K63-linked ubiquitination
evidence_type: IDA
original_reference_id: PMID:29358211
qualifier: involved_in
review:
summary: Mechanistic detail - KCTD10 directs K63-linked polyubiquitination of RHOB.
action: KEEP_AS_NON_CORE
reason: Accurately captures the linkage type used on RHOB (PMID:29358211); a substrate-specific mechanistic feature of the core adapter activity.
- term:
id: GO:0016567
label: protein ubiquitination
evidence_type: IEA
original_reference_id: GO_REF:0000041
qualifier: involved_in
review:
summary: Core process (electronic, UniPathway-derived).
action: ACCEPT
reason: Consistent with the experimentally supported ubiquitination role; redundant with the IBA/ISS annotations to the same term.
- term:
id: GO:0043161
label: proteasome-mediated ubiquitin-dependent protein catabolic process
evidence_type: IDA
original_reference_id: PMID:30404837
qualifier: involved_in
review:
summary: Core process, experimentally demonstrated (CEP97 proteasomal degradation).
action: ACCEPT
reason: Directly supported (PMID:30404837); KCTD10 drives proteasomal degradation of its substrates.
- term:
id: GO:0160020
label: positive regulation of ferroptosis
evidence_type: IDA
original_reference_id: PMID:30404837
qualifier: involved_in
review:
summary: Substrate-specific outcome - KCTD10 destabilizes SLC7A11, promoting ferroptosis. CITATION IS WRONG.
action: KEEP_AS_NON_CORE
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.
additional_reference_ids:
- PMID:38959043
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: Nuclear localization observed by immunofluorescence (HPA).
action: ACCEPT
reason: Corroborates the nucleus annotation and KCTD10's nuclear roles (e.g. PCNA/POLD2 association, transcription-replication conflict resolution).
- term:
id: GO:0005112
label: Notch binding
evidence_type: IPI
original_reference_id: PMID:25401743
qualifier: enables
review:
summary: Specific interaction with Notch1, in a cardiovascular/Notch developmental context.
action: ACCEPT
reason: A specific, informative binding (PMID:25401743) consistent with KCTD10 acting on Notch1 during early development; retained but not a core catalytic function.
supported_by:
- reference_id: PMID:25401743
supporting_text: KCTD10 negatively regulated Notch signaling by mediating Notch1 proteolytic degradation.
- term:
id: GO:0006511
label: ubiquitin-dependent protein catabolic process
evidence_type: IDA
original_reference_id: PMID:25401743
qualifier: acts_upstream_of_or_within
review:
summary: Core process in the Notch/cardiovascular developmental context (Notch1 proteolytic degradation).
action: ACCEPT
reason: Directly supported (PMID:25401743); consistent with KCTD10's substrate-degradation activity.
supported_by:
- reference_id: PMID:25401743
supporting_text: KCTD10 negatively regulated Notch signaling by mediating Notch1 proteolytic degradation.
- term:
id: GO:0016567
label: protein ubiquitination
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
summary: Core process (sequence-similarity transfer from orthologs).
action: ACCEPT
reason: Consistent with experimental evidence; redundant with the IBA/IEA annotations to the same term.
- term:
id: GO:0031463
label: Cul3-RING ubiquitin ligase complex
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: part_of
review:
summary: Core complex membership (sequence-similarity transfer).
action: ACCEPT
reason: Consistent with directly demonstrated CUL3-RBX1-KCTD10 complex formation; redundant with the IBA annotation.
- term:
id: GO:0043161
label: proteasome-mediated ubiquitin-dependent protein catabolic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
summary: Core process (sequence-similarity transfer).
action: ACCEPT
reason: Consistent with the IDA/IBA evidence for the same term.
core_functions:
- description: >-
Substrate-recognition (BTB/POZ) adapter subunit of a Cullin-3-RBX1 (CRL3/BCR)
RING E3 ubiquitin ligase that selects diverse substrates - including CEP97,
RHOB and SLC7A11 - for poly-ubiquitination and subsequent proteasomal or
lysosomal degradation. This single adapter activity underlies KCTD10's
pleiotropic roles in ciliogenesis, Rho signaling, ferroptosis and immunity.
supported_by:
- reference_id: PMID:30404837
supporting_text: Cullin-3-KCTD10-mediated CEP97 degradation promotes primary cilium formation.
- reference_id: PMID:38959043
supporting_text: KCTD10 destabilizes SLC7A11 by promoting its polyubiquitylation for subsequent proteasome degradation, leading to shortened protein half-life.
