HGNC Approved Gene Symbol: CUL3
Cytogenetic location: 2q36.2 Genomic coordinates (GRCh38): 2:224,470,150-224,585,363 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q36.2 | Neurodevelopmental disorder with or without autism or seizures | 619239 | Autosomal dominant | 3 |
| Pseudohypoaldosteronism, type IIE | 614496 | Autosomal dominant | 3 |
The CUL3 gene encodes a scaffolding component of the Cullin-RING ligase (CRL) complex, which belongs to a class of E3 ubiquitin ligases that mediate polyubiquitination of specific target proteins destined for degradation (summary by Nakashima et al., 2020).
CUL3 is a component of a ubiquitin E3 ligase that is essential for mitotic division (Sumara et al., 2007).
Kipreos et al. (1996) identified a conserved gene family, designated cullins (see CUL1, 603134), with at least 5 members in nematodes, 6 in humans, and 3 in S. cerevisiae. Human CUL3 is an ortholog of nematode cul3. Michel and Xiong (1998) identified human CUL3 cDNAs and reported that the predicted protein is 768 amino acids long.
By sequencing clones isolated from a size-fractionated human brain cDNA library, Ishikawa et al. (1998) isolated CUL3, which they designated KIAA0617. The deduced protein contains 768 amino acids. RT-PCR analysis detected highest CUL3 expression in ovary, followed by skeletal muscle and brain. Weaker expression was detected in heart, lung, liver, kidney, and testis, with little to no expression in other tissues examined.
Du et al. (1998) identified CUL3 as a gene whose expression in human fibroblasts was induced by phorbol 12-myristate 13-acetate (PMA) and suppressed by salicylate. They reported that the sequences of the human and C. elegans cul3 proteins share 46% identity. Northern blot analysis revealed that CUL3 is expressed as major 2.8- and minor 4.3-kb transcripts in various human tissues, with the highest levels in skeletal muscle and heart.
By analysis of a radiation hybrid panel, Ishikawa et al. (1998) mapped the CUL3 gene to human chromosome 2.
Hartz (2012) mapped the CUL3 gene to chromosome 2q36.2 based on an alignment of the CUL3 sequence (GenBank AF062537) with the genomic sequence (GRCh37).
Sumara et al. (2007) found that KLHL9 (611201), KLHL13 (300655), and CUL3 interacted directly in a 370-kD protein complex in HeLa cell lysates. The CUL3/KLHL9/KLHL13 complex was the minimum unit required for correct chromosome alignment in metaphase, proper midzone and midbody formation, and completion of cytokinesis. CUL3/KLHL9/KLHL13 acted as an E3 ligase and regulated dynamic localization of the chromosomal passenger complex (CPC) protein Aurora B (AURKB; 604970) on mitotic chromosomes and accumulation of Aurora B on the central spindle after anaphase onset. Aurora B directly bound the substrate-recognition domains of KLHL9 and KLHL13 in vitro and coimmunoprecipitated with the CUL3/KLHL9/KLHL13 complex during mitosis. Moreover, Aurora B was ubiquitylated in a CUL3-dependent manner in vivo and by reconstituted CUL3/KLHL9/KLHL13 in vitro. Sumara et al. (2007) concluded that CUL3/KLHL9/KLHL13 is an E3 ligase that controls the dynamic behavior of Aurora B on mitotic chromosomes and thereby coordinates faithful mitotic progression and completion of cytokinesis.
