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| Symbol | CUL3 |
| Full Name | Cullin 3 |
| Chromosome | 2q36.2 |
| NCBI Gene | 8452 |
| Ensembl | ENSG00000036257 |
| OMIM | 603136 |
| UniProt | Q13618 |
| Diseases | [Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), Autism Spectrum Disorder |
| Expression | Ubiquitous, enriched in brain and testis |
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Scaffold for CRL3 E3 ubiquitin ligase complexes
Partners with KEAP1 to regulate NRF2
~80 BTB-domain substrate adaptors |
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-CUL3-RBX1 E3 ligase that constitutively ubiquitinates NRF2, 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. See the protein page for detailed structural and functional information.
CUL3 serves as the central scaffold in CRL3 complexes:
- N-terminal domain: Binds BTB-domain substrate adaptors (e.g., KEAP1, KLHL20, SPOP, KCTD13)
- C-terminal cullin homology domain: Binds RBX1 (RING-finger protein), which recruits E2 ubiquitin-conjugating enzymes
- Neddylation: 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 substrates
| Complex |
Adaptor |
Substrate |
Relevance |
| CRL3^KEAP1 |
KEAP1 |
NRF2 |
Oxidative stress response |
| CRL3^KLHL20 |
KLHL20 |
DAPK1 |
Autophagy regulation |
| CRL3^SPOP |
SPOP |
Various |
Protein quality control |
| CRL3^KCTD13 |
KCTD13 |
RhoA |
Synaptic development, ASD |
| CRL3^BTBD6 |
BTBD6 |
PLZF |
Neuronal differentiation |
| CRL3^KLHL12 |
KLHL12 |
SEC31A |
ER-to-Golgi transport |
The KEAP1-CUL3-RBX1 complex is the primary negative regulator of the NRF2 antioxidant pathway:
- 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 is simultaneously degraded, further derepressing NRF2 targets
CUL3-mediated protein quality control is compromised in AD:
- 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
- CRL3 complexes regulate tau phosphorylation indirectly through control of kinase levels
- Amyloid-beta accumulation overwhelms proteasomal capacity, competing with CRL3 substrates
In PD, CUL3 intersects with multiple pathogenic pathways:
- CRL3^KEAP1 regulation of NRF2 is critical for dopaminergic neuron survival against oxidative stress
- CUL3 interacts with PARKIN, another E3 ligase mutated in familial PD, in mitochondrial quality control
- PINK1-dependent phosphorylation events affect CRL3 substrate recognition
- CUL3 dysregulation contributes to alpha-synuclein accumulation by impairing proteasomal and autophagic clearance
- 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
CUL3 is ubiquitously expressed with enrichment in:
- Brain: Cortical neurons, hippocampal neurons, cerebellar Purkinje cells
- Developing brain: High expression during neurogenesis and synaptogenesis
- Testis: Spermatocytes and spermatids
- Immune cells: Macrophages (including microglia)