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Ubiquitin-Binding Protein CG5445 Suppresses Aggregation and Cytotoxicity of Amyotrophic Lateral Sclerosis-Linked TDP-43 in Drosophila
- Publication Year :
- 2018
- Publisher :
- American Society for Microbiology, 2018.
-
Abstract
- Ubiquitin-mediated protein degradation plays essential roles in proteostasis and is involved in the pathogenesis of neurodegenerative diseases in which ubiquitin-positive aberrant proteins accumulate. However, how such aberrant proteins are processed inside cells has not been fully explored. Here, we show that the product of CG5445, a previously uncharacterized Drosophila gene, prevents the accumulation of aggregate-prone ubiquitinated proteins. We found that ubiquitin conjugates were associated with CG5445, the knockdown of which caused the accumulation of detergent-insoluble ubiquitinated proteins. Furthermore, CG5445 rescued eye degeneration caused by the amyotrophic lateral sclerosis (ALS)-linked mutant TAR DNA-binding protein of 43 kDa (TDP-43), which often forms ubiquitin-positive aggregates in cells through the capacity of CG5445 to bind to ubiquitin chains. Biochemically, CG5445 inhibited the accumulation of insoluble forms and promoted their clearance. Our results demonstrate a new possible mechanism by which cells maintain ubiquitinated aggregation-prone proteins in a soluble form to decrease their cytotoxicity until they are degraded.
- Subjects :
- 0301 basic medicine
Proteasome Endopeptidase Complex
Ubiquitin binding
Mutant
Protein degradation
Eye
Animals, Genetically Modified
03 medical and health sciences
Ubiquitin
Animals
Drosophila Proteins
Cytotoxicity
Molecular Biology
Gene
Adaptor Proteins, Signal Transducing
Gene knockdown
biology
Heterogeneous-Nuclear Ribonucleoprotein Group F-H
Amyotrophic Lateral Sclerosis
Ubiquitination
Cell Biology
Cell biology
DNA-Binding Proteins
030104 developmental biology
Proteostasis
Drosophila melanogaster
Gene Expression Regulation
Solubility
Gene Knockdown Techniques
Mutation
biology.protein
Research Article
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....4cb711918bc9cf5d284a3a62e3079ab1