Affinage

KCTD13

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

Length
329 aa
Mass
36.4 kDa
Annotated
2026-04-28
19 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCTD13 is a substrate-specific adapter for CUL3-based E3 ubiquitin ligase complexes that regulates brain development, synaptic function, and genitourinary tract morphogenesis by controlling the turnover of multiple substrates. In neurons, KCTD13–CUL3 ubiquitinates RhoA to regulate neuronal progenitor proliferation, cortical neuron positioning, and synaptic transmission, with pharmacological RhoA/ROCK inhibition rescuing both electrophysiological and cognitive deficits in Kctd13-deficient mice (PMID:29088697, PMID:33436060); it also ubiquitinates the NMDAR subunit GluN1 via K48-linked polyubiquitination at Lys-860, promoting proteasomal degradation and limiting seizure susceptibility (PMID:37142655), and targets adenylosuccinate synthetase (ADSS) to regulate purine metabolism (PMID:33409479). In androgen-responsive tissues, KCTD13 directly binds the androgen receptor (AR) through its BTB domain with a dual regulatory logic: it promotes CUL3-dependent AR ubiquitination while simultaneously competing with STUB1 for AR binding to shield AR from STUB1-mediated degradation, and loss of KCTD13 causes cryptorchidism and micropenis through reduced nuclear AR (PMID:39968753, PMID:36196997). KCTD13 protein levels are themselves controlled by KCTD10-mediated ubiquitin-dependent degradation, establishing a regulatory cascade in cortical progenitor cells (PMID:38489388).

Mechanistic history

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

    Established that KCTD13 is the critical dosage-sensitive gene within 16p11.2, whose copy number bidirectionally controls brain size by regulating neuronal progenitor proliferation and apoptosis.

    Evidence Zebrafish overexpression/morpholino knockdown and mouse embryo analyses quantifying proliferation and apoptosis

    PMID:22596160

    Open questions at the time
    • Molecular mechanism by which KCTD13 controls proliferation was unknown
    • Downstream signaling pathway not identified
    • No mammalian loss-of-function model yet available
  2. 2015 Medium

    Identified the KCTD13–CUL3–RhoA ubiquitination axis as the molecular pathway linking KCTD13 to brain size regulation, positioning KCTD13 as a CUL3 adapter targeting RhoA for degradation.

    Evidence Protein interaction network integrating yeast two-hybrid, mass spectrometry, and spatiotemporal brain expression data

    PMID:25695269

    Open questions at the time
    • RhoA ubiquitination not directly reconstituted in vitro
    • Functional validation of RhoA as causal effector awaited genetic/pharmacological epistasis
  3. 2016 Medium

    Demonstrated that KCTD13 interacts with Rnd2/Rnd3 GTPases and controls cortical neuron positioning and dendritic morphogenesis, extending its role beyond progenitor proliferation to postmitotic neuron maturation.

    Evidence In vitro binding assays combined with in utero electroporation knockdown/overexpression and postnatal cortical neuron morphology analysis in mice

    PMID:26969432

    Open questions at the time
    • Whether Rnd2/Rnd3 are ubiquitination substrates of KCTD13–CUL3 was not tested
    • Relationship between Rnd-mediated positioning and RhoA degradation unclear
  4. 2017 High

    Validated RhoA as the causal effector downstream of KCTD13 loss by showing that Kctd13 KO mice accumulate RhoA and display reduced synaptic transmission, both reversed by pharmacological RhoA pathway inhibition.

    Evidence Kctd13 knockout mouse electrophysiology, RhoA western blots, pharmacological rescue with RhoA inhibitor; replicated in zebrafish

    PMID:29088697

    Open questions at the time
    • Direct in vitro reconstitution of KCTD13-mediated RhoA ubiquitination still lacking
    • Whether additional substrates contribute to synaptic phenotype not addressed
  5. 2019 Medium

    Revealed that in human iPSC-derived cortical neurons, KCTD13 loss impairs neurite formation and network activity through ERBB signaling rather than RhoA, indicating species- or context-dependent pathway engagement.

