Identification of an RNA Polymerase III Regulator Linked to Disease-Associated Protein AggregationSin, O., de Jong, T., Mata-Cabana, A., Kudron, M., Zaini, M. A., Aprile, F. A., Seinstra, R. I., Stroo, E., Prins, R. W., Martineau, C. N., Wang, H. H., Hogewerf, W., Steinhof, A., Wanker, E. E., Vendruscolo, M., Calkhoven, C. F., Reinke, V., Guryev, V. & Nollen, E. A. A., 16-Mar-2017, In : Molecular Cell. 65, 6, p. 1096-1108 19 p.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||19|
|Publication status||Published - 16-Mar-2017|
- ZINC-FINGER PROTEINS, DIFFERENTIAL EXPRESSION ANALYSIS, CAENORHABDITIS-ELEGANS, C.-ELEGANS, TRANSCRIPTION FACTORS, HUNTINGTON-DISEASE, GENE-EXPRESSION, POSTTRANSLATIONAL MODIFICATIONS, NEURODEGENERATIVE DISEASES, POLYGLUTAMINE PROTEIN