RRC ID 54286
著者 Sin O, de Jong T, Mata-Cabana A, Kudron M, Zaini MA, Aprile FA, Seinstra RI, Stroo E, Prins RW, Martineau CN, Wang HH, Hogewerf W, Steinhof A, Wanker EE, Vendruscolo M, Calkhoven CF, Reinke V, Guryev V, Nollen EA.
タイトル Identification of an RNA Polymerase III Regulator Linked to Disease-Associated Protein Aggregation.
ジャーナル Mol Cell
Abstract 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.
巻・号 65(6)
ページ 1096-1108.e6
公開日 2017-3-16
DOI 10.1016/j.molcel.2017.02.022
PII S1097-2765(17)30137-5
PMID 28306505
PMC PMC5364375
MeSH Active Transport, Cell Nucleus Animals Animals, Genetically Modified Binding Sites Caenorhabditis elegans / enzymology* Caenorhabditis elegans / genetics Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cell Nucleus / enzymology Cytosol / enzymology Disease Models, Animal Neurodegenerative Diseases / enzymology* Neurodegenerative Diseases / genetics Neurodegenerative Diseases / pathology Peptides / metabolism* Promoter Regions, Genetic Protein Aggregates* Protein Aggregation, Pathological* Protein Binding RNA Interference RNA Polymerase III / genetics RNA Polymerase III / metabolism* RNA, Small Untranslated / genetics RNA, Small Untranslated / metabolism Transcription Factors / genetics Transcription Factors / metabolism* Transcription, Genetic
IF 15.584
引用数 5
リソース情報
線虫 tm813