    Evidence CRISPR knockout in human iPSCs, neural differentiation, RNA-seq, pharmacological rescue with ERBB activators

    PMID:31402430

    Open questions at the time
    • Whether ERBB pathway components are direct ubiquitination substrates of KCTD13–CUL3 is unknown
    • Discrepancy with mouse RhoA mechanism not fully reconciled
  6. 2020 Medium

    Identified ADSS as an additional KCTD13–CUL3 ubiquitination substrate, linking KCTD13 to purine metabolism; Kctd13 mutant neurons accumulate the metabolite succinyl-adenosine.

    Evidence Ubiquitylome mass spectrometry comparing Kctd13 mutant and wild-type neurons; metabolite measurement; ADSS inhibitor rescue

    PMID:33409479

    Open questions at the time
    • Direct in vitro ubiquitination of ADSS by reconstituted KCTD13–CUL3 not shown
    • Contribution of purine metabolism dysregulation to neurological phenotypes not delineated
  7. 2021 Medium

    Extended the RhoA mechanism to cognition by showing chronic ROCK inhibition rescues object recognition memory in Kctd13 heterozygous and 16p11.2 deletion mice, providing preclinical validation of the KCTD13–RhoA axis.

    Evidence Kctd13 haploinsufficient and 16p11.2 deletion mice treated chronically with fasudil; behavioral testing

    PMID:33436060

    Open questions at the time
    • Whether cognitive rescue reflects synaptic or progenitor defects is unresolved
    • Long-term safety and specificity of ROCK inhibition not evaluated
  8. 2022 Medium

    Discovered that KCTD13 loss reduces nuclear AR and SOX9 expression, causing cryptorchidism and micropenis in mice — the first link between KCTD13 and androgen-dependent genitourinary development.

    Evidence Kctd13 KO and haploinsufficient mice; subcellular fractionation of AR; immunofluorescence; cell line knockdown

    PMID:36196997

    Open questions at the time
    • Whether KCTD13 directly interacts with AR or acts indirectly was unknown
    • Mechanism by which loss of a ubiquitin ligase adapter paradoxically reduces AR levels not explained
  9. 2023 High

    Identified GluN1 as a direct KCTD13–CUL3 ubiquitination substrate at Lys-860 via K48-linked chains, establishing a mechanism by which KCTD13 limits NMDAR surface expression and suppresses seizure susceptibility.

    Evidence In vitro ubiquitination assays with K860 mutagenesis; KCTD13 knockdown/overexpression in mouse hippocampus; proteasome inhibitor experiments; seizure assays rescued by memantine

    PMID:37142655

    Open questions at the time
    • Whether KCTD13-mediated GluN1 degradation is synapse-type specific is not known
    • Relative contribution of GluN1 versus RhoA degradation to KCTD13 neuronal phenotypes not dissected
  10. 2024 High

    Established that KCTD13 itself is regulated by KCTD10-mediated ubiquitin-dependent degradation, creating a hierarchical regulatory cascade in cortical progenitors where KCTD10 restrains KCTD13 abundance.

    Evidence Co-IP identifying KCTD10–KCTD13 interaction; Kctd10 brain-specific KO mouse; ubiquitination assays; in utero electroporation epistasis experiments

    PMID:38489388

    Open questions at the time
    • Whether KCTD10 targets KCTD13 through CUL3 or an independent E3 complex is not fully resolved
    • Stoichiometric relationship between KCTD10 and KCTD13 in vivo not quantified
  11. 2025 High

    Resolved the paradox of how KCTD13 loss reduces AR levels by demonstrating that KCTD13 has a dual role: it promotes CUL3-dependent AR ubiquitination but simultaneously shields AR from STUB1-mediated degradation via competitive BTB-domain binding, with the protective effect predominating in vivo.

    Evidence Recombinant protein direct binding assays; reconstituted ubiquitination with CUL3 and STUB1; BTB domain deletion mutagenesis; genetic AR/SOX9 rescue in Kctd13-KO mice; penile morphometry