Using mass spectrometric analysis, Maerki et al. (2009) found that KLHL21 (616262) and KLHL22 (618020) immunoprecipitated with CUL3, KLHL9, and KLHL13 from HeLa cell lysates. KLHL21 also interacted with Aurora B. Deletion analysis revealed that the BTB domain of KLHL21 was required for interaction with CUL3. Time-lapse microscopy revealed that knockdown of KLHL21 or KLHL22 via small interfering RNA delayed prometaphase and led to failure of proper metaphase plate formation. Knockdown of KLHL21, but not KLHL22, also caused multinucleation and failure of cytokinesis in a large number of cells. During anaphase, loss of KLHL21 inhibited translocation of Aurora B from segregating chromosomes to the spindle midzone and caused loss of CUL3 localization at the midzone. Likewise, knockdown of CUL3 caused loss of KLHL21 from the midzone. Sucrose gradient and gel filtration experiments revealed that KLHL21 and KLHL9 fractionated into overlapping but distinct CUL3 complexes, suggesting that KLHL21, KLHL9, and KLHL13 assemble distinct CUL3 complexes to regulate CPC localization during mitosis. CUL3-KLHL21 complexes also ubiquitinated Aurora B in vitro. Maerki et al. (2009) concluded that different CUL3 complexes with KLHL9, KLHL13, and KLHL21 may target different pools of Aurora B for mitotic progression.
Rondou et al. (2008) showed that interaction between KLHL12 (614522) and the CUL3 ubiquitin ligase complex directed ubiquitination of dopamine receptor D4 (DRD4; 126452). KLHL12 interacted directly with CUL3 and with the polymorphic intracellular loop-3 of D4. Knockdown of KLHL12 in KLHL12-overexpressing HEK293 cells abolished association of D4 with CUL3, and knockdown of CUL3 decreased ubiquitination of D4.
Using yeast 2-hybrid and immunoprecipitation analyses, Cummings et al. (2009) showed that human KLHDC5 (KLHL42; 618919) and CUL3 physically interacted through the BTB domain of KLHDC5. Overexpression of KLHDC5 in HeLa cells stabilized microtubules and inhibited microtubule depolymerization required for normal cell morphology and mitosis, resulting in cells with multiple nuclei. In contrast, knockdown of KLHDC5 caused a dramatic loss of microtubule structure. Like KLHDC5, the microtubule-severing protein p60 (KATNA1; 606696) was also expressed in mitotic cells, and its levels in were regulated by KLHDC5. p60 interacted with both CUL3 and KLHDC5, and at least 1 of the 3 kelch domains of KLHDC5 was required for the interaction. KLHDC5 served as a substrate recognition adaptor to recruit p60 to the CUL3-KLHDC5 complex, and CUL3 facilitated ubiquitination of p60 to mediate its degradation. CUL3 regulation of p60 abundance was vital for faithful progression of mitosis, as knockdown of CUL3 in HeLa cells increased p60 levels and resulted in accumulation of multinucleated cells due to their inability to complete cytokinesis.
Jin et al. (2012) found that depletion of either Klhl12 or Cul3 in mouse embryonic stem cells resulted in cell compaction and delayed proliferation. Depletion of Cul3 in mouse fibroblasts had a much weaker effect. Overexpression and depletion studies showed that interaction of Klhl12 with Cul3 was required for monoubiquitination of the coat protein complex II (COPII) component Sec31 (see 610257). Overexpression of Klhl12 resulted in expansion of the diameter of Sec31-containing COPII vesicles, and this expansion was required for transport and secretion of large cargo proteins, such as procollagens (see 120150). A Sec31-binding mutant of Klhl12 neither colocalized with Sec31 nor induced formation of large vesicles. Disruption of KLHL12-CUL3 function in human HT1080 fibrosarcoma cells impaired COPII vesicle expansion and collagen export, but it had no effect on export of smaller cargo by small COPII vesicles. Jin et al. (2012) concluded that KLHL12-CUL3 monoubiquitination of SEC31 is required for COPII vesicle expansion to accommodate large or bulky cargo molecules.
