Affinage

KCTD13

BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1 · UniProt Q8WZ19

Length
329 aa
Mass
36.4 kDa
Annotated
2026-06-10
15 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCTD13 is a BTB-domain substrate-specific adapter for CUL3-based E3 ubiquitin ligase complexes whose dosage bidirectionally controls neuronal progenitor proliferation, cortical neuron positioning, dendritic maturation, synaptic transmission, and cognition, and underlies brain-size phenotypes linked to the 16p11.2 copy-number variant (PMID:22596160, PMID:25695269). Mechanistically, KCTD13-CUL3 targets RhoA for degradation, and Kctd13 loss elevates RhoA to depress synaptic transmission and impair recognition memory; both the synaptic and cognitive deficits are reversed by RhoA/ROCK pathway inhibition (PMID:29088697, PMID:33436060). KCTD13 additionally promotes K48-linked polyubiquitination of the NMDAR obligatory subunit GluN1 at lysine-860, driving its proteasomal degradation to restrain membrane GluN1, excitatory transmission, and seizure susceptibility (PMID:37142655), and ubiquitinates adenylosuccinate synthetase (ADSS), coupling its loss to elevated succinyl-adenosine in a purine-metabolism axis (PMID:33409479). Beyond the nervous system, KCTD13 controls androgen receptor (AR) handling: its BTB domain directly binds AR and the competing ligase STUB1, so that KCTD13 increases CUL3-dependent AR ubiquitination while simultaneously blocking STUB1-mediated AR ubiquitination, and Kctd13 loss reduces nuclear AR and SOX9 to cause cryptorchidism and micropenis (PMID:36196997, PMID:39968753, PMID:39888193). KCTD13 protein levels are themselves set by KCTD10, which physically interacts with and degrades KCTD13, placing KCTD10 upstream in cortical development (PMID:38489388). In human iPSC-derived neurons KCTD13 loss reduces proliferation and neurite formation through ERBB signaling rather than RhoA accumulation, indicating context-dependent substrate engagement (PMID:31402430).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2012 High

    Established that KCTD13 dosage, not just its presence, drives brain-size phenotypes, nominating it as the key 16p11.2 CNV driver of microcephaly/macrocephaly.

    Evidence Reciprocal overexpression and morpholino knockdown in zebrafish with mouse embryo proliferation/apoptosis assays

    PMID:22596160

    Open questions at the time
    • Molecular mechanism (ligase activity, substrates) not yet defined
    • Does not identify direct binding partners
  2. 2016 Medium

    Connected KCTD13 to cortical circuit architecture by showing it binds Rnd GTPases and controls neuron positioning and dendrite/spine properties.

    Evidence In vitro binding assays with Rnd2/Rnd3 plus in utero electroporation knockdown/overexpression and postnatal histology in mouse cortex

    PMID:26969432

    Open questions at the time
    • No demonstration that Rnd proteins are ubiquitination substrates
    • Single-lab in vitro pulldown without reconstituted ligase activity
  3. 2015 Medium

    Placed KCTD13 in a CUL3-RhoA E3 ligase pathway active in the mid-fetal cortical plate, framing it as a node controlling brain size and connectivity.

    Evidence Protein-protein interaction mapping integrated with developing human brain spatiotemporal expression

    PMID:25695269

    Open questions at the time
    • No in vitro reconstitution of RhoA ubiquitination in this study
    • Functional consequence inferred from expression layering
  4. 2017 High

    Demonstrated causally that KCTD13/CUL3-mediated RhoA degradation controls synaptic transmission, converting a correlation into a mechanism.

    Evidence Kctd13 knockout mouse electrophysiology with RhoA protein quantification and pharmacological RhoA inhibitor rescue

    PMID:29088697

    Open questions at the time
    • Direct biochemical ubiquitination of RhoA not reconstituted here
    • Does not address non-RhoA substrates
  5. 2019 Medium

    Revealed context-dependence: in human iPSC-derived neurons KCTD13 acts through ERBB signaling and not RhoA accumulation, qualifying the RhoA model.