    PMID:39888193 PMID:39968753

    Open questions at the time
    • Structural basis of BTB-domain competition between KCTD13 and STUB1 for AR binding not determined
    • Whether the protective mechanism generalizes to other KCTD13 substrates is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of substrate selectivity by KCTD13–CUL3, the reconciliation of RhoA versus ERBB pathway dependencies across species and cell types, and whether the protective (anti-degradation) function observed for AR extends to neuronal substrates.
  • No high-resolution structure of KCTD13–CUL3 complex or substrate-bound state
  • Species/context-dependent pathway usage (RhoA vs ERBB) not mechanistically explained
  • Relative in vivo contributions of individual substrates (RhoA, GluN1, ADSS, AR) to specific phenotypes remain unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1266738 Developmental Biology 3 R-HSA-112316 Neuronal System 2 R-HSA-162582 Signal Transduction 2
Partners
ADSSARCUL3GLUN1KCTD10RHOARND3STUB1
Complex memberships
CUL3-KCTD13 E3 ubiquitin ligase complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 KCTD13 is a major driver of mirrored neuroanatomical phenotypes associated with 16p11.2 CNV: overexpression in zebrafish induces microcephaly via decreased proliferation of neuronal progenitors and increased apoptosis, while suppression yields macrocephaly via increased proliferation without changes in apoptosis. Zebrafish overexpression and morpholino knockdown screens; mouse embryo analyses; quantification of neuronal progenitor proliferation and apoptosis Nature High 22596160
2015 KCTD13 functions in a KCTD13-CUL3-RhoA pathway in layer 4 of the inner cortical plate, where it acts as a substrate-specific adapter for CUL3-based E3 ubiquitin ligase regulating RhoA levels to control brain size and connectivity. Protein interaction network analysis integrating physical interactions (yeast two-hybrid/mass spectrometry) with spatiotemporal brain gene expression data Neuron Medium 25695269
2017 Kctd13 deletion in mice reduces synaptic transmission, which correlates with increased RhoA protein levels (a KCTD13/CUL3 ubiquitin ligase substrate); pharmacological RhoA inhibition reverses the synaptic transmission deficit, establishing RhoA as a mechanistic downstream effector. Kctd13 knockout mouse; electrophysiology; western blot for RhoA; pharmacological rescue with RhoA inhibitor; kctd13 deletion in zebrafish Nature High 29088697
2016 KCTD13 (Bacurd1) physically interacts with Rnd2 and Rnd3 GTPases in vitro and regulates long-term positioning and dendritic maturation of cerebral cortical neurons; forced expression alters dendritic branching and spine properties of layer II/III projection neurons. In vitro interaction assays; in utero electroporation in mice with knockdown/overexpression; postnatal cortical neuron positioning and morphology analysis Neural development Medium 26969432
2020 KCTD13 acts as a CUL3-based E3 ubiquitin ligase adapter that targets adenylosuccinate synthetase (ADSS) for ubiquitination; Kctd13 mutant neurons accumulate succinyl-adenosine (S-Ado) downstream of ADSS, linking KCTD13 to purine metabolism regulation. Comparison of Kctd13 mutant and wild-type neuronal ubiquitylomes by mass spectrometry; metabolite measurement; ADSS inhibitor rescue iScience Medium 33409479
2021 Kctd13 heterozygous deletion induces cognitive deficits in mice via dysregulation of the RHOA pathway; chronic treatment with fasudil (ROCK inhibitor) restores object recognition memory in adult Kctd13 heterozygous and 16p11.2 deletion mice, confirming RHOA pathway as the mechanistic link. Kctd13 heterozygous deletion mouse model; chronic fasudil pharmacological intervention; behavioral testing; RHOA pathway biochemical analysis Molecular autism Medium 33436060
2019 KCTD13 knockout in human iPSC-derived cortical neurons reduces neurite formation and spontaneous network activity via ERBB signaling (not RhoA); ERBB kinase activation rescues impaired neurite formation, while RhoA inhibitors had no effect in this human neuronal context. CRISPR/Cas9 knockout in human iPSCs; neural differentiation; RNA-sequencing and pathway analysis; pharmacological rescue with ERBB activators/inhibitors Molecular neurobiology Medium 31402430
2023 KCTD13, acting as a CUL3-based E3 ubiquitin ligase adapter, ubiquitinates GluN1 (obligatory NMDAR subunit) via K48-linked polyubiquitination at lysine-860, leading to proteasomal degradation of GluN1 and reduced membrane expression of glutamate receptors; KCTD13 knockdown enhances seizure susceptibility, reversed by NMDAR inhibitor memantine. KCTD13 knockdown/overexpression in mouse hippocampus; ubiquitination assays; site-directed mutagenesis (K860); proteasome inhibitor experiments; seizure behavioral assays; NMDAR pharmacological rescue Cell death and differentiation High 37142655
2022 Loss of KCTD13 reduces nuclear androgen receptor (AR) levels and SOX9 expression in genitourinary tract development; Kctd13 haploinsufficiency and homozygous deletion in mice cause cryptorchidism and micropenis with reduced nuclear AR. Kctd13 knockout and haploinsufficient mouse models; subcellular fractionation of AR; immunofluorescence; cell line knockdown experiments FASEB journal Medium 36196997
2025 KCTD13 directly binds AR via its BTB domain, and has a dual role in AR ubiquitination: (1) it increases CUL3-dependent AR ubiquitination without affecting CUL3-AR binding; (2) it decreases STUB1-mediated AR ubiquitination by competitively dissociating the AR/STUB1 complex via the BTB domain, thereby protecting AR from STUB1-driven degradation. KCTD13 ΔBTB mutant cannot bind AR and fails to block STUB1-mediated AR ubiquitination. Recombinant protein direct binding assay; ubiquitination assays with CUL3 and STUB1; BTB domain deletion mutagenesis; AR target gene expression (FOXJ1); Kctd13-deficient mouse testis biochemistry FASEB journal High 39968753
2025 Restoration of AR (in urethral mesenchyme) or SOX9 (in urethral epithelium) rescues micropenis in Kctd13-KO mice; ectopic KCTD13 expression in HEK293 cells reduces AR ubiquitination in a proteasome-dependent manner mediated by STUB1, while KCTD13's effect on SOX9 ubiquitination is minimal. Transgenic mice with cell-type-specific AR or SOX9 restoration in Kctd13-KO background; ubiquitination assays in HEK293 cells; proteasome inhibitor experiments; penile morphometry and fertility assays Andrology Medium 39888193
2024 KCTD10 interacts with KCTD13 and mediates ubiquitination-dependent degradation of KCTD13; KCTD10 ablation leads to increased KCTD13 expression in the developing cortex, and KCTD13 overexpression in neuronal progenitors mirrors the proliferation and cell distribution defects of KCTD10 deficiency. Co-IP screening identifying KCTD10-KCTD13 interaction; Kctd10 brain-specific knockout mouse; ubiquitination assays; in utero electroporation of KCTD13 overexpression; neuronal progenitor proliferation and distribution assays Proceedings of the National Academy of Sciences of the United States of America High 38489388