Mathew et al. (2012) reported that PLZF is prominently associated with CUL3 in natural killer T cell thymocytes. PLZF transports CUL3 to the nucleus, where the 2 proteins are associated within a chromatin modifying complex. Furthermore, PLZF expression results in selective ubiquitination changes of several components of this complex. CUL3 was also found associated with the BTB-ZF transcription factor BCL6 (109565), which directs the germinal center B cell and follicular T-helper cell programs. Conditional CUL3 deletion in mice demonstrated an essential role for CUL3 in the development of PLZF- and BCL6-dependent lineages. Mathew et al. (2012) concluded that distinct lineage-specific BTB-ZF transcription factors recruit CUL3 to alter the ubiquitination pattern of their associated chromatin-modifying complex. They proposed that this function is essential to direct the differentiation of several T- and B-cell effector programs, and may also be involved in the oncogenic role of PLZF and BCL6 in leukemias and lymphomas.
KBTBD8 (616607) functions as an adaptor for substrate recognition by CUL3. Using mass spectrometric analysis, Werner et al. (2015) found that KBTBD8 interacted with TCOF1 (606847) and NOLC1 (602394). CUL3-KBTBD8 monoubiquitinated TCOF1 and NOLC1 in a manner that required the cofactor beta-arrestin (see 107940). Knockdown of KBTBD8, TCOF1, or NOLC1 in human embryonic stem cells (hESCs) via short hairpin RNA inhibited hESC differentiation into neural crest cells and accelerated hESC differentiation into central nervous system (CNS) precursors. Affinity purification revealed that ubiquitinated TCOF1-NOLC1 complexes engaged RNA polymerase I into complexes with the small ribosomal processing complex. Werner et al. (2015) hypothesized that KBTBD8-dependent ubiquitination drives formation of a TCOF1-NOLC1 platform in hESCs that connects RNA polymerase I with ribosome modification enzymes at specific mRNAs to delay accumulation of CNS precursor proteins until neural crest specification has occurred.
By coimmunoprecipitation and mass spectrometric analyses, Zhang et al. (2016) showed that ACLY (108728) interacted indirectly with CUL3 through KLHL25 (619893) to form a complex in human lung cancer H1299 cells. KLHL25 interacted directly with ACLY and functioned as a substrate adaptor to bridge ACLY to CUL3. CUL3-KLHL25 negatively regulated ACLY protein levels in cells through protein ubiquitination and degradation, and low CUL3 expression was associated with high ACLY expression in human lung cancer. Through negative regulation of ACLY, CUL3-KLHL25 reduced acetyl-CoA levels and inhibited lipid synthesis, which in turn contributed to the inhibitory effect of CUL3-KLHL25 on proliferation and anchorage-independent growth of lung cancer cells. In vivo analysis revealed that CUL3-KLHL25 inhibited growth of xenograft lung tumors in mice through negative regulation of ACLY.
Tian et al. (2021) found that Acly regulated differentiation of mouse inducible regulatory T cells (iTregs). Tgfb1 (190180) induced Acly downregulation through Cul3-Klhl25-mediated ubiquitination and degradation, which in turn facilitated iTreg differentiation. Analysis with human iTregs confirmed the conserved role of CUL3-KLHL25-mediated ACLY ubiquitination in iTreg differentiation. Analysis with a mouse inflammatory bowel disease (IBD; see 266600) model revealed an important role of Cul3-Klhl25-mediated Acly ubiquitination in colitis alleviation and in regulation of diarrhea.
Zhang et al. (2018) showed that PDL1 (605402) protein abundance is regulated by cyclin D (168461)-CDK4 (123829) and the CUL3-SPOP (602650) E3 ligase via proteasome-mediated degradation. Inhibition of CDK4 and CDK6 (603368) in vivo increases PDL1 protein levels by impeding cyclin D-CDK4-mediated phosphorylation of SPOP and thereby promoting SPOP degradation by the anaphase-promoting complex activator FZR1 (603619). Loss-of-function mutations in SPOP compromise ubiquitination-mediated PDL1 degradation, leading to increased PDL1 levels and reduced numbers of tumor-infiltrating lymphocytes in mouse tumors and in primary human prostate cancer specimens. Notably, combining CDK4/6 inhibitor treatment with anti-PD1 (600244) immunotherapy enhances tumor regression and markedly improves overall survival rates in mouse tumor models. Zhang et al. (2018) concluded that their study uncovered a novel molecular mechanism for regulating PDL1 protein stability by a cell cycle kinase and revealed the potential for using combination treatment with CDK4/6 inhibitors and PD1-PDL1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers.