    Evidence CRISPR/Cas9 isogenic KO in human iPSC neurons with proliferation/neurite/MEA assays, RNA-seq, and ERBB activator/inhibitor rescue

    PMID:31402430

    Open questions at the time
    • Mechanism linking KCTD13 to ERBB signaling unresolved
    • Reconciliation with rodent RhoA findings not established
  6. 2020 Medium

    Expanded the substrate repertoire to purine metabolism by identifying ADSS as a KCTD13/CUL3 ubiquitination target with a disease-relevant metabolite readout.

    Evidence Quantitative ubiquitylome mass spectrometry of Kctd13 mutant vs WT neurons, metabolite measurement, and ADSS inhibitor treatment

    PMID:33409479

    Open questions at the time
    • Direct ubiquitination site on ADSS not mapped
    • Single-lab finding
  7. 2021 Medium

    Linked KCTD13 dosage to cognition mechanistically by rescuing memory deficits through ROCK inhibition.

    Evidence Kctd13 heterozygous KO mice with chronic fasudil treatment and novel object recognition behavioral assays

    PMID:33436060

    Open questions at the time
    • Cell-type and circuit locus of RhoA/ROCK action not defined
    • Single-lab behavioral rescue
  8. 2022 Medium

    Extended KCTD13 function beyond the brain, showing it controls nuclear AR and SOX9 levels with genitourinary developmental consequences.

    Evidence KCTD13 knockdown cell lines and Kctd13 haploinsufficient/KO mice with subcellular fractionation, AR/SOX9 immunodetection, and genitourinary phenotyping

    PMID:36196997

    Open questions at the time
    • Direct AR binding not yet demonstrated at this stage
    • Mechanism of AR localization control unresolved here
  9. 2023 High

    Defined a precise biochemical substrate event—K48-linked polyubiquitination of GluN1 at K860—linking KCTD13 to excitatory transmission and seizure threshold.

    Evidence Hippocampal KD/OE in mice, Co-IP, K48-specific ubiquitination assays, K860 site-directed mutagenesis, memantine rescue, electrophysiology, and seizure assays

    PMID:37142655

    Open questions at the time
    • Whether GluN1 and RhoA targeting occur in the same neurons not established
    • Structural basis of GluN1 recognition unknown
  10. 2025 High

    Resolved the AR mechanism: the BTB domain directly binds AR and competitively excludes STUB1, so KCTD13 both ubiquitinates AR via CUL3 and protects it from STUB1, with conditional rescue confirming sufficiency for normal genital development.

    Evidence Recombinant protein binding, Co-IP, CUL3/STUB1 ubiquitination assays, BTB deletion mutagenesis, HEK293 overexpression with proteasome inhibition, and Twist2cre/Shhcre conditional AR/SOX9 rescue in Kctd13-KO mice

    PMID:39888193 PMID:39968753

    Open questions at the time
    • How the dual pro- and anti-ubiquitination outcomes are balanced in vivo is unclear
    • Single-lab mechanistic reconstitution
  11. 2024 High

    Identified the upstream control of KCTD13 itself, showing KCTD10 binds and degrades KCTD13 to govern cortical progenitor behavior.

    Evidence Co-IP, ubiquitination assay, Kctd10 conditional KO mouse with KCTD13 protein readout, and epistatic KCTD13 overexpression in neuronal progenitors

    PMID:38489388

    Open questions at the time
    • Linkage type and sites of KCTD13 ubiquitination by KCTD10 not specified
    • Whether KCTD10 regulates KCTD13 outside cortex unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How KCTD13 selects among its diverse substrates (RhoA, GluN1, ADSS, AR) in different cell types and developmental windows, and what governs the switch between RhoA-dependent and ERBB-dependent outputs, remains unresolved.
  • No unifying model for tissue-specific substrate choice
  • Structure of KCTD13-CUL3-substrate complexes not determined
  • Reconciliation of rodent RhoA and human ERBB findings outstanding

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-112316 Neuronal System 2
Partners
ADSSARCUL3GLUN1KCTD10RHOARND2STUB1
Complex memberships
CUL3-based E3 ubiquitin ligase

