Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 38, Issue 3, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00195-17
Keywords
protein homeostasis; ubiquitin
Categories
Funding
- JSPS KAKENHI [JP25221102, JP26111704]
- AMED-CREST from Japan Agency for Medical Research and Development
- Grants-in-Aid for Scientific Research [26111010, 17K19884] Funding Source: KAKEN
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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.
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