Canning et al. (2013) determined the crystal structure of the BTB-BACK domains of human KLHL11 (619078) at 2.6-angstrom resolution. The BTB-BACK domains formed a homodimer with an elongated shape. KLHL11 had 8 alpha helices in total, with the 2 N-terminal helices forming the 3-box motif through which KLHL11 binds CUL3 to form E3 ubiquitin ligases. A 16-angstrom deep and 18-angstrom wide hydrophobic groove between the BTB and BACK domains exposed the 3-box for cullin interaction. The authors also determined the crystal structure of the BTB-BACK domains of KLHL11 in complex with the N-terminal cullin repeat domain of CUL3 at 2.8-angstrom resolution. The structure revealed interaction between the specific N-terminal extension sequence of CUL3 and the 3-box motif of KLHL11. In KLHL11-CUL3 assemblies, each subunit in the KLHL11 homodimer bound to 1 molecule of CUL3 and exhibited a 2-fold symmetry axis across the BTB dimer in a heterotetramer, further highlighting the importance of the N-terminal extension for CUL3 binding. Using other structures, the authors built the missing structural domains in the E3 ligase and proposed a working model of the complete dimeric BTB-Kelch class of E3 ligase.
Pseudohypoaldosteronism Type II
Boyden et al. (2012) identified mutations in CUL3 segregating in de novo or autosomal dominant forms of pseudohypoaldosteronism type II (PHA2E; 614496). Seventeen of 52 PHA2 kindreds had mutations in CUL3; all were heterozygous. Eight of the 17 were documented to be de novo, providing overwhelming evidence that these mutations are disease-causing. CUL3 mutations all clustered in sites implicated in splicing of exon 9, including the intron 8 splice acceptor (n = 4), the intron 9 splice donor (n = 5), the putative intron 8 splice branch site (n = 5), and a putative splice enhancer in exon 9 (n = 3, within a TTGGA(T/A)) splice enhancer consensus sequence.
Neurodevelopmental Disorder with or without Autism or Seizures
In a 3-year-old boy (family 2) with neurodevelopmental disorder with or without autism or seizures (NEDAUS; 619239), Thiffault et al. (2018) identified a de novo heterozygous missense mutation in the CUL3 gene (Y58C; 603136.0008). The mutation, which was found by trio-based next-generation sequencing, was considered to be pathogenic after curation using a point-based system. Functional studies of the variant were not performed. The authors noted that several large studies had identified de novo mutations in the CUL3 gene in patients with variable neurodevelopmental disorders. For example, Kong et al. (2012) identified a de novo heterozygous loss-of-function R546X variant in 1 of 44 Icelandic individuals with autism spectrum disorder.
In a 12-year-old Brazilian girl (F1389-1) with NEDAUS, da Silva Montenegro et al. (2020) identified a de novo heterozygous nonsense mutation in the CUL3 gene (S133X; 603136.0009). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was classified as pathogenic according to ACMG criteria.
In 3 unrelated children with NEDAUS, Nakashima et al. (2020) identified de novo heterozygous mutations in the CUL3 gene (603136.0010-603136.0012). There were 2 frameshift mutations and 1 missense mutation. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the dbSNP (build 153) or gnomAD databases. All were predicted or demonstrated to result in a loss of function and haploinsufficiency. Two patients were ascertained from a cohort of 1,230 individuals with childhood-onset epilepsy who underwent whole-exome sequencing; the third patient was identified through the GeneMatcher program.