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Overexpression of KCTD13 in zebrafish embryos induces microcephaly (decreased neuronal progenitor proliferation with increased apoptosis), while suppression yields macrocephaly (increased proliferation, no change in apoptosis), establishing KCTD13 dosage as a major driver of brain size phenotypes associated with 16p11.2 CNV. Zebrafish overexpression and morpholino knockdown; mouse embryo analyses; proliferation and apoptosis assays Nature High 22596160
2015 KCTD13 forms a pathway with Cullin-3 (CUL3) and RhoA, where KCTD13-CUL3 acts as an E3 ubiquitin ligase complex targeting RhoA; protein interaction network analysis places this pathway in layer 4 of the inner cortical plate during the late mid-fetal period, suggesting it controls brain size and connectivity. Protein–protein interaction mapping integrated with spatiotemporal gene expression from developing human brain Neuron Medium 25695269
2017 Deletion of Kctd13 in mice reduces synaptic transmission, correlating with increased RhoA protein levels; pharmacological RhoA inhibition reverses the synaptic transmission deficit, establishing KCTD13/CUL3-mediated ubiquitination of RhoA as the mechanistic link. Kctd13 knockout mouse; electrophysiology; RhoA protein quantification; RhoA inhibitor rescue experiment Nature High 29088697
2016 KCTD13 (Bacurd1) physically interacts with Rnd2 and Rnd3 GTPases in vitro. Disruption of Kctd13 expression via in utero electroporation impairs long-term positioning of cortical neurons and alters dendritic branching and spine properties of layer II/III projection neurons. In vitro binding assay (Bacurd1/Kctd13 interaction with Rnd proteins); in utero electroporation knockdown/overexpression in mouse cortex; postnatal histological analysis Neural development Medium 26969432
2020 KCTD13, acting as a CUL3 ubiquitin ligase adapter, ubiquitinates adenylosuccinate synthetase (ADSS), an enzyme in AMP synthesis; loss of Kctd13 in neurons leads to increased ADSS and elevated succinyl-adenosine (S-Ado), a metabolite also elevated in adenylosuccinate lyase deficiency (a disorder with autism and epilepsy features). Ubiquitylome comparison between Kctd13 mutant and wild-type neurons (mass spectrometry); metabolite measurement; ADSS inhibitor treatment iScience Medium 33409479
2021 Heterozygous deletion of Kctd13 in mice causes cognitive deficits (impaired object recognition memory) that are rescued by chronic fasudil (ROCK inhibitor) treatment, confirming that KCTD13 regulates cognition via the RhoA/ROCK pathway. Kctd13 heterozygous knockout mouse; chronic fasudil pharmacological treatment; behavioral assays (novel object recognition); RhoA pathway biochemical assessment Molecular autism Medium 33436060
2023 KCTD13 acts as a substrate-specific adapter for CUL3-based E3 ubiquitin ligase to promote K48-linked polyubiquitination of GluN1 (NMDAR obligatory subunit) at lysine-860, targeting it for proteasomal degradation; KCTD13 knockdown increases membrane GluN1, enhances excitatory synaptic transmission, and increases seizure susceptibility, while overexpression has opposite effects. Hippocampal knockdown/overexpression in mice; co-immunoprecipitation; ubiquitination assays with K48-linkage specificity; site-directed mutagenesis (K860 site); memantine (NMDAR inhibitor) rescue; electrophysiology; seizure susceptibility assays Cell death and differentiation High 37142655
2022 Loss of KCTD13 in cell lines and Kctd13-deficient mice decreases nuclear androgen receptor (AR) protein levels and reduces SOX9 expression, causing cryptorchidism and micropenis; KCTD13 functions as a CUL3 E3 ubiquitin ligase adapter and affects AR subcellular localization. KCTD13 knockdown in cell lines; Kctd13 haploinsufficient and homozygous knockout mice; subcellular fractionation; AR and SOX9 immunodetection; mouse genitourinary phenotyping FASEB journal Medium 36196997
2025 Recombinant KCTD13 directly binds recombinant AR via its BTB domain (which also binds STUB1); KCTD13 increases CUL3-dependent AR ubiquitination while simultaneously decreasing STUB1-mediated AR ubiquitination by blocking STUB1 binding to AR. KCTD13 ΔBTB mutant cannot bind AR and fails to block STUB1-mediated AR ubiquitination, confirming BTB domain dependence. KCTD13 also increases expression of AR target gene FOXJ1. Recombinant protein binding assay; co-immunoprecipitation; ubiquitination assays with CUL3 and STUB1; BTB domain deletion mutagenesis; AR target gene expression assay FASEB journal High 39968753
2025 Ectopic expression of KCTD13 in HEK293 cells strongly reduces AR ubiquitination via the proteasome pathway in a STUB1-dependent manner; rescue of AR or SOX9 in specific penile cell populations of Kctd13-KO mice restores normal penile length, confirming that KCTD13 regulation of AR (in urethral mesenchyme) and SOX9 (in urethral epithelium) are each sufficient to drive normal penile development. HEK293 cell overexpression; proteasome inhibitor treatment; conditional transgenic rescue (Twist2cre-driven AR, Shhcre-driven SOX9 in Kctd13-KO mice); penile morphometry and fertility assays Andrology Medium 39888193
2024 KCTD10 physically interacts with KCTD13 and mediates ubiquitination-dependent degradation of KCTD13; Kctd10 ablation causes increased KCTD13 protein in the developing cortex, and KCTD13 overexpression in neuronal progenitors phenocopies Kctd10 deficiency (reduced proliferation, abnormal cell distribution), placing KCTD10 upstream of KCTD13 in a developmental pathway. Co-immunoprecipitation (KCTD10–KCTD13 interaction); ubiquitination assay; Kctd10 conditional knockout mouse; KCTD13 overexpression in neuronal progenitors; cortical histology and proliferation analysis Proceedings of the National Academy of Sciences of the United States of America High 38489388
2019 CRISPR/Cas9 knockout of KCTD13 in human iPSC-derived neural precursor cells reduces DNA synthesis and proliferation; KCTD13-deficient cortical neurons show decreased neurite formation and reduced spontaneous network activity. RNA-seq implicated ERBB signaling; ERBB kinase activation rescued impaired neurite formation. Notably, RhoA did not accumulate and RhoA inhibition did not rescue neurite defects in human neurons, in contrast to findings in non-neuronal cells. CRISPR/Cas9 KO in human iPSCs; neural differentiation; proliferation assays; neurite morphometry; MEA network activity; RNA-seq; ERBB kinase activator/inhibitor treatment; RhoA protein quantification Molecular neurobiology Medium 31402430

