Identification of an RNA polymerase III regulator linked to disease-associated protein aggregation
Autor/innen
- O. Sin
- T. de Jong
- A. Mata-Cabana
- M. Kudron
- M.A. Zaini
- F.A. Aprile
- R.I. Seinstra
- E. Stroo
- R.W. Prins
- C.N. Martineau
- H.H. Wang
- Wytse Hogewerf
- A. Steinhof
- E.E. Wanker
- M. Vendruscolo
- C.F. Calkhoven
- V. Reinke
- V. Guryev
- E.A.A. Nollen
Journal
- Molecular Cell
Quellenangabe
- Mol Cell 65 (6): 1096-1108
Zusammenfassung
Protein aggregation is associated with age-related neurodegenerative disorders, such as Alzheimer's and polyglutamine diseases. As a causal relationship between protein aggregation and neurodegeneration remains elusive, understanding the cellular mechanisms regulating protein aggregation will help develop future treatments. To identify such mechanisms, we conducted a forward genetic screen in a C. elegans model of polyglutamine aggregation and identified the protein MOAG-2/LIR-3 as a driver of protein aggregation. In the absence of polyglutamine, MOAG-2/LIR-3 regulates the RNA polymerase III-associated transcription of small non-coding RNAs. This regulation is lost in the presence of polyglutamine, which mislocalizes MOAG-2/LIR-3 from the nucleus to the cytosol. We then show biochemically that MOAG-2/LIR-3 can also catalyze the aggregation of polyglutamine-expanded huntingtin. These results suggest that polyglutamine can induce an aggregation-promoting activity of MOAG-2/LIR-3 in the cytosol. The concept that certain aggregation-prone proteins can convert other endogenous proteins into drivers of aggregation and toxicity adds to the understanding of how cellular homeostasis can be deteriorated in protein misfolding diseases.