In a 4-year-old Japanese girl with NEDAUS, Iwafuchi et al. (2021) identified a de novo heterozygous frameshift mutation in the CUL3 gene (603136.0013). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was predicted to lead to nonsense-mediated mRNA decay and haploinsufficiency. Functional studies of the variant were not performed.
Papizan et al. (2018) found that mice with skeletal muscle-specific deletion of Cul3 were born in normal mendelian ratios but became cyanotic shortly after birth and died due to inability to breathe. At embryonic day 18.5, mutant embryos displayed physical features characteristic of defective myogenesis or excitation-contraction coupling. Histologic analysis of tongue musculature revealed reduced muscle mass, disorganized sarcomeres, and multinucleated myofibers in mutant mice. Proteomic analysis showed that deletion of Cul3 affected extracellular matrix deposition and sarcomere maturation/function. The authors found that mice with cardiomyocyte-specific deletion of Cul3 were born in normal mendelian ratios and were morphologically indistinguishable from wildtype at birth. However, these mutant mice exhibited failure to thrive, were much smaller compared with wildtype by postnatal day 5 (P5), and died around P6 with severe cardiomyopathy. Histologic examination of heart muscles showed widespread cardiomyocyte vacuolization and protein aggregate deposition. Proteomic analysis revealed an altered metabolic profile, indicating that Cul3-dependent proteostasis is a critical regulator of cardiac antioxidative and metabolic processes.
Dong et al. (2020) found that mice with homozygous deletion of Cul3 had reduced body size and brain weight compared with wildtype and died prematurely. Mice heterozygous for Cul3 deletion (Cul3-deficient mice) had more than 40% reduced level of Cul3, but they were viable and fertile, survived as long as wildtype, and did not show deficits observed in mice with homozygous Cul3 deletion. Cul3-deficient mice exhibited social behavioral deficits and anxiety-like behaviors. Hippocampus of Cul3-deficient mice had increased spine density, neuronal excitability, and synaptic transmission and disrupted excitation-inhibition (E-I) balance in CA1 neurons. Similar deficits were observed in pyramidal neurons with Cul3 deficiency, demonstrating a cell-autonomous role of Cul3 for synaptic function, E-I balance, and behavior. Proteomic analysis identified Eif4g1 (600495) as a target of Cul3-dependent ubiquitination. Consequently, Cul3 deficiency increased Eif4g1 level and upregulated Cap-dependent protein synthesis in brain. Inhibition of Cap-dependent translation diminished synaptic and social deficits in Cul3-deficient mice, but it had little effect on anxiety-like behaviors. However, chemogenetic inhibition of pyramidal neuron activity in hippocampus attenuated anxiety-like behavior in mutant mice.
In 4 families, 3 with de novo occurrence of pseudohypoaldosteronism, type IIE (PHA2E; 614496), Boyden et al. (2012) identified an A-to-G transition at the -26 position of the intron 8 splice acceptor site in the CUL3 gene.
In a family segregating autosomal dominant pseudohypoaldosteronism type IIE (PHA2E; 614496), Boyden et al. (2012) identified an T-to-G transversion at the -28 position of the intron 8 splice branch point in the CUL3 gene.
In a patient with pseudohypoaldosteronism type IIE (PHA2E; 614496), Boyden et al. (2012) identified an T-to-G transversion in the CUL3 gene, at the -12 position of the intron 8 splice acceptor site, within the polypyrimidine tract.
In a de novo case of pseudohypoaldosteronism type IIE (PHA2E; 614496), Boyden et al. (2012) identified an T-to-A transversion in the CUL3 gene, at the -5 position of the intron 8 splice acceptor site, within the polypyrimidine tract.
In a de novo case of pseudohypoaldosteronism type IIE (PHA2E; 614496), Boyden et al. (2012) identified a C-to-T transition at the -3 position of the intron 8 splice acceptor site of the CUL3 gene.
