FipoQ/FBXO33, a Cullin‐1‐based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein

Abstract

Polyglutamine (polyQ) diseases describe a group of progressive neurodegenerative disorders caused by the CAG triplet repeat expansion in the coding region of the disease genes. To date, nine such diseases, including spinocerebellar ataxia type 3 (SCA3), have been reported. The formation of SDS‐insoluble protein aggregates in neurons causes cellular dysfunctions, such as impairment of the ubiquitin‐proteasome system, and contributes to polyQ pathologies. Recently, the E3 ubiquitin ligases, which govern substrate specificity of the ubiquitin‐proteasome system, have been implicated in polyQ pathogenesis. The Cullin (Cul) proteins are major components of Cullin‐RING ubiquitin ligases (CRLs) complexes that are evolutionarily conserved in the Drosophila genome. In this study, we examined the effect of individual Culs on SCA3 pathogenesis and found that the knockdown of Cul1 expression enhances SCA3‐induced neurodegeneration and reduces the solubility of expanded SCA3‐polyQ proteins. The F‐box proteins are substrate receptors of Cul1‐based CRL. We further performed a genetic modifier screen of the 19 Drosophila F‐box genes and identified F‐box involved in polyQ pathogenesis (FipoQ) as a genetic modifier of SCA3 degeneration that modulates the ubiquitination and solubility of expanded SCA3‐polyQ proteins. In the human SK‐N‐MC cell model, we identified that F‐box only protein 33 (FBXO33) exerts similar functions as FipoQ in modulating the ubiquitination and solubility of expanded SCA3‐polyQ proteins. Taken together, our study demonstrates that Cul1‐based CRL and its associated F‐box protein, FipoQ/FBXO33, modify SCA3 protein toxicity. These findings will lead to a better understanding of the disease mechanism of SCA3 and provide insights for developing treatments against SCA3. Cover Image for this issue: doi: .

An Amyotrophic Lateral Sclerosis-Associated Mutant of C21ORF2 Is Stabilized by NEK1-Mediated Hyperphosphorylation and the Inability to Bind FBXO3

“…Mutations in the F box protein FBXO7 (encoded by PARK15 ), for example, have been shown to give rise to early-onset autosomal recessive Parkinson's disease ( Shojaee et al., 2008 ), and SCF FBXL5 has been found to catalyze ubiquitylation of α-synuclein, which contributes to the Lewy body-like pathology of Parkinson's disease ( Gerez et al., 2019 ). In addition, down-regulation of CUL1 and SKP1 has been observed in animal models of Huntington's disease and spinocerebellar ataxia type 3 (SCA3) ( Bhutani et al., 2012 ), and SCF FBXO33 modulates the ubiquitylation and solubility of the polyglutamine protein SCA3 ( Chen et al., 2019 ). However, no biological data have been available on the potential role of SCF-type ubiquitin ligases in the pathogenesis of ALS.…”

Effect of Missing Data Imputation on Deep Learning Prediction Performance for Vesicoureteral Reflux and Recurrent Urinary Tract Infection Clinical Study

“…Healthcare records contain a lot of missing values which imposes difficulties for researchers who plan to model these datasets. Clinical datasets, especially for laboratory measurements, and imaging records often contain missing values [ 45 ]. These shortcomings bring difficulties to capture the patterns in clinical datasets.…”

Isolation and Identification of a Novel Anti-protein Aggregation Activity of Lignin-Carbohydrate Complex From Chionanthus retusus Leaves

“…Given their antioxidant capabilities, we next tested if our LCC and lignin preparations would elicit any effect on modifying polyQ protein aggregation. A polyQ disease cell model was established with the overexpression of SCA type3 (SCA3) disease protein ATXN3Q71 (Ataxin-3 protein harboring 71 repeats of glutamine) in a human neuroblastoma cell line SK-N-MC (Chen Z. S. et al, 2018;Chen et al, 2019). The percentage of cells with polyQ protein aggregates was used as readout to evaluate the protein aggregation-modulatory effects of LCCs and lignin.…”