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 316 22596160
2015 Spatiotemporal 16p11.2 protein network implicates cortical late mid-fetal brain development and KCTD13-Cul3-RhoA pathway in psychiatric diseases. Neuron 122 25695269
2017 Kctd13 deletion reduces synaptic transmission via increased RhoA. Nature 109 29088697
2021 Targeting the RHOA pathway improves learning and memory in adult Kctd13 and 16p11.2 deletion mouse models. Molecular autism 31 33436060
2016 Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd proteins which influence the long-term positioning and dendritic maturation of cerebral cortical neurons. Neural development 27 26969432
2023 KCTD13-mediated ubiquitination and degradation of GluN1 regulates excitatory synaptic transmission and seizure susceptibility. Cell death and differentiation 24 37142655
2019 CRISPR/Cas9-mediated Knockout of the Neuropsychiatric Risk Gene KCTD13 Causes Developmental Deficits in Human Cortical Neurons Derived from Induced Pluripotent Stem Cells. Molecular neurobiology 21 31402430
2022 Gene dosage changes in KCTD13 result in penile and testicular anomalies via diminished androgen receptor function. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 12 36196997
2020 Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features. iScience 11 33409479
2024 KCTD10 regulates brain development by destabilizing brain disorder-associated protein KCTD13. Proceedings of the National Academy of Sciences of the United States of America 8 38489388
2016 Identification of rare variants in KCTD13 at the schizophrenia risk locus 16p11.2. Psychiatric genetics 8 27668412
2023 Changes in social behavior with MAPK2 and KCTD13/CUL3 pathways alterations in two new outbred rat models for the 16p11.2 syndromes with autism spectrum disorders. Frontiers in neuroscience 6 37465586
2025 Androgen receptor ubiquitination links KCTD13 to genitourinary tract defects. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2 39968753
2025 Role of Kctd13 in modulating AR and SOX9 expression in different penile cell populations. Andrology 1 39888193
2024 Novel evidence of CNV deletion in KCTD13 related to the severity of isolated hypospadias in Chinese population. Frontiers in pediatrics 1 39318621

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