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Reciprocal efficiency of RNQ1 and polyglutamine detoxification in the cytosol and nucleus

Peter M Douglas1, Daniel W Summers, Hong-Yu Ren

  • 1Department of Cell and Developmental Biology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7090, USA.

Molecular Biology of the Cell
|August 7, 2009
PubMed

Insights

Altering protein location, like shifting Rnq1-green fluorescent protein (GFP) to the nucleus, can reduce proteotoxicity. Nuclear Rnq1-GFP aggregates sequester toxic huntingtin fragments, reducing their harmful aggregation.

Area of Science:

  • Cell Biology
  • Neurodegenerative Diseases
  • Protein Biochemistry

Background:

  • Proteotoxicity, a hallmark of misfolding diseases, is associated with altered protein subcellular localization.
  • The precise factors governing these localization shifts and their impact on disease progression remain incompletely understood.

Purpose of the Study:

  • To investigate how changes in protein localization affect proteotoxicity.
  • To examine the roles of Rnq1-green fluorescent protein (GFP) and huntingtin exon-1 fragment (Htt-103Q) in proteotoxicity, particularly in the presence of [RNQ+] prions.

Main Methods:

  • Manipulating heat-shock protein 40 chaperone activity to alter Rnq1-GFP localization from the cytosol to the nucleus.
  • Assessing the aggregation efficiency and toxicity of Rnq1-GFP and Htt-103Q in different cellular compartments.
  • Investigating the interaction between [RNQ+] prions, Rnq1-GFP, and Htt-103Q.

Main Results:

  • Increased chaperone activity promoted nuclear accumulation of Rnq1-GFP, leading to more efficient benign aggregation and reduced toxicity.
  • [RNQ+] prions formed complexes with Htt-103Q, and nuclear Rnq1-GFP aggregates sequestered Htt-103Q.
  • Nuclear sequestration of Htt-103Q reduced its conversion into SDS-resistant aggregates but exacerbated its toxicity.

Conclusions:

  • Molecular chaperone activity and interaction partner localization influence disease protein cellular location.
  • The cytosol and nucleus exhibit differential efficiencies in assembling proteins into benign states, thereby impacting proteotoxicity.

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