QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 20, Issue 19, 4162-4173, October 1, 2009

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E09-02-0170v1 20/19/4162    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Douglas, P. M. Articles by Cyr, D. M. PubMed PubMed Citation Articles by Douglas, P. M. Articles by Cyr, D. M.

Reciprocal Efficiency of RNQ1 and Polyglutamine Detoxification in the Cytosol and Nucleus

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

Submitted February 27, 2009; Revised July 16, 2009; Accepted July 28, 2009
Monitoring Editor: Ramanujan S. Hegde

Onset of proteotoxicity is linked to change in the subcellular location of proteins that cause misfolding diseases. Yet, factors that drive changes in disease protein localization and the impact of residence in new surroundings on proteotoxicity are not entirely clear. To address these issues, we examined aspects of proteotoxicity caused by Rnq1-green fluorescent protein (GFP) and a huntingtin's protein exon-1 fragment with an expanded polyglutamine tract (Htt-103Q), which is dependent upon the intracellular presence of [RNQ⁺] prions. Increasing heat-shock protein 40 chaperone activity before Rnq1-GFP expression, shifted Rnq1-GFP aggregation from the cytosol to the nucleus. Assembly of Rnq1-GFP into benign amyloid-like aggregates was more efficient in the nucleus than cytosol and nuclear accumulation of Rnq1-GFP correlated with reduced toxicity. [RNQ⁺] prions were found to form stable complexes with Htt-103Q, and nuclear Rnq1-GFP aggregates were capable of sequestering Htt-103Q in the nucleus. On accumulation in the nucleus, conversion of Htt-103Q into SDS-resistant aggregates was dramatically reduced and Htt-103Q toxicity was exacerbated. Alterations in activity of molecular chaperones, the localization of intracellular interaction partners, or both can impact the cellular location of disease proteins. This, in turn, impacts proteotoxicity because the assembly of proteins to a benign state occurs with different efficiencies in the cytosol and nucleus.

Address correspondence to: Douglas M. Cyr (dmcyr{at}med.unc.edu).

Abbreviations used: CUP1, copper-inducible promoter element; GAL1, galactose-inducible promoter element; GPD, glyceraldehyde-3-phosphate dehydrogenase promoter element; Htt, Huntingtin; mRFP, monomeric red fluorescent protein; NES, nuclear export signal; NLS, nuclear localization signal; SDD-AGE, semidenaturing detergent agarose gel electrophoresis.