Identification of an RNA Polymerase III Regulator Linked to Disease-Associated Protein Aggregation

Mol Cell. 2017 Mar 16;65(6):1096-1108.e6. doi: 10.1016/j.molcel.2017.02.022.


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.

Keywords: C. elegans; MOAG-2/LIR-3; RNA polymerase III; non-coding RNA; polyglutamine; protein aggregation; protein homeostasis; protein quality control; snoRNA; tRNA.

MeSH terms

  • 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


  • Caenorhabditis elegans Proteins
  • LIR-3 protein, C elegans
  • Peptides
  • Protein Aggregates
  • RNA, Small Untranslated
  • Transcription Factors
  • polyglutamine
  • RNA Polymerase III