Source papers

Stage 0 corpus · 19 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 313 22596160
2015 Spatiotemporal 16p11.2 protein network implicates cortical late mid-fetal brain development and KCTD13-Cul3-RhoA pathway in psychiatric diseases. Neuron 121 25695269
2017 Kctd13 deletion reduces synaptic transmission via increased RhoA. Nature 108 29088697
2005 Cloning of two rat PDIP1 related genes and their interactions with proliferating cell nuclear antigen. Journal of experimental zoology. Part A, Comparative experimental biology 38 15726626
2021 Targeting the RHOA pathway improves learning and memory in adult Kctd13 and 16p11.2 deletion mouse models. Molecular autism 31 33436060
2005 A novel PDIP1-related protein, KCTD10, that interacts with proliferating cell nuclear antigen and DNA polymerase delta. Biochimica et biophysica acta 31 15982757
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 21 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
2012 B-Myb promotes S-phase independently of its sequence-specific DNA binding activity and interacts with polymerase delta-interacting protein 1 (Pdip1). Cell cycle (Georgetown, Tex.) 14 23032261
2005 Genomic organization, promoter characterization and roles of Sp1 and AP-2 in the basal transcription of mouse PDIP1 gene. FEBS letters 12 15757666
2020 Regulation of purine metabolism connects KCTD13 to a metabolic disorder with autistic features. iScience 11 33409479
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 10 36196997
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 5 37465586
2025 Role of Kctd13 in modulating AR and SOX9 expression in different penile cell populations. Andrology 1 39888193
2025 Androgen receptor ubiquitination links KCTD13 to genitourinary tract defects. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 39968753
2024 Novel evidence of CNV deletion in KCTD13 related to the severity of isolated hypospadias in Chinese population. Frontiers in pediatrics 0 39318621