- reference_id: PMID:29358211
supporting_text: RhoB is primarily K63 polyubiquitinated and subsequently degraded in lysosomes.
molecular_function:
id: GO:1990756
label: ubiquitin-like ligase-substrate adaptor activity
in_complex:
id: GO:0031463
label: Cul3-RING ubiquitin ligase complex
directly_involved_in:
- id: GO:0016567
label: protein ubiquitination
- id: GO:0043161
label: proteasome-mediated ubiquitin-dependent protein catabolic process
locations:
- id: GO:0005737
label: cytoplasm
- id: GO:0005634
label: nucleus
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
findings: []
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
by curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000041
title: Gene Ontology annotation based on UniPathway vocabulary mapping
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
vocabulary mapping, accompanied by conservative changes to GO terms applied by
UniProt
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to
orthologs using Ensembl Compara
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: PMID:19125419
title: KCTD10 interacts with proliferating cell nuclear antigen and its down-regulation
could inhibit cell proliferation.
findings:
- statement: KCTD10 interacts with PCNA, consistent with a nuclear, replication-associated role.
supporting_text: KCTD10 can interact with PCNA.
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: PubMed-verified; source for the PCNA interaction and nuclear localization of KCTD10.
- id: PMID:19615732
title: Defining the human deubiquitinating enzyme interaction landscape.
findings: []
- id: PMID:28963344
title: Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin
ligases.
findings:
- statement: KCTD10 forms a pentameric BTB assembly typical of the KCTD family, the basis of its 5:5 assembly with CUL3.
supporting_text: (KCTD10 and KCTD13), open pentamer (KCTD16) and closed pentamer (KCTD17).
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: PubMed-verified; structural basis for KCTD10's pentameric BTB assembly and CUL3 binding.
- id: PMID:21145461
title: Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative
proteomics.
findings: []
- id: PMID:25401743
title: KCTD10 is involved in the cardiovascular system and Notch signaling during
early embryonic development.
findings:
- statement: KCTD10 negatively regulates Notch signaling by mediating proteolytic degradation of Notch1.
supporting_text: KCTD10 negatively regulated Notch signaling by mediating Notch1 proteolytic degradation.
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: PubMed-verified; supports KCTD10's role in Notch1 degradation during cardiovascular development.
- id: PMID:29358211
title: The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrier function via
K63 ubiquitination of RhoB.
findings:
- statement: KCTD10 mediates K63-linked polyubiquitination of RHOB, targeting it for lysosomal degradation to preserve endothelial barrier function.
supporting_text: RhoB is primarily K63 polyubiquitinated and subsequently degraded in lysosomes.
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: PubMed-verified; primary experimental source for the RHOB substrate and the K63/endothelial-barrier function.
- id: PMID:30404837
title: Cullin-3-KCTD10-mediated CEP97 degradation promotes primary cilium formation.
findings:
- statement: KCTD10 directs proteasomal degradation of CEP97, enabling removal of the CEP97-CP110 complex from mother centrioles and primary cilium formation.
supporting_text: Cullin-3-KCTD10-mediated CEP97 degradation promotes primary cilium formation.
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Primary source for the CEP97 substrate, the adapter activity, and cytoplasmic
localization. NOTE: this paper is mis-cited in GOA as the IDA evidence for
GO:0160020 (positive regulation of ferroptosis); its abstract contains no
ferroptosis/SLC7A11 content. The correct ferroptosis source is PMID:38959043.
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the human
interactome.
findings: []
- id: PMID:34591642
title: A protein network map of head and neck cancer reveals PIK3CA mutant drug
sensitivity.
findings: []
- id: PMID:40205054
title: Multimodal cell maps as a foundation for structural and functional genomics.
findings: []
- id: PMID:38959043
title: The CRL3(KCTD10) ubiquitin ligase-USP18 axis coordinately regulates cystine
uptake and ferroptosis by modulating SLC7A11.
findings:
- statement: KCTD10 (CRL3) destabilizes SLC7A11 by polyubiquitylation/proteasomal degradation, reducing cystine uptake and promoting ferroptosis; USP18 is the opposing deubiquitinase.
supporting_text: KCTD10 destabilizes SLC7A11 by promoting its polyubiquitylation for subsequent proteasome degradation, leading to shortened protein half-life.
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PMC-verified full text. The correct primary source for KCTD10's positive
regulation of ferroptosis via SLC7A11 (the function GOA mis-attributes to
PMID:30404837). UniProt cites this paper for the same function.