CUL3 — Cullin 3 <table class="infobox infobox-gene">
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CUL3 — Cullin 3 <table class="infobox infobox-gene">
Overview
Mermaid diagram (expand to render)
CUL3 (Cullin 3) encodes a scaffold protein that nucleates Cullin-RING E3 ubiquitin ligase complexes (CRL3s). CUL3 assembles with BTB-domain substrate adaptor proteins and the RING-finger protein RBX1 to form multisubunit complexes that ubiquitinate specific substrates for proteasomal degradation. The most neuroscience-relevant CRL3 complex is the [KEAP1](/genes/keap1)-CUL3-RBX1 E3 ligase that constitutively ubiquitinates [NRF2](/genes/nfe2l2), the master regulator of antioxidant gene expression.
CUL3 haploinsufficiency causes autism spectrum disorder, and CUL3-dependent protein quality control pathways are critical for neuronal homeostasis in aging and neurodegenerative disease. Disruption of CRL3 complexes leads to accumulation of misfolded proteins, oxidative damage, and neuronal dysfunction.
The protein encoded by CUL3 is [Cullin-3 Protein](/proteins/cul3-protein). See the protein page for detailed structural and functional information.
Function
E3 Ubiquitin Ligase Scaffold CUL3 serves as the central scaffold in CRL3 complexes:
N-terminal domain : Binds BTB-domain substrate adaptors (e.g., [KEAP1](/genes/keap1), KLHL20, SPOP, KCTD13)C-terminal cullin homology domain : Binds RBX1 (RING-finger protein), which recruits E2 ubiquitin-conjugating enzymesNeddylation : CUL3 is activated by conjugation of NEDD8, which induces conformational change promoting ubiquitin transfer~80 BTB adaptors : CUL3 partners with approximately 80 different BTB-domain proteins, each recruiting distinct substratesKey CRL3 Complexes in Neurodegeneration | Complex | Adaptor | Substrate | Relevance |
KEAP1-NRF2 Pathway The KEAP1-CUL3-RBX1 complex is the primary negative regulator of the [NRF2 antioxidant pathway](/mechanisms/oxidative-stress):
Under basal conditions, KEAP1 bridges NRF2 to CUL3, promoting polyubiquitination and proteasomal degradation
Oxidative/electrophilic stress modifies KEAP1 cysteine sensors (C151, C273, C288)
Modified KEAP1 cannot present NRF2 for ubiquitination
NRF2 accumulates, translocates to the nucleus, and activates ARE-dependent genes
[BACH1](/genes/bach1) is simultaneously degraded, further derepressing NRF2 targets
Disease Associations
Alzheimer's Disease CUL3-mediated protein quality control is compromised in [AD](/diseases/alzheimers-disease):
Reduced CUL3 neddylation efficiency in aged brain, impairing CRL3 activity
Impaired KEAP1-CUL3 degradation of NRF2 paradoxically combined with reduced NRF2 nuclear accumulation in AD [neurons](/entities/neurons)
CRL3 complexes regulate [tau](/proteins/tau) phosphorylation indirectly through control of kinase levels
[Amyloid-beta](/proteins/amyloid-beta) accumulation overwhelms proteasomal capacity, competing with CRL3 substrates
Parkinson's Disease In [PD](/diseases/parkinsons-disease), CUL3 intersects with multiple pathogenic pathways:
CRL3^KEAP1 regulation of NRF2 is critical for dopaminergic neuron survival against oxidative stress
CUL3 interacts with [PARKIN](/genes/prkn), another E3 ligase mutated in familial PD, in mitochondrial quality control
[PINK1](/genes/pink1)-dependent phosphorylation events affect CRL3 substrate recognition
CUL3 dysregulation contributes to [alpha-synuclein](/proteins/alpha-synuclein) accumulation by impairing proteasomal and autophagic clearance
Autism Spectrum Disorder
CUL3 haploinsufficiency identified in large-scale ASD exome sequencing studies
CRL3^KCTD13 complex regulates RhoA levels; excess RhoA disrupts dendritic spine morphogenesis
CUL3 heterozygous mice show social behavior deficits and synaptic abnormalities
Connects ubiquitin-proteasome dysfunction to neurodevelopmental disorders
Expression CUL3 is ubiquitously expressed with enrichment in:
Brain : Cortical neurons, hippocampal neurons, cerebellar Purkinje cellsDeveloping brain : High expression during neurogenesis and synaptogenesisTestis : Spermatocytes and spermatidsImmune cells : Macrophages (including [microglia](/cell-types/microglia))See Also
[KEAP1](/genes/keap1) — Primary CUL3 adaptor for NRF2 regulation
[NFE2L2 (NRF2)](/genes/nfe2l2) — CRL3^KEAP1 substrate, antioxidant master regulator
[BACH1](/genes/bach1) — NRF2 competitor at AREs
[PRKN (Parkin)](/genes/prkn) — E3 ligase in PD, interacts with CUL3 pathway
[Ubiquitin-Proteasome System](/mechanisms/ubiquitin-proteasome-system) — Proteostasis pathway
External Links
[NCBI Gene: CUL3](https://www.ncbi.nlm.nih.gov/gene/8452)
[UniProt: Q13618](https://www.uniprot.org/uniprot/Q13618)
[GeneCards: CUL3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=CUL3)
[OMIM: 603136](https://omim.org/entry/603136)
References
[Pintard et al., Cullin-based ubiquitin ligases: Cul3-BTB complexes join the family (2004) (2004)](https://doi.org/10.1093/emboj/cdg527)
[Furukawa & Bhatt et al., BTB protein KEAP1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase (2005) (2005)](https://doi.org/10.1128/MCB.25.1.162-171.2005)
[Kong et al., Genetic variants in CUL3 contribute to autism susceptibility (2020) (2020)](https://doi.org/10.1038/s41380-019-0557-x)
[Cheng et al., CUL3-KLHL20 ubiquitin ligase: discovery, regulation, and roles in signaling (2020) (2020)](https://doi.org/10.1016/j.tibs.2020.01.010)
[Lin et al., Loss of the haploinsufficient gene CUL3 in autism triggers cortical excitation/inhibition imbalance (2021) (2021)](https://doi.org/10.1016/j.celrep.2021.109813)
[Unknown, Baird & Bhatt, The cytoprotective role of the KEAP1-NRF2 pathway (2020) (2020)](https://doi.org/10.1016/j.abb.2019.108164)
Pathway Diagram The following diagram shows the key molecular relationships involving CUL3 — Cullin 3 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)
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