In 3 affected members of a 2-generation family with pseudohypoaldosteronism type IIE (PHA2E; 614496), Boyden et al. (2012) identified a G-to-A transition in the CUL3 gene, at the -1 position of the intron 8 splice acceptor site.
In 2 families with undetermined pseudohypoaldosteronism type IIE (PHA2E; 614496), Boyden et al. (2012) identified an A-to-G transition resulting in an asp-to-gly substitution at codon 413 (D413G) within exon 9 of the CUL3 gene that resulted in an ES enhancer.
In a 3-year-old boy (family 2) with neurodevelopmental disorder without seizures or autism (NEDAUS; 619239), Thiffault et al. (2018) identified a de novo heterozygous c.173A-G transition in the CUL3 gene, resulting in a tyr58-to-cys (Y58C) substitution. The mutation, which was found by trio-based next-generation sequencing, was considered to be pathogenic after curation using a point-based system. Functional studies of the variant were not performed. The child had failure to thrive, microcephaly, speech delay, and absent thumb.
In a 12-year-old Brazilian girl (F1389-1) with neurodevelopmental disorder with autism but without seizures (NEDAUS; 619239), da Silva Montenegro et al. (2020) identified a de novo heterozygous c.398C-G transversion (c.398C-G, NM_001257197) in exon 4 of the CUL3 gene, resulting in a ser133-to-ter (S133X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was classified as pathogenic according to ACMG criteria. The patient had autism spectrum disorder, with mild motor and speech delay. She did not have seizures. Functional studies of the variant were not performed, but it was predicted to result in a loss of function.
In a 3-year-old Japanese girl (patient 1) with neurodevelopmental disorder without autism but with seizures (NEDAUS; 619239), Nakashima et al. (2020) identified a de novo heterozygous c.854T-C transition (c.854T-C, NM_003590.4) in the CUL3 gene, resulting in a val285-to-ala (V285A) substitution in the CR3 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 153) or gnomAD databases. In vitro functional expression studies showed that the mutant protein had significantly weaker interaction with KEAP1 (606016) compared to wildtype, suggesting that it caused instability of the CRL complex. The patient had onset of intractable spasms and tonic seizures at 2 months of age. EEG showed a suppression-burst pattern, consistent with West syndrome.
In a 10-year-old Malaysian boy (patient 2) with neurodevelopmental disorder without autism but with seizures (NEDAUS; 619239), Nakashima et al. (2020) identified a de novo heterozygous 1-bp deletion (c.137delG, NM_003590.4), resulting in a frameshift and premature termination (Arg46LeufsTer32). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 153) or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function and haploinsufficiency. The patient had onset of intractable seizures at 6 months of age; EEG showed hypsarrhythmia, consistent with West syndrome.
In a 4-year-old Dutch girl (patient 3) with neurodevelopmental disorder without autism or seizures (NEDAUS; 619239), Nakashima et al. (2020) identified a de novo heterozygous 1-bp deletion (c.1239del, NM_003590.4) in the CUL3 gene, resulting in a frameshift and premature termination (Asp413GlufsTer42). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 153) or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function and haploinsufficiency. The patient had mild intellectual disability with poor speech. She did not have seizures.
In a 4-year-old Japanese girl with neurodevelopmental disorder with autism and seizures (NEDAUS; 619239), Iwafuchi et al. (2021) identified a de novo heterozygous 2-bp insertion (c.1758_1759insTG, NM_003590.5) in exon 13 of the CUL3 gene, resulting in a frameshift and premature termination (Thr587Ter). The mutation, which was found whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The mutation was predicted to lead to nonsense-mediated mRNA decay and haploinsufficiency. Functional studies of the variant were not performed. The patient presented at age 21 months with status epilepticus and thereafter showed developmental regression with loss of eye contact, autistic features, and features of Rett syndrome (RTT; 312750).
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