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absence of specific yeast heat-shock proteins leads to abnormal aggregation and compromised autophagic clearance of mutant Huntingtin proteins.

Title: The absence of specific yeast heat-shock proteins leads to abnormal aggregation and compromised autophagic clearance of mutant Huntingtin proteins.
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Name(s): Higgins, Ryan, author
Kabbaj, Marie-Helene, author
Hatcher, Alexa, author
Wang, Yanchang, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2018-01-18
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: The functionality of a protein depends on its correct folding, but newly synthesized proteins are susceptible to aberrant folding and aggregation. Heat shock proteins (HSPs) function as molecular chaperones that aid in protein folding and the degradation of misfolded proteins. Trinucleotide (CAG) repeat expansion in the Huntingtin gene (HTT) results in the expression of misfolded Huntingtin protein (Htt), which contributes to the development of Huntington's disease. We previously found that the degradation of mutated Htt with polyQ expansion (Htt103QP) depends on both ubiquitin proteasome system and autophagy. However, the role of heat shock proteins in the clearance of mutated Htt remains poorly understood. Here, we report that cytosolic Hsp70 (Ssa family), its nucleotide exchange factors (Sse1 and Fes1), and a Hsp40 co-chaperone (Ydj1) are required for inclusion body formation of Htt103QP proteins and their clearance via autophagy. Extended induction of Htt103QP-GFP leads to the formation of a single inclusion body in wild-type yeast cells, but mutant cells lacking these HSPs exhibit increased number of Htt103QP aggregates. Most notably, we detected more aggregated forms of Htt103QP in sse1Δ mutant cells using an agarose gel assay. Increased protein aggregates are also observed in these HSP mutants even in the absence Htt103QP overexpression. Importantly, these HSPs are required for autophagy-mediated Htt103QP clearance, but are less critical for proteasome-dependent degradation. These findings suggest a chaperone network that facilitates inclusion body formation of misfolded proteins and the subsequent autophagic clearance.
Identifier: FSU_pmch_29346421 (IID), 10.1371/journal.pone.0191490 (DOI), PMC5773196 (PMCID), 29346421 (RID), 29346421 (EID), PONE-D-17-24723 (PII)
Grant Number: R01 GM102115, RO1GM102115
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773196.
Subject(s): Autophagy
Heat-Shock Proteins/metabolism
Huntingtin Protein/genetics
Mutation
Saccharomyces cerevisiae/genetics
Saccharomyces cerevisiae/metabolism
Saccharomyces cerevisiae Proteins/metabolism
Trinucleotide Repeats
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_29346421
Host Institution: FSU
Is Part Of: PloS one.
1932-6203
Issue: iss. 1, vol. 13

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Higgins, R., Kabbaj, M. -H., Hatcher, A., & Wang, Y. (2018). The absence of specific yeast heat-shock proteins leads to abnormal aggregation and compromised autophagic clearance of mutant Huntingtin proteins. Plos One. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_29346421