Chaperone Mediated Protective Protein Aggregation and Spatial Quality Control
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Wolfe, Katie Jean. Chaperone Mediated Protective Protein Aggregation and Spatial Quality Control. University of North Carolina at Chapel Hill, 2013. https://doi.org/10.17615/qnrh-kh17APA
Wolfe, K. (2013). Chaperone Mediated Protective Protein Aggregation and Spatial Quality Control. University of North Carolina at Chapel Hill. https://doi.org/10.17615/qnrh-kh17Chicago
Wolfe, Katie Jean. 2013. Chaperone Mediated Protective Protein Aggregation and Spatial Quality Control. University of North Carolina at Chapel Hill. https://doi.org/10.17615/qnrh-kh17- Last Modified
- March 22, 2019
- Creator
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Wolfe, Katie Jean
- Affiliation: School of Medicine, Department of Cell Biology and Physiology
- Abstract
- The accumulation of amyloid-like aggregates is a characteristic of protein conformational disorders such as Huntington Disease, but whether amyloid-like aggregation is causative or a cytoprotective mechanism remains unclear. Molecular chaperones act as the front line of defense against proteotoxicity, as they protect cells by partitioning misfolded proteins towards refolding, degradation, or assembly into large benign aggregates. Herein, a yeast model of proteotoxicity was utilized to study cellular mechanisms for protective aggregation. Ectopic expression of polyglutamine (polyQ) expanded Huntingtin (Htt103Q) is toxic in yeast, and targeting it to the nucleus enhances toxicity while decreasing SDS-resistant aggregation. I utilized this nuclear Htt103Q as the substrate for a high copy toxicity suppressor screen in yeast which identified Sti1 as a molecule that promotes protective aggregation of Htt103Q. The Hsp70 co-chaperone Sti1 regulates spatial quality control of amyloid-like proteins as it induces formation of perinuclear foci containing SDS-resistant material. Accumulation of distinct perinuclear foci correlates with suppression of toxicity and increased complex formation with the Hsp70/Hsp40 chaperone machinery. Endogenous Sti1 appears to be a crucial player in a chaperone-facilitated protective aggregation pathway, because deletion of Sti1 enhances Htt103Q toxicity while decreasing aggregation. In addition to Sti1, the screen produced a group of polyQ-rich proteins, Nab3, Pop2 and Cbk1, as high-copy suppressors of Htt103Q toxicity. PolyQ proteins play different roles in Htt103Q toxicity, either to a detrimental outcome where a Q-rich protein is titrated away from its normal function, or beneficially via interactions that promote protective aggregation. Over-expression of Nab3 appears to suppress Htt103Q toxicity by replacing a functional pool of Nab3 that was lost to aberrant polyQ interaction. Over-expression of Pop2 and Cbk1each suppresses toxicity and promotes aggregation of Htt103Q in a slightly different way, but neither can carry out this function in the absence of Sti1. Therefore, Pop2 and Cbk1 act upstream of Sti1 in pathway which promotes protective aggregation of amyloid-like assemblies. These proteins alter the cellular outcome of proteotoxic insult caused by Htt103Q by modulating spatial quality control.
- Date of publication
- December 2013
- DOI
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- In Copyright
- Advisor
- Cyr, Douglas
- Degree
- Doctor of Philosophy
- Degree granting institution
- University of North Carolina at Chapel Hill
- Graduation year
- 2013
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